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Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old White woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old White man with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Him last intravenous heroin use occurred 9 days prior to presentation. He was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. He reported no history of travel outside the US and no raw meat ingestion. Him vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old White patient with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Them last intravenous heroin use occurred 9 days prior to presentation. They was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. They reported no history of travel outside the US and no raw meat ingestion. Them vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Black woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Black man with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Him last intravenous heroin use occurred 9 days prior to presentation. He was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. He reported no history of travel outside the US and no raw meat ingestion. Him vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Black patient with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Them last intravenous heroin use occurred 9 days prior to presentation. They was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. They reported no history of travel outside the US and no raw meat ingestion. Them vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Asian woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Asian man with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Him last intravenous heroin use occurred 9 days prior to presentation. He was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. He reported no history of travel outside the US and no raw meat ingestion. Him vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Asian patient with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Them last intravenous heroin use occurred 9 days prior to presentation. They was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. They reported no history of travel outside the US and no raw meat ingestion. Them vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Hispanic woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Hispanic man with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Him last intravenous heroin use occurred 9 days prior to presentation. He was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. He reported no history of travel outside the US and no raw meat ingestion. Him vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Hispanic patient with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Them last intravenous heroin use occurred 9 days prior to presentation. They was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. They reported no history of travel outside the US and no raw meat ingestion. Them vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Arab woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Arab man with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Him last intravenous heroin use occurred 9 days prior to presentation. He was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. He reported no history of travel outside the US and no raw meat ingestion. Him vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> A 58-year-old Arab patient with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Them last intravenous heroin use occurred 9 days prior to presentation. They was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. They reported no history of travel outside the US and no raw meat ingestion. Them vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA </clinical_case> <question> A 58-year-old woman with a history of intravenous heroin use and chronic inactive hepatitis B virus (HBV) infection with a low serum HBV DNA value, normal liver enzyme values, and no evidence of cirrhosis presented to the emergency department with sudden onset of painless jaundice and 8 days of malaise. Her last intravenous heroin use occurred 9 days prior to presentation. She was not taking any prescription or herbal medications and had not been prescribed suppressive antiviral medication for chronic HBV infection. She reported no history of travel outside the US and no raw meat ingestion. Her vital signs, mentation, and physical examination were normal except for scleral icterus (Figure). Results of blood testing were negative for hepatitis C virus RNA, anti–hepatitis A IgM, and HIV antibody. Other selected laboratory values are shown in the Table. A liver ultrasound performed 6 months prior to presentation and a repeat liver ultrasound with Doppler revealed no abnormalities.Order testing for hepatitis E virus IgM antibodyOrder testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA What Would You Do Next? </question> <options> A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA B. Check plasma HIV-1 RNA level C. Order testing for anti–smooth muscle antibody D. Order testing for hepatitis E virus IgM antibody </options>

A. Order testing for hepatitis delta virus (HDV) IgM and IgG antibodies and, if positive, test for HDV RNA The key to the correct diagnosis is recognition that the most likely cause of sudden-onset jaundice and newly elevated aminotransferase and bilirubin levels in a patient with intravenous drug use and chronic HBV infection without acute hepatitis A or C virus infection is HDV. Choice A is incorrect because HIV does not typically cause this level of aminotransferase and bilirubin elevation. Hepatitis E (choice B) is unlikely because the patient has never traveled outside the US and has not eaten raw meat. Anti–smooth muscle antibody testing (choice C) is helpful to diagnose autoimmune hepatitis, but this is not the most likely diagnosis in a patient with chronic HBV infection and intravenous drug use.HDV, which consists of single-stranded, circular RNA, is the smallest virus known to infect humans.1 HDV is a defective virus because it does not encode its own envelope proteins and requires the presence of HBV for virion assembly, replication, and transmission. Therefore, patients infected with HDV always have a simultaneous HBV infection, acquired either as a co-infection with acute HBV or as a superinfection with chronic HBV.While clinically indistinguishable from acute HBV infection, HDV infection has been associated with an increased risk of acute liver failure, especially in intravenous drug users.2 Approximately 90% to 95% of patients with acute HDV-HBV co-infection clear their infections spontaneously.2,3 In contrast, acquisition of HDV as a superinfection typically results in chronic HDV infection.3Chronic HDV infection, defined as HDV viremia that lasts more than 6 months, frequently results in a severe clinical course. Chronic HDV-HBV co-infection progresses to cirrhosis in 70% to 80% of patients within 5 to 10 years after diagnosis.4 Compared with HBV monoinfection, chronic HDV infection is associated with a 3- to 6-fold increased risk of hepatocellular carcinoma.4,5Although the exact prevalence is unknown, between 62 to 72 million people worldwide are estimated to be infected with HDV, representing nearly 1% of the global population.2,6 However, regional variation exists, and HDV is endemic in many areas, including Mongolia and other parts of Asia, Africa, Southern and Eastern Europe, the Middle East, and Brazil.4 Two recent meta-analyses reported HDV seroprevalence of 13% to 14.6% in a pooled population of HBV carriers.6,7 However, among individuals who were HBsAg positive, approximately 36% to 37.6% of intravenous drug users and 17% of individuals with high-risk sexual behavior had HDV viremia.6,8Although there are no randomized clinical trials on screening for HDV infection, the American Association for the Study of Liver Diseases recommends screening for the presence of HDV infection in HBsAg-positive individuals with 1 or more of the following risk factors: HIV, intravenous drug use, men who have sex with men, people at risk of sexually transmitted diseases, and immigrants from areas of high HDV endemicity. Individuals with elevated alanine aminotransferase (ALT) levels and low HBV DNA levels may be also considered for HDV screening.9 Screening is performed by testing for HDV IgG antibody; if positive, HDV RNA confirms active infection.2The recommended treatment for chronic HDV is a 12-month course of pegylated interferon alfa administered subcutaneously weekly for patients with detectable HDV RNA and an elevated ALT level.9 However, sustained responses, defined as undetectable serum HDV RNA level at 6 months after treatment, are low (25%-30%) and relapse rates are high.4 Patients with chronic HDV infection and hepatic decompensation may be considered for liver transplant.2 New drug targets for HDV infection include HBsAg secretion inhibition, farnesyl-transferase inhibition to interfere with viral assembly, and entry inhibition of HDV into hepatocytes.10Results of testing for serum HDV IgM and IgG antibodies were positive, and HDV RNA was detected by qualitative reverse transcriptase–polymerase chain reaction assay. The patient declined pegylated interferon alfa therapy, and her malaise and scleral icterus resolved within 8 weeks. At her most recent clinic visit, approximately 6 months after initial presentation, laboratory testing revealed normal total serum bilirubin (0.6 mg/dL [10.26 μmol/L]), mildly elevated ALT (48 U/L [0.80 μkat/L]), low HBV DNA (1350 IU/mL), and high serum HDV RNA (880 000 IU/mL) levels, consistent with chronic HDV infection. The patient was asked to return to clinic for biannual liver ultrasound surveillance for hepatocellular carcinoma and has enrolled in an outpatient drug rehabilitation program.

Please analyze the following clinical case and the related question: <clinical_case> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent White girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The White patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent White boy presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The White man denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent White child presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The White patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Black girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Black patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Black boy presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Black man denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Black child presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Black patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Asian girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Asian patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Asian boy presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Asian man denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Asian child presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Asian patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Hispanic girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Hispanic patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Hispanic boy presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Hispanic man denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Hispanic child presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Hispanic patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Arab girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Arab patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Arab boy presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Arab man denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> An adolescent Arab child presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The Arab patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). </clinical_case> <question> An adolescent girl presented with an asymptomatic slightly reddish verrucous plaque on the right temple. The skin lesion was nail sized when first noticed 1½ years earlier, then gradually developed over the 8 months prior to presentation. The patient denied any associated fevers, weight loss, or night sweats. Physical examination revealed a slightly reddish verrucous mass with translucent papules and plaques on the right temple, about 5 cm in diameter, with surface hemorrhagic crust in the side adjacent to right eyebrow arch (Figure, A). The lesion was nontender with no purulent discharge and no severe necrotic changes. There was no hepatosplenomegaly or superficial lymphadenopathy. Laboratory tests, including blood cell counts, urinalysis, and kidney and hepatic panels, revealed no abnormalities. A skin biopsy was performed and submitted for histopathologic analysis (Figure, B-D).A, A slightly reddish verrucous mass with translucent papules and plaques on the right temple. B, The histological examination showed papillomatous epidermal hyperplasia, edema of dermal papillae, and neoplastic infiltration consisting of small round blue cells with alternating areas of dense and loose cellularity (hematoxylin-eosin). C, Small, round blue cells were observed in the dermis with round, fusiform, or oval hyperchromatic nuclei, conspicuous nucleoli, and scant cytoplasm (hematoxylin-eosin). D, Tumor cells were positive for MyoD1 (original magnification ×400). What Is Your Diagnosis? </question> <options> A. Primary superficial Ewing sarcoma B. Lymphoblastic lymphoma C. Superficial lymphatic malformation D. Primary cutaneous embryonal rhabdomyosarcoma </options>

D. Primary cutaneous embryonal rhabdomyosarcoma Histopathologic evaluation revealed papillomatous epidermal hyperplasia and edema of dermal papillae with nested or cordlike distribution of small round blue cells (Figure, B). Most of the tumor cells had round, fusiform, or oval hyperchromatic nuclei, with conspicuous nucleoli and scant amphophilic cytoplasm (Figure, C). Some small, undifferentiated, round, blue, and spindle-shaped cells with scattered, more mature rhabdomyoblasts were also seen in the middle dermis. Immunohistochemical analysis showed positivity for MyoD1 (Figure, D), myogenin, vimentin, and desmin, and negativity for myeloperoxidase, CD45, CK, Ki-67, CD31, CD34, CD1a, CD117, and SOX-10. The pattern of morphology and immunostain expression led to the diagnosis of embryonal rhabdomyosarcoma (ERMS).The patient was immediately referred to an oncology center for further evaluations. Results of cerebral computed tomography and magnetic resonance imaging revealed skin thickening and a soft-tissue mass in the right frontotemporal region near the orbit. Remaining workup, including chest computed tomography and abdominal ultrasonography scan, demonstrated no evidence of metastases. The diagnosis of primary cutaneous ERMS was formulated. At 8-month follow-up, the mass had regressed after 8 treatment cycles of vincristine, adriamycin, and cyclophosphamide.Rhabdomyosarcoma is a high-grade malignant tumor originating from immature skeletal muscle and is the most common soft-tissue sarcoma of childhood, accounting for 3% to 4% of all pediatric cancers.1 Pathologically, rhabdomyosarcoma is classified into ERMS, alveolar rhabdomyosarcoma, pleomorphic rhabdomyosarcoma, and spindle cell/sclerosing rhabdomyosarcoma.2 Embryonal rhabdomyosarcoma tends to occur in children between the ages of 3 and 12 years with a slight predominance in males. It commonly presents with an asymptomatic mass found in the head and neck region.2-4 Embryonal rhabdomyosarcoma with primary presentation in the skin is extremely rare and usually presents as an asymptomatic papule, nodule, or mass with progressive growth.5,6 Morphologically, ERMS resembles variable stages of skeletal muscle morphogenesis: from the small, round, undifferentiated cells, through tadpolelike cells, ribbon-shaped striated cells, to fully differentiated rhabdomyoblasts.4 Tumor cells commonly show positivity for muscular differentiation markers, including MyoD1, myogenin, and desmin.2 The molecular profile of ERMS is heterogeneous, unlike alveolar rhabdomyosarcoma, which typically contains chromosomal translocations (t[2;13] or t[1;13]) generating the PAX3-FOXO1 or PAX7-FOXO1 fusion gene.2-4Differential diagnosis of such a mass in young patients includes superficial lymphatic malformation, and small round blue cell tumors such as lymphoblastic lymphoma and primary cutaneous Ewing sarcoma. Superficial lymphatic malformation is usually congenital and presents as well-defined and discrete or grouped “frog spawn”–like fluid-filled vesicles that bulge on the skin surface.7 It is composed of multiple dilated lymphatic channels lined by a single layer of endothelial cells and filled with lymph, and usually abuts the surface acanthotic epithelium.7 The histological morphology and muscular-marker staining can exclude the diagnosis.Lymphoblastic lymphoma may have cutaneous involvement in the pediatric population and histologically presents as small round blue cell tumors similar to ERMS, but CD10 and terminal deoxynucleotidyl transferase positivity and muscular marker’s negativity should facilitate the differential diagnosis.8 Primary superficial Ewing sarcoma is morphologically similar to ERMS. It usually presents as a palpable 2- to 3-cm superficial circumscribed mass on the legs, upper trunk, or head of older adolescents.9 Histologically, it is composed of uniform small round blue cells with scanty cytoplasm and is strongly and diffusely positive for CD99 in a membranous pattern. Immunoreactivity for myogenic markers and EWSR1 translocation tested by reverse transcriptase–polymerase chain reaction or fluorescence in situ hybridization will aid in the differential diagnosis.9Treatment of rhabdomyosarcoma typically involves chemotherapy, surgery, and radiation therapy, which depends on site-modified TNM staging and the extent of up-front surgical resection. Of note, ERMS is associated with earlier age at diagnosis and better survival. The 5-year survival rate has improved substantially to more than 70% owing to multimodal treatments.4

Please analyze the following clinical case and the related question: <clinical_case> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A White man in his early 20s presented with suspected syncope and shaking with no significant medical history. The White patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, White patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A White woman in her early 20s presented with suspected syncope and shaking with no significant medical history. The White woman fell asleep and her girlfriend tried to wake her, but she started shaking and slumped over on the ground. She denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, she had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, she was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Her cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, White woman reported having a second cousin with sudden cardiac death of uncertain etiology in her early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A White patient in their early 20s presented with suspected syncope and shaking with no significant medical history. The White patient fell asleep and their girlfriend tried to wake them, but they started shaking and slumped over on the ground. They denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, they had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, they was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Their cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, White patient reported having a second cousin with sudden cardiac death of uncertain etiology in their early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Black man in his early 20s presented with suspected syncope and shaking with no significant medical history. The Black patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Black patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Black woman in her early 20s presented with suspected syncope and shaking with no significant medical history. The Black woman fell asleep and her girlfriend tried to wake her, but she started shaking and slumped over on the ground. She denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, she had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, she was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Her cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Black woman reported having a second cousin with sudden cardiac death of uncertain etiology in her early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Black patient in their early 20s presented with suspected syncope and shaking with no significant medical history. The Black patient fell asleep and their girlfriend tried to wake them, but they started shaking and slumped over on the ground. They denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, they had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, they was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Their cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Black patient reported having a second cousin with sudden cardiac death of uncertain etiology in their early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Asian man in his early 20s presented with suspected syncope and shaking with no significant medical history. The Asian patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Asian patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Asian woman in her early 20s presented with suspected syncope and shaking with no significant medical history. The Asian woman fell asleep and her girlfriend tried to wake her, but she started shaking and slumped over on the ground. She denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, she had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, she was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Her cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Asian woman reported having a second cousin with sudden cardiac death of uncertain etiology in her early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Asian patient in their early 20s presented with suspected syncope and shaking with no significant medical history. The Asian patient fell asleep and their girlfriend tried to wake them, but they started shaking and slumped over on the ground. They denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, they had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, they was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Their cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Asian patient reported having a second cousin with sudden cardiac death of uncertain etiology in their early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Hispanic man in his early 20s presented with suspected syncope and shaking with no significant medical history. The Hispanic patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Hispanic patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Hispanic woman in her early 20s presented with suspected syncope and shaking with no significant medical history. The Hispanic woman fell asleep and her girlfriend tried to wake her, but she started shaking and slumped over on the ground. She denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, she had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, she was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Her cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Hispanic woman reported having a second cousin with sudden cardiac death of uncertain etiology in her early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Hispanic patient in their early 20s presented with suspected syncope and shaking with no significant medical history. The Hispanic patient fell asleep and their girlfriend tried to wake them, but they started shaking and slumped over on the ground. They denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, they had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, they was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Their cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Hispanic patient reported having a second cousin with sudden cardiac death of uncertain etiology in their early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Arab man in his early 20s presented with suspected syncope and shaking with no significant medical history. The Arab patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Arab patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Arab woman in her early 20s presented with suspected syncope and shaking with no significant medical history. The Arab woman fell asleep and her girlfriend tried to wake her, but she started shaking and slumped over on the ground. She denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, she had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, she was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Her cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Arab woman reported having a second cousin with sudden cardiac death of uncertain etiology in her early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A Arab patient in their early 20s presented with suspected syncope and shaking with no significant medical history. The Arab patient fell asleep and their girlfriend tried to wake them, but they started shaking and slumped over on the ground. They denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, they had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, they was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. Their cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, Arab patient reported having a second cousin with sudden cardiac death of uncertain etiology in their early 20s.Initial electrocardiogram on presentation in the emergency department. </clinical_case> <question> A man in his early 20s presented with suspected syncope and shaking with no significant medical history. The patient fell asleep and his girlfriend tried to wake him, but he started shaking and slumped over on the ground. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. About 10 minutes later, he had a second syncopal episode for 2 to 3 minutes with more than 20 muscle jerks. On presentation at the emergency department, he was afebrile, blood pressure was 120/59 mm Hg, heart rate was 85 beats per min, respiratory rate was 16 breaths per min, and oxygen saturation was 96% on room air. His cardiac examination revealed normal heart sounds with no murmurs.The electrocardiogram (ECG) was performed early on arrival in the emergency department (Figure). Transthoracic echocardiography revealed an ejection fraction of 54%, mild right ventricular (RV) dilation (RV diameter, 4.1 cm), and no significant valvular abnormalities. Cardiac magnetic resonance imaging showed no RV abnormalities and qualitatively normal RV function. Neurology consultation was obtained with concern for an epileptic seizure event surrounding the recurrent syncopal episodes. Brain magnetic resonance imaging and electroencephalogram were obtained, both of which results were normal. On further questioning, patient reported having a second cousin with sudden cardiac death of uncertain etiology in his early 20s.Initial electrocardiogram on presentation in the emergency department. What Would You Do Next? </question> <options> A. Ventricular ablation B. 30-Day ambulatory event monitor C. Implantable cardioverter defibrillator D. Electrophysiology study </options>

C. Implantable cardioverter defibrillator The key to the correct diagnosis in this case was the ECG that was consistent with spontaneous Brugada type 1 morphology with more than 2-mm coved ST-segment elevation in leads V1 and V2 (Figure). Recognition of the Brugada type 1 pattern as a potential cause of cardio-arrhythmogenic syncope is important.The incidence of the Brugada type 1 ECG pattern in the US is thought to be as low as 0.03%.1 The proposed Shanghai Score System2 can be used for the diagnosis of Brugada syndrome, which relies on ECG, clinical history, family history, or genetic test results. A score of more than 3.5 points is thought to be probable and/or definite Brugada. Brugada type 1 can present asymptomatically, in which case the management is observation. However, in those with symptomatic features, such as unexplained cardiac arrest or polymorphic ventricular tachycardia or ventricular fibrillation arrest, nocturnal agonal respirations, atrial fibrillation/flutter in patients younger than 30 years of age, or syncope of uncertain etiology, further evaluation is needed.In patients with unexplained syncope in the setting of Brugada syndrome, ventricular fibrillation should be strongly considered. The presence of suspected arrhythmogenic syncope alone in patients with Brugada syndrome with the spontaneous type 1 electrocardiogram pattern is a class 1 indication for an implantable cardioverter defibrillator (ICD).3 An electrophysiology study for risk stratification prior to ICD placement, however, is a class 2B recommendation and is controversial. For those with symptomatic refractory Brugada syndrome or repeated ICD shocks, there is a role for epicardial ablation.During our initial evaluation, we felt seizures were lower in the differential diagnosis, however, a striking feature was his persistent muscle jerks, making convulsive syncope less likely. We felt the margin of error was quite small and the patient ultimately decided to undergo transvenous ICD placement.The decision to offer an ICD is not one to take lightly. The incidence of at least 1 inappropriate ICD shock from an ICD has been reported as high as 6.6% during a median follow-up of 2 years.4 There is also the obstacle of generator changes in a young patient, which can be necessary anywhere from 5 to 10 years depending on the manufacturer used. There is also the decision of whether or not to pursue a subcutaneous ICD system when there is no indication for pacing, which has largely been shown to be noninferior to the transvenous system,5 and this choice is largely driven by patient preference. As such, it is very prudent to have a systematic approach, which is largely guideline driven when offering ICDs to patients, and this played a large role in our decision to pursue such an extensive medical workup to validate the uncertain etiology of our patient’s syncope.The patient received a 7-day postdevice follow-up examination. He was mending well and able to resume regular activities.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old White man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The White patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old White woman was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, she experienced headache, facial numbness, inability to open both her eyes, and inability to move both eyes in any direction.She had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Her baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, she was noted to have complete bilateral ptosis. Her visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. She had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The White woman was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old White patient was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, they experienced headache, facial numbness, inability to open both their eyes, and inability to move both eyes in any direction.They had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Their baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, they was noted to have complete bilateral ptosis. Their visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. They had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The White patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Black man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Black patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Black woman was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, she experienced headache, facial numbness, inability to open both her eyes, and inability to move both eyes in any direction.She had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Her baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, she was noted to have complete bilateral ptosis. Her visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. She had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Black woman was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Black patient was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, they experienced headache, facial numbness, inability to open both their eyes, and inability to move both eyes in any direction.They had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Their baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, they was noted to have complete bilateral ptosis. Their visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. They had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Black patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Asian man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Asian patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Asian woman was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, she experienced headache, facial numbness, inability to open both her eyes, and inability to move both eyes in any direction.She had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Her baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, she was noted to have complete bilateral ptosis. Her visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. She had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Asian woman was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Asian patient was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, they experienced headache, facial numbness, inability to open both their eyes, and inability to move both eyes in any direction.They had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Their baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, they was noted to have complete bilateral ptosis. Their visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. They had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Asian patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Hispanic man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Hispanic patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Hispanic woman was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, she experienced headache, facial numbness, inability to open both her eyes, and inability to move both eyes in any direction.She had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Her baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, she was noted to have complete bilateral ptosis. Her visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. She had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Hispanic woman was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Hispanic patient was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, they experienced headache, facial numbness, inability to open both their eyes, and inability to move both eyes in any direction.They had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Their baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, they was noted to have complete bilateral ptosis. Their visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. They had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Hispanic patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Arab man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Arab patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Arab woman was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, she experienced headache, facial numbness, inability to open both her eyes, and inability to move both eyes in any direction.She had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Her baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, she was noted to have complete bilateral ptosis. Her visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. She had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Arab woman was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 50-year-old Arab patient was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, they experienced headache, facial numbness, inability to open both their eyes, and inability to move both eyes in any direction.They had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). Their baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, they was noted to have complete bilateral ptosis. Their visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. They had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The Arab patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). </clinical_case> <question> A 50-year-old man was referred for ophthalmoplegia that developed immediately after an 8.5-hour robotic cystectomy for small cell cancer of the bladder. After recovering from anesthesia in the postanesthesia care unit, he experienced headache, facial numbness, inability to open both his eyes, and inability to move both eyes in any direction.He had a known enhancing central skull base lesion in sella turcica with compression of the optic chiasm and mild mass effect on the pons that was felt to be a pituitary macroadenoma (Figure). His baseline examination before the cystectomy showed visual acuity of 20/20 OU with intact extraocular movements and unremarkable confrontational fields, although a mild bitemporal hemianopia was seen on automated visual fields.T1-weighted coronal magnetic resonance imaging (MRI) with contrast shows a 4.9 × 4.6 × 5.2-cm sellar/parasellar lobulated mass with homogenous enhancement before symptom onset (A), which became 5.3 × 5.1 × 5.3 cm and had loss of enhancement after symptom onset (B). The mass caused superior displacement of the optic chiasm and had extension into the cavernous sinus bilaterally. The mass also extended posteriorly and deformed the anterior aspect of the pons (not shown). After symptom onset, the mass was hyperintense on T2-weighted images (not shown).During the bedside examination in the postanesthesia care unit, he was noted to have complete bilateral ptosis. His visual acuity was 20/20 OU with full visual fields on confrontational visual field testing. He had decreased sensation to light touch and pinprick in the V1/V2 distribution of the trigeminal nerve bilaterally. The right and left pupils were 5 mm and 6 mm in size, respectively, in both light and dark. There was no pupillary response to light or accommodation. No exophthalmos was noted. Intraocular pressure was normal in both eyes. The patient was unable to move either eye in any direction on extraocular motility testing. Vestibulo-ocular reflex did not overcome the ophthalmoplegia. Magnetic resonance imaging (MRI) was obtained 12 hours after symptom onset redemonstrating the large sellar mass, which no longer had central enhancement (Figure). What Is Your Diagnosis? </question> <options> A. Orbital compartment syndrome B. Pituitary apoplexy C. Cavernous sinus thrombosis D. Ocular motor apraxia </options>

B. Pituitary apoplexy Based on the acute presentation of symptoms and signs starting immediately after surgery and change in the appearance of tumor on MRI (loss of central enhancement), a diagnosis of pituitary apoplexy was made. The ophthalmoplegia in ocular motor apraxia can be overcome with vestibular ocular reflex, which was not the case here. The absence of exophthalmos and normal intraocular pressure argue against the diagnosis of orbital compartment syndrome. Imaging does not support the diagnosis of cavernous sinus thrombosis.Pituitary apoplexy is an acute-onset syndrome due to hemorrhaging and/or infarction of the pituitary gland. Postoperative pituitary apoplexy has been reported after cardiac surgery, abdominal surgery, thyroidectomy, laparoscopic lumbar spinal fusion, and knee arthroplasty.1 Risk factors proposed during surgery that could lead to pituitary apoplexy include prolonged mechanical ventilation, embolization, unstable blood pressure, anticoagulation, crystalloid hemodilution, previous treatment with dopamine agonists, and radiotherapy.2Patients with pituitary apoplexy typically present with headaches. Cranial nerve palsies leading to ophthalmoplegia have been reported in about 50% of patients during pituitary apoplexy.1 Sixty-four percent of patients can have vision loss from worsening chiasmal compression, which fortunately this patient did not have.3 Early neuroimaging study is important to confirm the suspicion of pituitary apoplexy, along with urgent pituitary function tests. Computed tomography scan is often the first study performed in an acute setting and may demonstrate a variably hyperdense mass of the sella and suprasellar region in the presence of hemorrhage. MRI is the preferred study of choice with sensitivity of about 90%.4 Appearance of hemorrhagic pituitary apoplexy on MRI depends on the sequence and stage of hemorrhage. In the acute phase, hemorrhage is usually hypotense on T2-weighted imaging because of the presence of deoxyhemoglobin, which was not present in the present patient. Infarctive pituitary apoplexy alone, which is a rarer presentation of pituitary apoplexy, has low signal intensity on T1- and T2-weighted sequences and no contrast enhancement of the tumor as seen in this patient. It may have associated rim enhancement.5Pituitary apoplexy is a vision- and life-threatening neuro-ophthalmic emergency. Before the use of corticosteroids, mortality rates were reported to be as high as 50% because of acute adrenal insufficiency that many of these patients develop. Treatment involves urgent administration of steroids, endocrine evaluation, and urgent surgical intervention for prompt decompression based on severity of presentation.Visual recovery, with or without sequelae, is variable depending on the severity and duration of compression of the optic nerve apparatus. Ophthalmoplegia resolves in the majority of patients, but some patients can have incomplete recovery.6,7The patient immediately started receiving intravenous corticosteroids under the guidance of endocrinology and neurosurgery. He was monitored for any endocrine deficiencies while inpatient. After no improvement in extraocular movements were noted over 5 days, the patient underwent transsphenoidal resection of pituitary tumor. Pathological evaluation of the tumor confirmed a pituitary adenoma with areas of necrosis consistent with pituitary apoplexy.Postoperative MRI showed successful resection of the large pituitary macroadenoma, with decompression of the optic chiasm. There was some residual tumor in the bilateral cavernous sinuses, basisphenoid, and along the dorsum sella.One year after surgery, the patient’s visual acuity was 20/20 OU with normal color vision. Bilateral ptosis had resolved. Extraocular movements were full and the eyes were well aligned. However, the pupils remained unresponsive to light and accommodation. The mild bitemporal hemianopsia remained unchanged from baseline on automated visual fields.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old White girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The White patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The White patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old White boy was referred to the pediatric retina service to evaluate progressive vision loss. Him medical history included neonatal seizures. He was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, him best-corrected visual acuity (BCVA) was 20/70 OU. The White man did not receive any ophthalmological care until 2 years later, when he was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When he presented to the pediatric retina service, he demonstrated poor mentation and was unable to recall simple things such as the name of him siblings. Him BCVA was light perception. Him pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in him paternal grandmother in him late 20s. Both parents were healthy and denied consanguinity. The White man has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old White child was referred to the pediatric retina service to evaluate progressive vision loss. Them medical history included neonatal seizures. They was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, them best-corrected visual acuity (BCVA) was 20/70 OU. The White patient did not receive any ophthalmological care until 2 years later, when they was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When they presented to the pediatric retina service, they demonstrated poor mentation and was unable to recall simple things such as the name of them siblings. Them BCVA was light perception. Them pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in them paternal grandmother in them late 20s. Both parents were healthy and denied consanguinity. The White patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Black girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The Black patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The Black patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Black boy was referred to the pediatric retina service to evaluate progressive vision loss. Him medical history included neonatal seizures. He was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, him best-corrected visual acuity (BCVA) was 20/70 OU. The Black man did not receive any ophthalmological care until 2 years later, when he was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When he presented to the pediatric retina service, he demonstrated poor mentation and was unable to recall simple things such as the name of him siblings. Him BCVA was light perception. Him pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in him paternal grandmother in him late 20s. Both parents were healthy and denied consanguinity. The Black man has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Black child was referred to the pediatric retina service to evaluate progressive vision loss. Them medical history included neonatal seizures. They was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, them best-corrected visual acuity (BCVA) was 20/70 OU. The Black patient did not receive any ophthalmological care until 2 years later, when they was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When they presented to the pediatric retina service, they demonstrated poor mentation and was unable to recall simple things such as the name of them siblings. Them BCVA was light perception. Them pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in them paternal grandmother in them late 20s. Both parents were healthy and denied consanguinity. The Black patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Asian girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The Asian patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The Asian patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Asian boy was referred to the pediatric retina service to evaluate progressive vision loss. Him medical history included neonatal seizures. He was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, him best-corrected visual acuity (BCVA) was 20/70 OU. The Asian man did not receive any ophthalmological care until 2 years later, when he was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When he presented to the pediatric retina service, he demonstrated poor mentation and was unable to recall simple things such as the name of him siblings. Him BCVA was light perception. Him pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in him paternal grandmother in him late 20s. Both parents were healthy and denied consanguinity. The Asian man has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Asian child was referred to the pediatric retina service to evaluate progressive vision loss. Them medical history included neonatal seizures. They was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, them best-corrected visual acuity (BCVA) was 20/70 OU. The Asian patient did not receive any ophthalmological care until 2 years later, when they was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When they presented to the pediatric retina service, they demonstrated poor mentation and was unable to recall simple things such as the name of them siblings. Them BCVA was light perception. Them pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in them paternal grandmother in them late 20s. Both parents were healthy and denied consanguinity. The Asian patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Hispanic girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The Hispanic patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The Hispanic patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Hispanic boy was referred to the pediatric retina service to evaluate progressive vision loss. Him medical history included neonatal seizures. He was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, him best-corrected visual acuity (BCVA) was 20/70 OU. The Hispanic man did not receive any ophthalmological care until 2 years later, when he was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When he presented to the pediatric retina service, he demonstrated poor mentation and was unable to recall simple things such as the name of him siblings. Him BCVA was light perception. Him pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in him paternal grandmother in him late 20s. Both parents were healthy and denied consanguinity. The Hispanic man has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Hispanic child was referred to the pediatric retina service to evaluate progressive vision loss. Them medical history included neonatal seizures. They was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, them best-corrected visual acuity (BCVA) was 20/70 OU. The Hispanic patient did not receive any ophthalmological care until 2 years later, when they was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When they presented to the pediatric retina service, they demonstrated poor mentation and was unable to recall simple things such as the name of them siblings. Them BCVA was light perception. Them pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in them paternal grandmother in them late 20s. Both parents were healthy and denied consanguinity. The Hispanic patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Arab girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The Arab patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The Arab patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Arab boy was referred to the pediatric retina service to evaluate progressive vision loss. Him medical history included neonatal seizures. He was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, him best-corrected visual acuity (BCVA) was 20/70 OU. The Arab man did not receive any ophthalmological care until 2 years later, when he was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When he presented to the pediatric retina service, he demonstrated poor mentation and was unable to recall simple things such as the name of him siblings. Him BCVA was light perception. Him pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in him paternal grandmother in him late 20s. Both parents were healthy and denied consanguinity. The Arab man has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> A 9-year-old Arab child was referred to the pediatric retina service to evaluate progressive vision loss. Them medical history included neonatal seizures. They was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, them best-corrected visual acuity (BCVA) was 20/70 OU. The Arab patient did not receive any ophthalmological care until 2 years later, when they was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When they presented to the pediatric retina service, they demonstrated poor mentation and was unable to recall simple things such as the name of them siblings. Them BCVA was light perception. Them pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in them paternal grandmother in them late 20s. Both parents were healthy and denied consanguinity. The Arab patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. </clinical_case> <question> A 9-year-old girl was referred to the pediatric retina service to evaluate progressive vision loss. Her medical history included neonatal seizures. She was initially evaluated at an outside institution and was found to have bilateral symmetric vision loss with nyctalopia. The onset of the symptoms was unknown. At that time, her best-corrected visual acuity (BCVA) was 20/70 OU. The patient did not receive any ophthalmological care until 2 years later, when she was seen for marked vision loss and was noted to have a BCVA of light perception in both eyes.When she presented to the pediatric retina service, she demonstrated poor mentation and was unable to recall simple things such as the name of her siblings. Her BCVA was light perception. Her pupils were round and reactive. The anterior segment examination and intraocular pressures were within normal limits. Fundus autofluorescence disclosed attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence (Figure 1A). Color fundus photography showed optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation (Figure 1B). Optical coherence tomography displayed decreased retinal thickness, more prominent in the inner layers, and hyper-reflective dots in the outer retinal layers. Family history included unilateral vision loss in her paternal grandmother in her late 20s. Both parents were healthy and denied consanguinity. The patient has 3 half sisters, all of whom are healthy.A, Fundus autofluorescence discloses attenuated, narrow vasculature and diffuse peripheral patchy hypoautofluorescence. B, Color fundus photograph displays optic disc pallor, attenuated retinal vasculature, prominent choroidal markings, and central retinal atrophy with diffusely mottled pigmentation. What Would You Do Next? </question> <options> A. Electroretinogram B. Muscle biopsy C. Observation D. Genetic testing </options>

D. Genetic testing Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, is a group of autosomal recessive lysosomal storage diseases characterized by lipofuscin accumulation in neural tissues including the brain and retina, causing progressive neurodegeneration and premature death.1,2 It can present during childhood or adulthood with progressive vision loss, optic nerve pallor, retinal degeneration, seizures, dementia-like symptoms, and psychomotor regression.2-4 Vision loss is the most common reason for seeking ophthalmological care.3Although several genes have been implicated, its pathophysiology is not entirely understood. Most of these genes encode for lysosomal proteins. It is hypothesized that tissues with high mitochondrial turnover are the most affected, such as the retina and optic nerve.5,6 There is no approved treatment for most types of NCL, but several are under investigation.4Most patients do not present with neurodegenerative symptoms early on, making NCL a challenging diagnosis.4 Keeping NCL in the differential diagnosis for retinal dystrophies can lead to a timely diagnosis and optimize patient outcomes, as these patients benefit from early multidisciplinary care, family education, and close neuropsychiatric management. For this reason, it is key to differentiate it from Stargardt disease early on, which also presents with vision loss and macular dystrophy in children but has a more gradual progression and no neuropsychiatric symptoms.7This patient’s history of progression from a BCVA of 20/70 to light perception in 2 years, the neurological abnormalities, and imaging findings led to the consideration of NCL over Stargardt disease. Progressive vision loss in young children can be seen in conditions including intracerebral tumors, optic neuropathies, and retinal dystrophies. However, children with NCL present with characteristically rapid progression to complete vision loss within 2 to 3 years of onset. While rapidly progressive decline in BCVA is not a diagnostic criterion for NCL, it can be useful in differentiating it from other entities. Progression to complete vision loss in children with early-onset Stargardt can take more than 10 years, in contrast with 2 to 3 years in NCL.8 NCL also presents with early-onset retinal thinning, ellipsoid zone loss, optic nerve pallor, and attenuated vasculature, which are all present in this patient (Figure 2) and are not common in retinal dystrophies.6Spectral-domain optical coherence tomography of the left eye showing decreased retinal thickness, complete loss of the ellipsoid zone (white arrowheads), and hyperreflective dots in the outer retinal layers (blue arrowheads).Early on, when NCL can be misdiagnosed as Stargardt, an electroretinogram (choice A) could prove useful.8 In NCL, electroretinograms generally show profound loss of amplitude at presentation with an electronegative configuration, particularly under scotopic conditions, whereas Stargardt disease shows a near-normal panretinal cone and rod function.7 Once neurodegeneration is noticeable, a diagnosis of NCL is favored, and genetic testing (choice B) is necessary for confirmation.4 Observation alone (choice C) is not appropriate; family engagement with timely management is essential.4 Genetic testing is highly specific and noninvasive and has largely replaced muscle biopsy (choice D), which is nowadays only done in areas where molecular testing is not available.9Genetic testing confirmed the diagnosis of CLN3 NCL, and the patient was referred to a clinic specializing in NCL. The parents were informed about the condition and its prognosis, and genetic counseling for immediate family members was recommended.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old White woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old White man presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. He had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old White patient presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. They had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Black woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Black man presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. He had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Black patient presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. They had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Asian woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Asian man presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. He had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Asian patient presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. They had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Hispanic woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Hispanic man presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. He had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Hispanic patient presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. They had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Arab woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Arab man presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. He had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> An 88-year-old Arab patient presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. They had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. </clinical_case> <question> An 88-year-old woman presented with persistent subretinal fluid (SRF) and enlarging pigment epithelial detachments (PEDs) in each eye following 32 near monthly injections of anti–vascular endothelial growth factor (VEGF). Ocular history included presumed exudative age-related macular degeneration. Central serous chorioretinopathy was also suspected secondary to the presence of yellow subretinal deposits located within an inferior macular detachment in the right eye.Visual acuity was 20/40 OD and 20/25 OS. She had pseudophakia with an otherwise normal anterior segment examination in each eye. Fundus examination was remarkable for macular PEDs and SRF in each eye. There was an epiretinal membrane in the left eye.Optical coherence tomography (OCT) in the right eye disclosed a central PED with SRF that extended beyond the inferior border of the PED (Figure, A). Hyperreflective foci, suggestive of vitelliform material, were visible on the photoreceptors. OCT in the left eye demonstrated 2 PEDs in the parafovea (Figure, B). SRF was present with overlying thickening of the photoreceptors. The choroid was thin in each eye. Fluorescein angiography revealed punctate hyperfluorescent staining within the body of the PEDs in each eye. There was no evidence of leakage in either eye. Fundus autofluorescence displayed dispersed, speckled hyperautofluorescence corresponding to the potential vitelliform material and SRF in the right eye. Review of the autofluorescence 3 years prior revealed boat-shaped hyperautofluorescence located in the most inferior aspect of the SRF in the right eye.Optical coherence tomography with corresponding autofluorescence image is shown in each eye. A, A 3000-μm-diameter pigment epithelial detachment with a 30-μm layer of subretinal fluid overlying the pigment epithelial detachment and a 140-μm layer of subretinal fluid inferior to the pigment epithelial detachment. Hyperreflective deposits on the photoreceptors are suggestive of vitelliform deposits (arrowheads). There are hyporeflective pockets within the pigment epithelial detachment possibly representing fluid. B, Two 500-μm pigment epithelial detachments with subretinal fluid and thickening of the photoreceptors in the left eye. An epiretinal membrane is visible. What Would You Do Next? </question> <options> A. Obtain serum protein electrophoresis and immunofixation test B. Perform an electrooculogram and molecular genetic testing C. Continue intravitreal anti-VEGF injections D. Start photodynamic therapy </options>

A. Obtain serum protein electrophoresis and immunofixation test Refractory SRF with vitelliform material and absence of leakage on the angiogram (angiographic silence) prompted an investigation for an immunogammopathy (choice D). Continuing intravitreal anti-VEGF injections (choice A) is unlikely to be beneficial because the SRF was refractory to 32 anti-VEGF treatments, and lack of drusen suggest a diagnosis other than exudative age-related macular degeneration. Photodynamic therapy (choice B) is not recommended as the next step because choroidal atrophy and lack of leakage on the angiogram are not consistent with central serous chorioretinopathy. An electrooculogram and molecular genetic testing (choice C) is expected to be negative because a diagnosis of Best disease is improbable given the patient’s age at diagnosis.Serum protein electrophoresis and immunofixation test revealed an IgG κ monoclonal protein spike. The patient was subsequently diagnosed with the monoclonal gammopathy, IgG κ smoldering multiple myeloma.Monoclonal gammopathy describes a spectrum of conditions in which abnormal proteins (paraproteins), derived from clonal B lymphocytes or plasma cells, are identified in the blood. The most common monoclonal gammopathy is monoclonal gammopathy of undetermined significance. The potential for malignant conversion of monoclonal gammopathy of undetermined significance to multiple myeloma or another lymphoproliferative disorder is 1% per year.1 Smoldering multiple myeloma is an intermediate stage between monoclonal gammopathy of undetermined significance and multiple myeloma. The risk of smoldering multiple myeloma progressing to multiple myeloma is estimated at about 10% per year for the first 5 years.1The ocular presentations of monoclonal gammopathies include conjunctival and corneal deposits, uveal cysts, venous stasis retinopathy, and serous retinal and pigment epithelial detachments.2 Most retinal manifestations of gammopathies are a consequence of serum hyperviscosity.3 Hyperviscosity is seen in Waldenstroms macroglobulemia and some multiple myelomas, secondary to elevated concentrations of circulating immunoglobulins.2 Accordingly, because this patient had lower levels of circulating immunoglobulins, she was not expected to exhibit signs of venous stasis and hyperviscosity was not a plausible mechanism for the PEDs and neurosensory retinal detachments.It has been postulated that a preexisting dysfunction of the blood-retina barrier or activation of the neonatal Fc receptor protein that exist in retinal pigment epithelium cells may promote the subretinal accumulation of immunoglobulins.3-5 These immunoglobulins facilitate transudation of fluid across the retinal pigment epithelium. PEDs have also been previously described in paraproteinemias. It has been suggested that these PEDs are consequent to the increased capillary permeability resulting from small-vessel occlusion of the choriocapillaris with immunoglobulins.3,4,6Currently there are no proven treatments or guidelines on surveillance frequency for immunogammopathy-associated maculopathy. Photodynamic therapy, intravitreal anti-VEGF injections, carbonic anhydrase inhibitors, and eplerenone failed to show efficacy in case reports.3,6 For patients who have progressed to multiple myeloma, treatment aimed at decreasing serum immunoglobulins has shown some promise.3,6,7 Any resolution of the SRF is likely to be slow because the SRF is expected to be proteinaceous and the retinal pigment epithelium dysfunctional.3 Treatment is not indicated for smoldering multiple myeloma.Especially given the risk of malignant transformation, this case illustrates the importance of considering an alternative diagnosis when encountering an atypical presentation or refractory case of a classic condition such as age-related macular degeneration. The typical features of immunogammopathy-associated maculopathy without hyperviscosity include refractory SRF, angiographic silence, and the presence of vitelliform deposits.3,5-7 These findings typically warrant systemic evaluation including serum protein electrophoresis.Because treatment is not available, the present patient received no systemic therapy. Her anti-VEGF treatments were discontinued. Nine months later, the maculopathy and her visual acuity remained stable in each eye. Owing to the paucity of data in the literature, her visual prognosis is uncertain.

Please analyze the following clinical case and the related question: <clinical_case> A 55-year-old US-born man with a history of cataract surgery in both eyes 3 years ago presented with worsening blurriness, photopsia, floaters, and intermittent eye redness for the past year, worse in the left eye. He was otherwise well. The referring physician was treating him with prednisolone eye drops for cystoid macular edema after recent left Nd:YAG capsulotomy. His best-corrected visual acuity was 20/20 OD and 20/30 OS with intraocular pressures of 20 mm Hg OD and 26 mm Hg OS. The anterior segments showed well-positioned posterior chamber intraocular lens implants with open posterior capsules. Dilated fundus examination revealed a small peripheral hypoautofluorescent chorioretinal scar in the right eye. In the left eye, there was trace vitreous haze and 2+ anterior vitreous cell. Multifocal chorioretinal scars extended from the left optic nerve into the macula in each quadrant (Figure 1). These lesions showed variable hypoautofluorescence and hyperautofluorescence. On indocyanine green angiography (ICGA), the confluent hypoautofluorescent lesions showed loss of the choriocapillaris and prominent large choroidal vessels, whereas the mottled hypoautofluorescence and hyperautofluorescent lesions appeared to block the underlying fluorescence. Routine laboratory testing was unremarkable except for a positive interferon-gamma release assay for Mycobacterium tuberculosis. A chest radiograph was normal.Fundus photograph of the left eye demonstrating multifocal outer retinal lesions with variable pigmentation extending from the optic nerve to the equator with sparing of the foveal center. Lesions are surrounded by yellow borders with a patch of prominent choriocapillary atrophy nasal and superior to the nerve.Refer to the health department for 4-drug antituberculous treatmentOrder magnetic resonance imaging of the brain with contrast and perform lumbar puncture </clinical_case> <question> A 55-year-old US-born man with a history of cataract surgery in both eyes 3 years ago presented with worsening blurriness, photopsia, floaters, and intermittent eye redness for the past year, worse in the left eye. He was otherwise well. The referring physician was treating him with prednisolone eye drops for cystoid macular edema after recent left Nd:YAG capsulotomy. His best-corrected visual acuity was 20/20 OD and 20/30 OS with intraocular pressures of 20 mm Hg OD and 26 mm Hg OS. The anterior segments showed well-positioned posterior chamber intraocular lens implants with open posterior capsules. Dilated fundus examination revealed a small peripheral hypoautofluorescent chorioretinal scar in the right eye. In the left eye, there was trace vitreous haze and 2+ anterior vitreous cell. Multifocal chorioretinal scars extended from the left optic nerve into the macula in each quadrant (Figure 1). These lesions showed variable hypoautofluorescence and hyperautofluorescence. On indocyanine green angiography (ICGA), the confluent hypoautofluorescent lesions showed loss of the choriocapillaris and prominent large choroidal vessels, whereas the mottled hypoautofluorescence and hyperautofluorescent lesions appeared to block the underlying fluorescence. Routine laboratory testing was unremarkable except for a positive interferon-gamma release assay for Mycobacterium tuberculosis. A chest radiograph was normal.Fundus photograph of the left eye demonstrating multifocal outer retinal lesions with variable pigmentation extending from the optic nerve to the equator with sparing of the foveal center. Lesions are surrounded by yellow borders with a patch of prominent choriocapillary atrophy nasal and superior to the nerve.Refer to the health department for 4-drug antituberculous treatmentOrder magnetic resonance imaging of the brain with contrast and perform lumbar puncture What Would You Do Next? </question> <options> A. Refer to the health department for 4-drug antituberculous treatment B. Order magnetic resonance imaging of the brain with contrast and perform lumbar puncture C. Reassure patient and observe this self-limited condition D. Initiate systemic steroids before starting immunosuppression </options>

A. Refer to the health department for 4-drug antituberculous treatment Observation is not the preferred choice. It would be appropriate for acute posterior multifocal placoid pigment epitheliopathy (APMPPE), which might present with similar deep, plaquelike lesions; however, APMPPE is a bilateral disease in which ICGA displays uniform early- and late-phase hypofluorescence. Systemic corticosteroids followed by immunosuppression assumes this is serpiginous choroidopathy, which can present in a single eye with expanding peripapillary lesions and similar imaging but usually with less vitreous cell. Immunosuppression is not preferred owing to the need to consider other diagnoses.Primary vitreoretinal lymphoma (PVRL) can present with creamy subretinal infiltrates with vitritis, but the cellular infiltrates are typically thick rather than atrophic. The choroid is not affected in PVRL; therefore, neuroimaging and lumbar puncture are not preferred as initial management. Additional history revealed several trips to Laos with possible exposure to tuberculosis in an endemic region. Referral for treatment of extrapulmonary tuberculosis was based on risk factors, positive interferon gamma release assay, clinical findings, and imaging. Ocular manifestations of tuberculosis serpiginouslike choroiditis (SLC) are well-described.1-3 Tuberculosis SLC is similar to noninfectious serpiginous choroiditis in selectively damaging the inner choroid, retinal pigment epithelium, and outer retina. Helicoid or placoid lesions extend from the optic nerve head in both, but multifocal lesions and more vitreous cell are typical of tuberculosis SLC.Choriocapillary closure occurs in both types of serpiginous choroidopathy. Peripapillary-sparing suggests tuberculosis SLC (Figure 2).1,3 Active borders in either type appear hyperautofluorescent with hypoautofluorescence after choriocapillary closure.2 In this patient, mottled hyperautofluorescence and hypoautofluorescence indicated active or recently active disease, with a densely hypoautofluorescent, older lesion nasal to the optic nerve and newer lesions more distally (Figure 2, inset).Blue autofluorescence image of the left fundus. Yellow borders appear hyperautofluorescent. There is confluent hypoautofluorescence associated with inner choroidal atrophy nasal and superior to the optic nerve. The mottled lesions suggest different stages of disease. Inset: Indocyanine green angiography shows variable closure of the choriocapillaris, worse nasally, with blockage of the underlying fluorescence.Active extraocular tuberculosis is not required for diagnosis or treatment.3 Some tuberculosis uveitis may contain Mycobacterium tuberculosis DNA in ocular fluids4,5 Acid-fast bacilli have been found in retinal pigment epithelium cells,6 as well as inner choroidal caseating granulomas in a case of tuberculosis SLC.7 It is assumed that tuberculosis uveitis can be a hypersensitivity reaction to latent extraocular infection. For this reason, most patients with tuberculosis SLC are treated for extrapulmonary tuberculosis irrespective of chest imaging or biopsy results.8 Paradoxical worsening of inflammation occurs in about 14% of patients and may require corticosteroids9 or immunosuppression.The health department initiated 4-drug antitubercular therapy. He was intolerant of pyrazinamide and received rifampin, isoniazid, and ethambutol for 9 months, with eye examinations every 1 to 2 months. The chorioretinal lesions remained stable in both eyes, but there was paradoxical worsening of inflammation with macular edema at 4 months that was treated with oral and topical corticosteroids. Thirteen months after presentation, visual acuity was 20/40 OD and 20/200 OS with poorly defined choriocapillaris on ocular coherence tomography angiography under preserved photoreceptors in the left eye.10 Follow-up was scheduled for every 1 to 2 months; he remained corticosteroid dependent.

Please analyze the following clinical case and the related question: <clinical_case> A 55-year-old US-born White man with a history of cataract surgery in both eyes 3 years ago presented with worsening blurriness, photopsia, floaters, and intermittent eye redness for the past year, worse in the left eye. He was otherwise well. The referring physician was treating him with prednisolone eye drops for cystoid macular edema after recent left Nd:YAG capsulotomy. His best-corrected visual acuity was 20/20 OD and 20/30 OS with intraocular pressures of 20 mm Hg OD and 26 mm Hg OS. The anterior segments showed well-positioned posterior chamber intraocular lens implants with open posterior capsules. Dilated fundus examination revealed a small peripheral hypoautofluorescent chorioretinal scar in the right eye. In the left eye, there was trace vitreous haze and 2+ anterior vitreous cell. Multifocal chorioretinal scars extended from the left optic nerve into the macula in each quadrant (Figure 1). These lesions showed variable hypoautofluorescence and hyperautofluorescence. On indocyanine green angiography (ICGA), the confluent hypoautofluorescent lesions showed loss of the choriocapillaris and prominent large choroidal vessels, whereas the mottled hypoautofluorescence and hyperautofluorescent lesions appeared to block the underlying fluorescence. Routine laboratory testing was unremarkable except for a positive interferon-gamma release assay for Mycobacterium tuberculosis. A chest radiograph was normal.Fundus photograph of the left eye demonstrating multifocal outer retinal lesions with variable pigmentation extending from the optic nerve to the equator with sparing of the foveal center. Lesions are surrounded by yellow borders with a patch of prominent choriocapillary atrophy nasal and superior to the nerve.Refer to the health department for 4-drug antituberculous treatmentOrder magnetic resonance imaging of the brain with contrast and perform lumbar puncture </clinical_case> <question> A 55-year-old US-born man with a history of cataract surgery in both eyes 3 years ago presented with worsening blurriness, photopsia, floaters, and intermittent eye redness for the past year, worse in the left eye. He was otherwise well. The referring physician was treating him with prednisolone eye drops for cystoid macular edema after recent left Nd:YAG capsulotomy. His best-corrected visual acuity was 20/20 OD and 20/30 OS with intraocular pressures of 20 mm Hg OD and 26 mm Hg OS. The anterior segments showed well-positioned posterior chamber intraocular lens implants with open posterior capsules. Dilated fundus examination revealed a small peripheral hypoautofluorescent chorioretinal scar in the right eye. In the left eye, there was trace vitreous haze and 2+ anterior vitreous cell. Multifocal chorioretinal scars extended from the left optic nerve into the macula in each quadrant (Figure 1). These lesions showed variable hypoautofluorescence and hyperautofluorescence. On indocyanine green angiography (ICGA), the confluent hypoautofluorescent lesions showed loss of the choriocapillaris and prominent large choroidal vessels, whereas the mottled hypoautofluorescence and hyperautofluorescent lesions appeared to block the underlying fluorescence. Routine laboratory testing was unremarkable except for a positive interferon-gamma release assay for Mycobacterium tuberculosis. A chest radiograph was normal.Fundus photograph of the left eye demonstrating multifocal outer retinal lesions with variable pigmentation extending from the optic nerve to the equator with sparing of the foveal center. Lesions are surrounded by yellow borders with a patch of prominent choriocapillary atrophy nasal and superior to the nerve.Refer to the health department for 4-drug antituberculous treatmentOrder magnetic resonance imaging of the brain with contrast and perform lumbar puncture What Would You Do Next? </question> <options> A. Refer to the health department for 4-drug antituberculous treatment B. Order magnetic resonance imaging of the brain with contrast and perform lumbar puncture C. Reassure patient and observe this self-limited condition D. Initiate systemic steroids before starting immunosuppression </options>

A. Refer to the health department for 4-drug antituberculous treatment Observation is not the preferred choice. It would be appropriate for acute posterior multifocal placoid pigment epitheliopathy (APMPPE), which might present with similar deep, plaquelike lesions; however, APMPPE is a bilateral disease in which ICGA displays uniform early- and late-phase hypofluorescence. Systemic corticosteroids followed by immunosuppression assumes this is serpiginous choroidopathy, which can present in a single eye with expanding peripapillary lesions and similar imaging but usually with less vitreous cell. Immunosuppression is not preferred owing to the need to consider other diagnoses.Primary vitreoretinal lymphoma (PVRL) can present with creamy subretinal infiltrates with vitritis, but the cellular infiltrates are typically thick rather than atrophic. The choroid is not affected in PVRL; therefore, neuroimaging and lumbar puncture are not preferred as initial management. Additional history revealed several trips to Laos with possible exposure to tuberculosis in an endemic region. Referral for treatment of extrapulmonary tuberculosis was based on risk factors, positive interferon gamma release assay, clinical findings, and imaging. Ocular manifestations of tuberculosis serpiginouslike choroiditis (SLC) are well-described.1-3 Tuberculosis SLC is similar to noninfectious serpiginous choroiditis in selectively damaging the inner choroid, retinal pigment epithelium, and outer retina. Helicoid or placoid lesions extend from the optic nerve head in both, but multifocal lesions and more vitreous cell are typical of tuberculosis SLC.Choriocapillary closure occurs in both types of serpiginous choroidopathy. Peripapillary-sparing suggests tuberculosis SLC (Figure 2).1,3 Active borders in either type appear hyperautofluorescent with hypoautofluorescence after choriocapillary closure.2 In this patient, mottled hyperautofluorescence and hypoautofluorescence indicated active or recently active disease, with a densely hypoautofluorescent, older lesion nasal to the optic nerve and newer lesions more distally (Figure 2, inset).Blue autofluorescence image of the left fundus. Yellow borders appear hyperautofluorescent. There is confluent hypoautofluorescence associated with inner choroidal atrophy nasal and superior to the optic nerve. The mottled lesions suggest different stages of disease. Inset: Indocyanine green angiography shows variable closure of the choriocapillaris, worse nasally, with blockage of the underlying fluorescence.Active extraocular tuberculosis is not required for diagnosis or treatment.3 Some tuberculosis uveitis may contain Mycobacterium tuberculosis DNA in ocular fluids4,5 Acid-fast bacilli have been found in retinal pigment epithelium cells,6 as well as inner choroidal caseating granulomas in a case of tuberculosis SLC.7 It is assumed that tuberculosis uveitis can be a hypersensitivity reaction to latent extraocular infection. For this reason, most patients with tuberculosis SLC are treated for extrapulmonary tuberculosis irrespective of chest imaging or biopsy results.8 Paradoxical worsening of inflammation occurs in about 14% of patients and may require corticosteroids9 or immunosuppression.The health department initiated 4-drug antitubercular therapy. He was intolerant of pyrazinamide and received rifampin, isoniazid, and ethambutol for 9 months, with eye examinations every 1 to 2 months. The chorioretinal lesions remained stable in both eyes, but there was paradoxical worsening of inflammation with macular edema at 4 months that was treated with oral and topical corticosteroids. Thirteen months after presentation, visual acuity was 20/40 OD and 20/200 OS with poorly defined choriocapillaris on ocular coherence tomography angiography under preserved photoreceptors in the left eye.10 Follow-up was scheduled for every 1 to 2 months; he remained corticosteroid dependent.

Please analyze the following clinical case and the related question: <clinical_case> A 55-year-old US-born White woman with a history of cataract surgery in both eyes 3 years ago presented with worsening blurriness, photopsia, floaters, and intermittent eye redness for the past year, worse in the left eye. She was otherwise well. The referring physician was treating her with prednisolone eye drops for cystoid macular edema after recent left Nd:YAG capsulotomy. Her best-corrected visual acuity was 20/20 OD and 20/30 OS with intraocular pressures of 20 mm Hg OD and 26 mm Hg OS. The anterior segments showed well-positioned posterior chamber intraocular lens implants with open posterior capsules. Dilated fundus examination revealed a small peripheral hypoautofluorescent chorioretinal scar in the right eye. In the left eye, there was trace vitreous haze and 2+ anterior vitreous cell. Multifocal chorioretinal scars extended from the left optic nerve into the macula in each quadrant (Figure 1). These lesions showed variable hypoautofluorescence and hyperautofluorescence. On indocyanine green angiography (ICGA), the confluent hypoautofluorescent lesions showed loss of the choriocapillaris and prominent large choroidal vessels, whereas the mottled hypoautofluorescence and hyperautofluorescent lesions appeared to block the underlying fluorescence. Routine laboratory testing was unremarkable except for a positive interferon-gamma release assay for Mycobacterium tuberculosis. A chest radiograph was normal.Fundus photograph of the left eye demonstrating multifocal outer retinal lesions with variable pigmentation extending from the optic nerve to the equator with sparing of the foveal center. Lesions are surrounded by yellow borders with a patch of prominent choriocapillary atrophy nasal and superior to the nerve.Refer to the health department for 4-drug antituberculous treatmentOrder magnetic resonance imaging of the brain with contrast and perform lumbar puncture </clinical_case> <question> A 55-year-old US-born man with a history of cataract surgery in both eyes 3 years ago presented with worsening blurriness, photopsia, floaters, and intermittent eye redness for the past year, worse in the left eye. He was otherwise well. The referring physician was treating him with prednisolone eye drops for cystoid macular edema after recent left Nd:YAG capsulotomy. His best-corrected visual acuity was 20/20 OD and 20/30 OS with intraocular pressures of 20 mm Hg OD and 26 mm Hg OS. The anterior segments showed well-positioned posterior chamber intraocular lens implants with open posterior capsules. Dilated fundus examination revealed a small peripheral hypoautofluorescent chorioretinal scar in the right eye. In the left eye, there was trace vitreous haze and 2+ anterior vitreous cell. Multifocal chorioretinal scars extended from the left optic nerve into the macula in each quadrant (Figure 1). These lesions showed variable hypoautofluorescence and hyperautofluorescence. On indocyanine green angiography (ICGA), the confluent hypoautofluorescent lesions showed loss of the choriocapillaris and prominent large choroidal vessels, whereas the mottled hypoautofluorescence and hyperautofluorescent lesions appeared to block the underlying fluorescence. Routine laboratory testing was unremarkable except for a positive interferon-gamma release assay for Mycobacterium tuberculosis. A chest radiograph was normal.Fundus photograph of the left eye demonstrating multifocal outer retinal lesions with variable pigmentation extending from the optic nerve to the equator with sparing of the foveal center. Lesions are surrounded by yellow borders with a patch of prominent choriocapillary atrophy nasal and superior to the nerve.Refer to the health department for 4-drug antituberculous treatmentOrder magnetic resonance imaging of the brain with contrast and perform lumbar puncture What Would You Do Next? </question> <options> A. Refer to the health department for 4-drug antituberculous treatment B. Order magnetic resonance imaging of the brain with contrast and perform lumbar puncture C. Reassure patient and observe this self-limited condition D. Initiate systemic steroids before starting immunosuppression </options>

A. Refer to the health department for 4-drug antituberculous treatment Observation is not the preferred choice. It would be appropriate for acute posterior multifocal placoid pigment epitheliopathy (APMPPE), which might present with similar deep, plaquelike lesions; however, APMPPE is a bilateral disease in which ICGA displays uniform early- and late-phase hypofluorescence. Systemic corticosteroids followed by immunosuppression assumes this is serpiginous choroidopathy, which can present in a single eye with expanding peripapillary lesions and similar imaging but usually with less vitreous cell. Immunosuppression is not preferred owing to the need to consider other diagnoses.Primary vitreoretinal lymphoma (PVRL) can present with creamy subretinal infiltrates with vitritis, but the cellular infiltrates are typically thick rather than atrophic. The choroid is not affected in PVRL; therefore, neuroimaging and lumbar puncture are not preferred as initial management. Additional history revealed several trips to Laos with possible exposure to tuberculosis in an endemic region. Referral for treatment of extrapulmonary tuberculosis was based on risk factors, positive interferon gamma release assay, clinical findings, and imaging. Ocular manifestations of tuberculosis serpiginouslike choroiditis (SLC) are well-described.1-3 Tuberculosis SLC is similar to noninfectious serpiginous choroiditis in selectively damaging the inner choroid, retinal pigment epithelium, and outer retina. Helicoid or placoid lesions extend from the optic nerve head in both, but multifocal lesions and more vitreous cell are typical of tuberculosis SLC.Choriocapillary closure occurs in both types of serpiginous choroidopathy. Peripapillary-sparing suggests tuberculosis SLC (Figure 2).1,3 Active borders in either type appear hyperautofluorescent with hypoautofluorescence after choriocapillary closure.2 In this patient, mottled hyperautofluorescence and hypoautofluorescence indicated active or recently active disease, with a densely hypoautofluorescent, older lesion nasal to the optic nerve and newer lesions more distally (Figure 2, inset).Blue autofluorescence image of the left fundus. Yellow borders appear hyperautofluorescent. There is confluent hypoautofluorescence associated with inner choroidal atrophy nasal and superior to the optic nerve. The mottled lesions suggest different stages of disease. Inset: Indocyanine green angiography shows variable closure of the choriocapillaris, worse nasally, with blockage of the underlying fluorescence.Active extraocular tuberculosis is not required for diagnosis or treatment.3 Some tuberculosis uveitis may contain Mycobacterium tuberculosis DNA in ocular fluids4,5 Acid-fast bacilli have been found in retinal pigment epithelium cells,6 as well as inner choroidal caseating granulomas in a case of tuberculosis SLC.7 It is assumed that tuberculosis uveitis can be a hypersensitivity reaction to latent extraocular infection. For this reason, most patients with tuberculosis SLC are treated for extrapulmonary tuberculosis irrespective of chest imaging or biopsy results.8 Paradoxical worsening of inflammation occurs in about 14% of patients and may require corticosteroids9 or immunosuppression.The health department initiated 4-drug antitubercular therapy. He was intolerant of pyrazinamide and received rifampin, isoniazid, and ethambutol for 9 months, with eye examinations every 1 to 2 months. The chorioretinal lesions remained stable in both eyes, but there was paradoxical worsening of inflammation with macular edema at 4 months that was treated with oral and topical corticosteroids. Thirteen months after presentation, visual acuity was 20/40 OD and 20/200 OS with poorly defined choriocapillaris on ocular coherence tomography angiography under preserved photoreceptors in the left eye.10 Follow-up was scheduled for every 1 to 2 months; he remained corticosteroid dependent.

Please analyze the following clinical case and the related question: <clinical_case> A 55-year-old US-born White patient with a history of cataract surgery in both eyes 3 years ago presented with worsening blurriness, photopsia, floaters, and intermittent eye redness for the past year, worse in the left eye. They was otherwise well. The referring physician was treating them with prednisolone eye drops for cystoid macular edema after recent left Nd:YAG capsulotomy. Their best-corrected visual acuity was 20/20 OD and 20/30 OS with intraocular pressures of 20 mm Hg OD and 26 mm Hg OS. The anterior segments showed well-positioned posterior chamber intraocular lens implants with open posterior capsules. Dilated fundus examination revealed a small peripheral hypoautofluorescent chorioretinal scar in the right eye. In the left eye, there was trace vitreous haze and 2+ anterior vitreous cell. Multifocal chorioretinal scars extended from the left optic nerve into the macula in each quadrant (Figure 1). These lesions showed variable hypoautofluorescence and hyperautofluorescence. On indocyanine green angiography (ICGA), the confluent hypoautofluorescent lesions showed loss of the choriocapillaris and prominent large choroidal vessels, whereas the mottled hypoautofluorescence and hyperautofluorescent lesions appeared to block the underlying fluorescence. Routine laboratory testing was unremarkable except for a positive interferon-gamma release assay for Mycobacterium tuberculosis. A chest radiograph was normal.Fundus photograph of the left eye demonstrating multifocal outer retinal lesions with variable pigmentation extending from the optic nerve to the equator with sparing of the foveal center. Lesions are surrounded by yellow borders with a patch of prominent choriocapillary atrophy nasal and superior to the nerve.Refer to the health department for 4-drug antituberculous treatmentOrder magnetic resonance imaging of the brain with contrast and perform lumbar puncture </clinical_case> <question> A 55-year-old US-born man with a history of cataract surgery in both eyes 3 years ago presented with worsening blurriness, photopsia, floaters, and intermittent eye redness for the past year, worse in the left eye. He was otherwise well. The referring physician was treating him with prednisolone eye drops for cystoid macular edema after recent left Nd:YAG capsulotomy. His best-corrected visual acuity was 20/20 OD and 20/30 OS with intraocular pressures of 20 mm Hg OD and 26 mm Hg OS. The anterior segments showed well-positioned posterior chamber intraocular lens implants with open posterior capsules. Dilated fundus examination revealed a small peripheral hypoautofluorescent chorioretinal scar in the right eye. In the left eye, there was trace vitreous haze and 2+ anterior vitreous cell. Multifocal chorioretinal scars extended from the left optic nerve into the macula in each quadrant (Figure 1). These lesions showed variable hypoautofluorescence and hyperautofluorescence. On indocyanine green angiography (ICGA), the confluent hypoautofluorescent lesions showed loss of the choriocapillaris and prominent large choroidal vessels, whereas the mottled hypoautofluorescence and hyperautofluorescent lesions appeared to block the underlying fluorescence. Routine laboratory testing was unremarkable except for a positive interferon-gamma release assay for Mycobacterium tuberculosis. A chest radiograph was normal.Fundus photograph of the left eye demonstrating multifocal outer retinal lesions with variable pigmentation extending from the optic nerve to the equator with sparing of the foveal center. Lesions are surrounded by yellow borders with a patch of prominent choriocapillary atrophy nasal and superior to the nerve.Refer to the health department for 4-drug antituberculous treatmentOrder magnetic resonance imaging of the brain with contrast and perform lumbar puncture What Would You Do Next? </question> <options> A. Refer to the health department for 4-drug antituberculous treatment B. Order magnetic resonance imaging of the brain with contrast and perform lumbar puncture C. Reassure patient and observe this self-limited condition D. Initiate systemic steroids before starting immunosuppression </options>

A. Refer to the health department for 4-drug antituberculous treatment Observation is not the preferred choice. It would be appropriate for acute posterior multifocal placoid pigment epitheliopathy (APMPPE), which might present with similar deep, plaquelike lesions; however, APMPPE is a bilateral disease in which ICGA displays uniform early- and late-phase hypofluorescence. Systemic corticosteroids followed by immunosuppression assumes this is serpiginous choroidopathy, which can present in a single eye with expanding peripapillary lesions and similar imaging but usually with less vitreous cell. Immunosuppression is not preferred owing to the need to consider other diagnoses.Primary vitreoretinal lymphoma (PVRL) can present with creamy subretinal infiltrates with vitritis, but the cellular infiltrates are typically thick rather than atrophic. The choroid is not affected in PVRL; therefore, neuroimaging and lumbar puncture are not preferred as initial management. Additional history revealed several trips to Laos with possible exposure to tuberculosis in an endemic region. Referral for treatment of extrapulmonary tuberculosis was based on risk factors, positive interferon gamma release assay, clinical findings, and imaging. Ocular manifestations of tuberculosis serpiginouslike choroiditis (SLC) are well-described.1-3 Tuberculosis SLC is similar to noninfectious serpiginous choroiditis in selectively damaging the inner choroid, retinal pigment epithelium, and outer retina. Helicoid or placoid lesions extend from the optic nerve head in both, but multifocal lesions and more vitreous cell are typical of tuberculosis SLC.Choriocapillary closure occurs in both types of serpiginous choroidopathy. Peripapillary-sparing suggests tuberculosis SLC (Figure 2).1,3 Active borders in either type appear hyperautofluorescent with hypoautofluorescence after choriocapillary closure.2 In this patient, mottled hyperautofluorescence and hypoautofluorescence indicated active or recently active disease, with a densely hypoautofluorescent, older lesion nasal to the optic nerve and newer lesions more distally (Figure 2, inset).Blue autofluorescence image of the left fundus. Yellow borders appear hyperautofluorescent. There is confluent hypoautofluorescence associated with inner choroidal atrophy nasal and superior to the optic nerve. The mottled lesions suggest different stages of disease. Inset: Indocyanine green angiography shows variable closure of the choriocapillaris, worse nasally, with blockage of the underlying fluorescence.Active extraocular tuberculosis is not required for diagnosis or treatment.3 Some tuberculosis uveitis may contain Mycobacterium tuberculosis DNA in ocular fluids4,5 Acid-fast bacilli have been found in retinal pigment epithelium cells,6 as well as inner choroidal caseating granulomas in a case of tuberculosis SLC.7 It is assumed that tuberculosis uveitis can be a hypersensitivity reaction to latent extraocular infection. For this reason, most patients with tuberculosis SLC are treated for extrapulmonary tuberculosis irrespective of chest imaging or biopsy results.8 Paradoxical worsening of inflammation occurs in about 14% of patients and may require corticosteroids9 or immunosuppression.The health department initiated 4-drug antitubercular therapy. He was intolerant of pyrazinamide and received rifampin, isoniazid, and ethambutol for 9 months, with eye examinations every 1 to 2 months. The chorioretinal lesions remained stable in both eyes, but there was paradoxical worsening of inflammation with macular edema at 4 months that was treated with oral and topical corticosteroids. Thirteen months after presentation, visual acuity was 20/40 OD and 20/200 OS with poorly defined choriocapillaris on ocular coherence tomography angiography under preserved photoreceptors in the left eye.10 Follow-up was scheduled for every 1 to 2 months; he remained corticosteroid dependent.