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JAMA_Chen2024

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https://jamanetwork.com/journals/jamadermatology/fullarticle/2758410

A male patient in his 70s presented an asymptomatic, slightly eroded, translucent nodule on his right nipple (Figure, A). There was a family history of cutaneous melanoma in his 2 sisters, daughter, and nephew and breast cancer in his mother and sister. We completed genetic testing of family members and found no genetic mutations in sera samples to predispose them to melanoma skin cancer or breast cancer. The main genes tested were the breast cancer type 1 susceptibility (BRCA1), breast cancer 2–DNA repair associated (BRCA2), partner and localizer of BRCA2 (PALB2), checkpoint kinase 2 (CHEK2), and tumor protein p53 (TP53) genes. A dermoscopic examination of the patient showed a translucent lesion with arborizing vessels and erosion (Figure, B). A punch biopsy was performed. What Is Your Diagnosis?

Basal cell carcinoma

Amelanotic melanoma

Ductal adenocarcinoma of the breast

Erosive adenomatosis of the nipple

C. Ductal adenocarcinoma of the breast

C

Ductal adenocarcinoma of the breast

Histological assessment of the lesion revealed a thinning of the epidermis, with a layer of hyperkeratosis and a proliferation of neoplastic cells that had created a glandular pattern in the dermis (Figure, C). There was no pagetoid cell proliferation in the epidermis (Figure, D). Immunohistochemistry staining revealed estrogen-receptor positivity, progesterone-receptor positivity, antigen KI-67 at 10%, and a human epidermal growth factor receptor 2 (Her2) score of +2. These findings were consistent with invasive ductal carcinoma of the breast. An additional clinical examination by a breast cancer specialist highlighted bilateral gynecomastia without any evidence for a palpable mass or adenopathy, although palpation by a pathologist of the specimen subsequently derived from a second resection showed a well-defined mass.The complete workup for extensive cancer was negative. The patient’s serum cancer antigen 15-3 levels were normal. A genetic analysis of the patient’s serum revealed no significant mutations. The patient underwent a right mastectomy with sentinel-node mapping. A pathologic examination showed infiltration of the subcutaneous tissue of the nipple by cancer cells organized in the same glandular pattern seen in the first, more superficial surgery. The excision had histologically clear margins, and the sentinel node was negative. The final diagnosis was an invasive ductal carcinoma with a Nottingham grade of 2 and a status of pT1c, pN0, and pM0.Breast cancer is very rare in men; the male:female ratio is 1:100, and annual incidence is 2:100 000 in the male population.1 The male breast is composed of fat tissue and ductal structures, and lobular tissue is generally absent. Thus, 90% of male breast cancers are ductal carcinomas.2 A lower survival rate in men is associated with frequent late diagnosis. The main risk factors for breast cancer in men are BRCA1 or BRCA2 mutations and a family history of breast cancer. In this case, mutations were not found in the family, although the patient’s mother and sister had been treated for breast cancer.Clinically, according to Hali et al,3 in male breast cancer, cutaneous involvement is up to 25%. A subcutaneous mass can be observed, as well as a retraction and/or ulceration of the nipple with or without bleeding or leaking. Rare male breast cancers develop as superficial cutaneous lesions.Camus et al4 reported on a series of 19 male patients affected by invasive ductal carcinoma. All had a palpable mass at diagnosis, and 8 (42%) had a nipple retraction. No erosive presentation was highlighted in this report.4 It is curious to note that, in the case of this patient, no mass had been palpated by the patient, dermatologist, or breast cancer specialist, but rather the pathologist on the specimen from the second resection.A broad differential diagnosis has to be taken into account during examination of an erosive nodular lesion on the nipple. Basal cell carcinoma (BCC) of the nipple is rare and often diagnosed in patients with excessive sun exposure on the trunk.5 In this patient, an initial misdiagnosis of BCC was probably attributable to the small lesion size and presence at dermoscopy of erosion and arborizing telangiectasia.6 However, these findings are nonspecific to BCC. Arborizing vessels are visible in various malignant tumors.7 Moreover, the absence of discharge and a palpable mass were equally misleading and in favor of BCC as a first diagnosis. Although nipple discharge has been described in BCC of the nipple,8 it is generally absent. A few elements described in literature in cases of BCC of the nipple and areola complex, including a grayish veil, spoke-wheel areas, and leaflike structures, were absent in this patient.9Achromic melanoma of the nipple should be considered as a diagnosis, especially because of the patient’s positive family history. Dermoscopic findings could be compatible with this diagnosis.Finally, erosive adenomatosis of the nipple develops from milk ducts. It is more frequent in middle-aged women, and it is constantly painful. Its clinical presentation usually consists of an erosive crusty nodule of the nipple. Histological testing shows a proliferation of glandular and duct structures with a plasmocytic infiltrate. According to 1 case report,10 dermoscopic inspection should be able to recognize erosive adenomatosis as a yellowish hyperkeratosis with sparse dotted vessels on a reddish-whitish background. Linear vessels on a pinkish background and increased red serpiginous and annular structures can also be observed.9It is important for a dermatologist to know that male breast cancer, although very rare, exists. Cases may have a cutaneous clinical presentation as a translucent, partially erosive nodule of the nipple, mimicking what seems to be a basal cell carcinoma on dermoscopic examination.The patient underwent radiotherapy and adjuvant tamoxifen therapy. He has been in remission for 2.5 years since surgical treatment.

Dermatology

A male patient in his 70s presented an asymptomatic, slightly eroded, translucent nodule on his right nipple (Figure, A). There was a family history of cutaneous melanoma in his 2 sisters, daughter, and nephew and breast cancer in his mother and sister. We completed genetic testing of family members and found no genetic mutations in sera samples to predispose them to melanoma skin cancer or breast cancer. The main genes tested were the breast cancer type 1 susceptibility (BRCA1), breast cancer 2–DNA repair associated (BRCA2), partner and localizer of BRCA2 (PALB2), checkpoint kinase 2 (CHEK2), and tumor protein p53 (TP53) genes. A dermoscopic examination of the patient showed a translucent lesion with arborizing vessels and erosion (Figure, B). A punch biopsy was performed.

what is your diagnosis?

What is your diagnosis?

Amelanotic melanoma

Basal cell carcinoma

Ductal adenocarcinoma of the breast

Erosive adenomatosis of the nipple

c

male

71-80

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2759136

A woman in her 40s with no significant medical history presented with a 1-year history of an umbilical nodule. She described occasional pain and intermittent bleeding from the site. Prior treatment with intralesional triamcinolone injections for a presumed keloid yielded no improvement. Physical examination showed a discrete, reddish-brown, noncompressible, smooth nodule within the umbilicus (Figure, A). There was no change in size with the Valsalva maneuver.Clinical image and punch biopsy specimen. A, Smooth reddish-brown nodule within the umbilicus. B, Low-power view showing glandular and stromal tissue within the dermis (hematoxylin-eosin). C, Higher-power view demonstrating a spindle-cell stroma with hemorrhage and hemosiderin-laden macrophages (hematoxylin-eosin). D, Glandular epithelium showing prominent decapitation secretion (hematoxylin-eosin).Histopathologic examination revealed stromal tissue and glandular epithelium within the dermis (Figure, B). The stroma tissue was characterized by small spindle cells, hemorrhage, and numerous hemosiderin-laden macrophages (Figure, C). Glandular epithelium composed of basophilic cuboidal cells and showing decapitation secretion was also present (Figure, D). Computed tomography scan of the abdomen showed a well-circumscribed nodule within the umbilicus without intrabdominal extension or herniation. Surgical excision followed by umbilical reconstruction was performed. What Is Your Diagnosis?

Metastatic adenocarcinoma

Primary umbilical endometriosis

Urachal duct cyst

Omphalomesenteric duct remnant

B. Primary umbilical endometriosis

B

Primary umbilical endometriosis

Endometriosis is a condition characterized by the presence of functional endometrial tissue outside of the uterine cavity. It occurs in 10% of women of reproductive age and most commonly occurs in the pelvic organs.1 While extrapelvic endometriosis is rare, numerous sites of involvement have been reported, including the eyes, brain, lungs, bowel, and skin.2Umbilical endometriosis comprises 0.5% to 1% of all extrapelvic cases.3 In secondary umbilical endometriosis, there is iatrogenic implantation of endometrial tissue into the umbilicus following surgery, most often a laparoscopic procedure.4 Primary umbilical endometriosis, which occurs in the absence of preceding surgery, is much less common. While the pathogenesis of the primary form is unknown, dissemination of endometrial cells via vascular or lymphatic channels has been suggested.5,6 Scar tissue may be particularly susceptible to this endometrial cell migration. In the present case, the endometrioma occurred within an umbilical piercing scar. Although it is unclear if cosmetic piercings increase the risk of umbilical endometriosis, one similar case has been reported.7Umbilical endometriosis is characterized by a reddish-brown nodule and may clinically resemble a keloid, urachal duct cyst, omphalomesenteric duct remnant, metastatic adenocarcinoma, abdominal hernia, or nodular melanoma.8 A key feature that distinguishes umbilical endometriosis from these other entities is pain and bleeding that coincides with menstrual periods. Although these symptoms are considered pathognomonic for endometriosis when they occur cyclically with menses, histopathologic analysis is mandatory for diagnosis. If any suspicion for abdominal hernia exists after thorough physical examination, ultrasound or computed tomography scan should be obtained prior to biopsy to prevent perforation of underlying bowel, which may be complicated by severe infection or even death.9 Examination findings suggestive of an uncomplicated hernia include a reducible umbilical mass that expands with the Valsalva maneuver.The general histopathologic features of cutaneous endometriosis are the presence of both stroma and glandular tissue.10 The stroma is characterized by small spindle cells, edema, and many hemosiderin-laden macrophages as a result of prior hemorrhage. The glandular epithelium is composed of basophilic cuboidal or tall columnar cells. Importantly, the histopathologic features of endometriosis vary depending on the menstrual phase during which biopsy is obtained. Endometrial glands may show marked mitotic activity during the proliferative phase, while they demonstrate decapitation secretion with little mitotic activity during the secretory phase. A CD10 immunohistochemical stain may be used to aid in diagnosis because it is a highly sensitive marker for endometrial stroma. Estrogen receptor and progesterone receptor immunostains show strong nuclear positivity, and a cytokeratin 7–positive/cytokeratin 20–negative profile is also observed. Importantly, this cytokeratin staining pattern may also occur in gastric adenocarcinoma, the most common cause of umbilical metastasis in men. A CDX2 immunostain may be used to reliably exclude metastases of intestinal origin when histopathologic results show atypia.Collectively, the histopathologic findings of endometriosis readily distinguish it from other conditions that may affect the umbilicus. An umbilical metastatic adenocarcinoma, also called Sister Mary Joseph nodule, would show atypical cells of the viscera of origin. A urachal duct cyst, which is an embryonic remnant between the urachus and bladder, would show a cystic structure lined by flattened urothelium with the surrounding dermis exhibiting fibrosis and calcification. An omphalomesenteric duct consists of remnants of the vitelline duct, which connects the small intestine to the yolk sac in early fetal development and normally involutes by birth. Histopathologic results would show a cystic structure lined by enteric mucosa. Nodular melanoma may also present as a reddish-brown umbilical nodule but is characterized microscopically by dermally based atypical melanocytes.The treatment of choice for umbilical endometriosis is surgical excision.3 Danazol has also been successfully used to alleviate pain and bleeding.5 Because long-term use of antigonadotropin therapy typically leads to antiestrogenic adverse effects, this treatment is more commonly used as a short-term adjunct to decrease endometrioma size preoperatively.Primary umbilical endometriosis is a rare but well-described clinical entity with unique histopathologic features. While the diagnosis should be suspected in an umbilical nodule that cyclically bleeds during menses, histopathologic evaluation is mandatory to exclude nodular melanoma, metastatic adenocarcinoma, and other malignant tumors.

Dermatology

A woman in her 40s with no significant medical history presented with a 1-year history of an umbilical nodule. She described occasional pain and intermittent bleeding from the site. Prior treatment with intralesional triamcinolone injections for a presumed keloid yielded no improvement. Physical examination showed a discrete, reddish-brown, noncompressible, smooth nodule within the umbilicus (Figure, A). There was no change in size with the Valsalva maneuver.Clinical image and punch biopsy specimen. A, Smooth reddish-brown nodule within the umbilicus. B, Low-power view showing glandular and stromal tissue within the dermis (hematoxylin-eosin). C, Higher-power view demonstrating a spindle-cell stroma with hemorrhage and hemosiderin-laden macrophages (hematoxylin-eosin). D, Glandular epithelium showing prominent decapitation secretion (hematoxylin-eosin).Histopathologic examination revealed stromal tissue and glandular epithelium within the dermis (Figure, B). The stroma tissue was characterized by small spindle cells, hemorrhage, and numerous hemosiderin-laden macrophages (Figure, C). Glandular epithelium composed of basophilic cuboidal cells and showing decapitation secretion was also present (Figure, D). Computed tomography scan of the abdomen showed a well-circumscribed nodule within the umbilicus without intrabdominal extension or herniation. Surgical excision followed by umbilical reconstruction was performed.

what is your diagnosis?

What is your diagnosis?

Primary umbilical endometriosis

Metastatic adenocarcinoma

Urachal duct cyst

Omphalomesenteric duct remnant

a

female

0-10

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2758263

An 82-year-old woman presented with dyspnea on exertion and weight gain of 5 kg over the past month. Her medical history included atrial fibrillation and lung adenocarcinoma (a lung lobectomy was performed 8 years ago). Her blood pressure was 112/60 mm Hg, her heart rate was 100 beats per minute, her respiratory rate was 37 breaths per minute, her body temperature was 36.6°C, and her oxygen saturation was 100% while breathing 10 L of oxygen. A cardiac examination was clinically significant for an irregular rhythm, an increased pulmonic closure sound, and jugular venous distension. Bibasilar coarse crackles and pretibial edema were also noted. A complete blood count had results within normal limits. The serum lactate dehydrogenase level was 278 U/L (to convert to microkatal per liter, multiply by 0.0167). A chest radiographic image showed bibasilar infiltrates. An electrocardiogram was notable for atrial fibrillation, and echocardiography revealed normal left ventricular function, mild right atrial and ventricular dilatation, and severe tricuspid regurgitation (transtricuspid pressure gradient, 40 mm Hg). A contrast-enhanced computed tomography image revealed bilateral ground-glass opacities and right basilar consolidations, with no evidence of thromboembolisms (Figure, A). Para-aortic and inguinal lymphadenopathies were also noted. Presumptive diagnoses of pulmonary hypertension (PH) and right-sided heart failure were made. The patient began receiving dobutamine and furosemide, but she continuously required 2 to 10 L of oxygen, and further invasive evaluations could not be performed. An echocardiogram identified aggravating PH (transtricuspid pressure gradient, 57 mm Hg). A thorough physical examination identified scaly, crusty genital skin lesions pathologically compatible with extramammary Paget disease. The patient deteriorated and died despite treatment. An autopsy was performed (Figure, B).A, The chest computed tomography showed ground-glass opacities (white arrowheads) and consolidative lesions (a yellow arrowhead), but no evidence of thromboembolism was obtained. B, Hematoxylin-eosin stain of the lung showed proliferation of intimal fibromuscular cells with (yellow arrowheads) or without (black arrowheads) the presence of Paget cells. Yellow arrowheads show embolized Paget cells. The encircled area (black arrowheads) indicates the vascular lumen, the inside of which is filled with proliferated fibromuscular cells but not Paget cells (original magnification ×400). What Is Your Diagnosis?

Left ventricular systolic dysfunction

Sarcoidosis

Pulmonary tumor thrombotic microangiopathy

Chronic thromboembolic pulmonary hypertension

C. Pulmonary tumor thrombotic microangiopathy

C

Pulmonary tumor thrombotic microangiopathy

The salient features of this case are the subacute exacerbation of right-sided heart failure and PH, along with ground-glass opacities on computed tomography and genital skin lesions. Pulmonary thromboembolism must be considered, but no evidence of thromboembolism was confirmed on imaging. With this in mind, clinicians must consider alternative causative mechanisms for worsening right-sided heart failure and PH, such as pulmonary tumor thrombotic microangiopathy (PTTM) and acute exacerbation of chronic thromboembolic pulmonary hypertension. For this patient, PTTM is the leading hypothesis, given her skin lesions, lymphadenopathies, and pathological findings compatible with extramammary Paget disease. No evidence of left ventricular systolic dysfunction was obtained by ultrasonography. Although sarcoidosis can cause PH, her medical history and pathology results were incompatible with this diagnosis.Pulmonary artery wedge sampling could not be performed for this patient because of the unstable, rapidly deteriorating clinical course. Three weeks after admission, her hypoxia became aggravated and she required noninvasive positive-pressure ventilation. She died despite treatment, and an autopsy revealed multiple gross metastases of Paget disease, including to the lymph nodes and adrenal glands. In the lungs, a gross metastasis in the right lower lobe and lymphangitis carcinoma were noted. In addition, tumor cell microembolism was identified in small pulmonary arteries and arterioles with fibrocellular and fibromuscular proliferation of the vascular wall (Figure, B).Pulmonary tumor thrombotic microangiopathy is characterized by widespread tumor cell microemboli, along with fibrocellular and fibromuscular proliferation in the small arteries and arterioles in the lungs. This causes occlusion of the pulmonary vasculature and subsequent PH. Direct hematogenous or lymphatic metastases are suggested to permit cancer cells to enter the venous system via the thoracic duct and pulmonary circulation.1 Cytokines, such as vascular endothelial growth factor and platelet-derived growth factor, may play critical roles in the pathogenesis.2 The most common cause of PTTM is gastric adenocarcinoma, followed by lung and breast carcinomas.3 Several reports also identified extramammary Paget disease as a rare entity for PTTM.4Patients with PTTM present with an acute or subacute cor pulmonale.1 This disease progresses rapidly, with a median time from the oxygen supplementation to death of 9 days.3 Although the differential diagnoses remain broad, a combination of progressive dyspnea and normal imaging findings should prompt the immediate consideration of PTTM. For this patient, the genital skin lesions raised the suspicion of skin cancer and PTTM.No specific laboratory or imaging studies exist for making the diagnosis. Microangiopathic hemolytic anemia or disseminated intravascular coagulation may emerge in the advanced stages.5 Imaging is usually nonspecific but may be appropriate to rule out alternative causes, notably pulmonary thromboembolism. Several cases of PTTM were diagnosed by positron emission tomography–computed tomography scanning,6 but its diagnostic accuracy remains questionable.3 Despite its diagnostic difficulties,7 pathological identification of tumor cells may lead to the antemortem, definitive diagnosis of PTTM and appropriate treatment of underlying malignant conditions. Performing the pulmonary wedge aspiration may be appropriate for patients with severe illness because of its limited invasiveness.Because PTTM has an almost complete case-fatality rate, treatment of underlying malignant conditions is the cornerstone of management.5 Several case reports identified imatinib as a treatment option to increase the survival rate and alleviate pulmonary hypertension associated with PTTM.8This case highlights the importance of considering PTTM as a differential diagnosis in patients presenting with a combination of aggravating dyspnea, PH, and normal pulmonary imaging findings. A high index of suspicion allows clinicians to perform both the treatment of the underlying malignant condition and advanced-care planning appropriately.

Oncology

An 82-year-old woman presented with dyspnea on exertion and weight gain of 5 kg over the past month. Her medical history included atrial fibrillation and lung adenocarcinoma (a lung lobectomy was performed 8 years ago). Her blood pressure was 112/60 mm Hg, her heart rate was 100 beats per minute, her respiratory rate was 37 breaths per minute, her body temperature was 36.6°C, and her oxygen saturation was 100% while breathing 10 L of oxygen. A cardiac examination was clinically significant for an irregular rhythm, an increased pulmonic closure sound, and jugular venous distension. Bibasilar coarse crackles and pretibial edema were also noted. A complete blood count had results within normal limits. The serum lactate dehydrogenase level was 278 U/L (to convert to microkatal per liter, multiply by 0.0167). A chest radiographic image showed bibasilar infiltrates. An electrocardiogram was notable for atrial fibrillation, and echocardiography revealed normal left ventricular function, mild right atrial and ventricular dilatation, and severe tricuspid regurgitation (transtricuspid pressure gradient, 40 mm Hg). A contrast-enhanced computed tomography image revealed bilateral ground-glass opacities and right basilar consolidations, with no evidence of thromboembolisms (Figure, A). Para-aortic and inguinal lymphadenopathies were also noted. Presumptive diagnoses of pulmonary hypertension (PH) and right-sided heart failure were made. The patient began receiving dobutamine and furosemide, but she continuously required 2 to 10 L of oxygen, and further invasive evaluations could not be performed. An echocardiogram identified aggravating PH (transtricuspid pressure gradient, 57 mm Hg). A thorough physical examination identified scaly, crusty genital skin lesions pathologically compatible with extramammary Paget disease. The patient deteriorated and died despite treatment. An autopsy was performed (Figure, B).A, The chest computed tomography showed ground-glass opacities (white arrowheads) and consolidative lesions (a yellow arrowhead), but no evidence of thromboembolism was obtained. B, Hematoxylin-eosin stain of the lung showed proliferation of intimal fibromuscular cells with (yellow arrowheads) or without (black arrowheads) the presence of Paget cells. Yellow arrowheads show embolized Paget cells. The encircled area (black arrowheads) indicates the vascular lumen, the inside of which is filled with proliferated fibromuscular cells but not Paget cells (original magnification ×400).

what is your diagnosis?

What is your diagnosis?

Pulmonary tumor thrombotic microangiopathy

Chronic thromboembolic pulmonary hypertension

Sarcoidosis

Left ventricular systolic dysfunction

a

female

81-90

White

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2759250

A 61-year-old woman presented with pleuritic chest pain, shortness of breath, and syncope. She had a medical history of end-stage renal disease secondary to autosomal dominant polycystic kidney disease, after renal transplant 5 years prior. She had concomitant polycystic liver disease and had undergone right hepatectomy and cyst fenestration, plus inferior vena cava (IVC) stent placement for intrahepatic caval compression due to hepatic cysts 9 years earlier. Initial laboratory evaluation results revealed elevated creatinine levels with concern of renal graft failure. Physical examination results revealed a blood pressure of 96/65 mm Hg, an elevated jugular venous pressure with blunted Y-descent, Kussmaul sign, and distant heart sounds. Chest radiography results revealed cardiomegaly and the IVC stent was evident, adjacent to her heart (Figure, A). Echocardiography (Video 1 and Figure, B) revealed a large circumferential pericardial effusion, diastolic right ventricular collapse, and exaggerated respiratory variation (>25%) in the mitral inflow velocity but a normal inferior vena cava size.Chest radiography and transthoracic echocardiogram illustrating cardiomegaly and pericardial effusion in addition to visualization of the inferior vena cava stent. The transthoracic echocardiographic image is a parasternal long axis view, demonstrating the large circumferential pericardial effusion.Urgent vascular surgery referral for IVC stent removalInitiation of nonsteroidal anti-inflammatory drugs and colchicine and observation What Would You Do Next?

Urgent referral for cardiovascular surgery

Pericardiocentesis with pericardial drain placement

Urgent vascular surgery referral for IVC stent removal

Initiation of nonsteroidal anti-inflammatory drugs and colchicine and observation

Pericardial effusion with tamponade caused by an IVC stent impinging on the coronary sinus

B

Pericardiocentesis with pericardial drain placement

This patient presented with evidence of clinical cardiac tamponade and tamponade physiology on transthoracic echocardiography, including right ventricular diastolic collapse and a mitral inflow variation of more than 25% with respiration. The IVC is not plethoric, but this could be secondary to residual compression from hepatic cysts. The presenting chest pain was most likely associated with pericardial inflammation. Nonsteroidal anti-inflammatory agents would be contraindicated in the setting of renal failure and medical therapy and observation alone are not appropriate given the evidence of tamponade. A pericardiocentesis with pericardial drain placement for 24 to 48 hours is the most appropriate first course of action. For this case, urgent cardiac surgery would be appropriate if urgent pericardiocentesis is not feasible or is unsuccessful in relieving tamponade. Given the IVC stent was placed 9 years prior, it was well incorporated into the endothelium of the vessel and removal was not feasible. Therefore, vascular surgery consultation should not be prioritized over addressing cardiac tamponade.During the echocardiography-guided pericardiocentesis, a procedure which was first described in 1983,1 a 5-cm angiocatheter was advanced through skin and subcutaneous tissue in a left intercostal space, near her sternum, and into her pericardial sac, with return of bloody fluid. When the initially aspirated fluid is bloody, it is imperative to inject agitated saline via the angiocatheter (Video 2) before replacing the catheter with an introducer sheath to ascertain that the catheter is in the pericardial space rather than in a cardiac chamber. Eventually, a short pigtail catheter was inserted through an introducer sheath into her pericardial space. A cardiac sonographer monitored the procedure, using a subcostal transducer position outside the sterile field, and verified resolution of the pericardial effusion as 700 mL of bloody fluid was removed into a vacuum bottle that was connected to the intrapericardial catheter. The pericardial fluid hemoglobin levels was 8.8 g/dL (to convert to grams per liter, multiply by 10), which exceeded the blood hemoglobin level (6.8 g/dL). The finding of a hemoglobin level equal to or higher than blood hemoglobin implies at least transient communication of a blood vessel or cardiac chamber with the pericardial space. Given her clinical history, there was high suspicion for partial erosion of the IVC stent into her pericardial space. Her serum creatinine levels improved following the pericardiocentesis, allowing for performance of gated cardiac computed tomography angiography. This illustrated that the IVC stent was fractured in multiple places, and tines protruded outside the lumen of the vena cava into the pericardial space, impinging on the coronary sinus (Video 3). Cardiovascular surgery, vascular surgery, and interventional radiology were consulted, but intervention was deferred given the higher than usual risk of intervention. The pericardial effusion did not reaccumulate over 72 hours and the pericardial catheter was removed. Repeated transthoracic echocardiography, before hospital dismissal and approximately 1 month later, revealed a tiny pericardial effusion with no echocardiography features of tamponade, and therefore further observation was chosen.Hemopericardium is a pericardial effusion with a pericardial hemoglobin level higher than 50% of the serum hemoglobin, and historical literature estimates that hemorrhagic pericardial effusions account for almost 50% of pericardiocenteses performed.2-4 The most common cause of hemopericardium is now iatrogenic, associated with cardiac perforation during ablations and percutaneous coronary interventions, or in the setting of cardiovascular surgery.5 Any time there is an intracardiac device close to the endocardium (such as some cases of atrial septal defect and patent foramen ovale occluders) or an intravascular device close to the pericardium, device erosion should be considered. Among noniatrogenic causes, malignancy and complications of acute myocardial infarction or aortic dissection are most common.2 Initial treatment of hemopericardium includes observation, pericardiocentesis, or cardiovascular surgery. It has recently been shown that most patients with hemopericardium can avoid acute surgical intervention with rescue echo-guided pericardiocentesis, with the exceptions of hemopericardium in the setting of a short-term type A aortic dissection or myocardial rupture.5

Cardiology

A 61-year-old woman presented with pleuritic chest pain, shortness of breath, and syncope. She had a medical history of end-stage renal disease secondary to autosomal dominant polycystic kidney disease, after renal transplant 5 years prior. She had concomitant polycystic liver disease and had undergone right hepatectomy and cyst fenestration, plus inferior vena cava (IVC) stent placement for intrahepatic caval compression due to hepatic cysts 9 years earlier. Initial laboratory evaluation results revealed elevated creatinine levels with concern of renal graft failure. Physical examination results revealed a blood pressure of 96/65 mm Hg, an elevated jugular venous pressure with blunted Y-descent, Kussmaul sign, and distant heart sounds. Chest radiography results revealed cardiomegaly and the IVC stent was evident, adjacent to her heart (Figure, A). Echocardiography (Video 1 and Figure, B) revealed a large circumferential pericardial effusion, diastolic right ventricular collapse, and exaggerated respiratory variation (>25%) in the mitral inflow velocity but a normal inferior vena cava size.Chest radiography and transthoracic echocardiogram illustrating cardiomegaly and pericardial effusion in addition to visualization of the inferior vena cava stent. The transthoracic echocardiographic image is a parasternal long axis view, demonstrating the large circumferential pericardial effusion.Urgent vascular surgery referral for IVC stent removalInitiation of nonsteroidal anti-inflammatory drugs and colchicine and observation

what would you do next?

What would you do next?

Pericardiocentesis with pericardial drain placement

Initiation of nonsteroidal anti-inflammatory drugs and colchicine and observation

Urgent vascular surgery referral for IVC stent removal

Urgent referral for cardiovascular surgery

a

female

61-70

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2756312

A 29-year-old man with a history of reactive airway disease and eczema presented to the clinic with progressive odynophagia, hoarseness, and dysphagia of solids, liquids, and secretions for the past 6 months. There were no respiratory symptoms, and results of a complete head and neck physical examination were unremarkable. Flexible nasolaryngoscopy was performed and revealed erythema and swelling to the right arytenoid. A 2-week course of doxycycline was completed for presumed infectious supraglottitis without a change in symptoms. A biopsy and culture of the lesion was then collected in the office and revealed inflammatory disease but ultimately was nondiagnostic. The patient chose observation vs further workup at that time.The patient returned 6 months later with worsening symptoms. Repeat flexible nasolaryngoscopy was performed and revealed significant edema of the right arytenoid extending into the aryepiglottic fold, limiting the mobility of the right vocal fold (Figure 1). Microdirect laryngoscopy and biopsy under general anesthesia was performed, and a specimen was sent to the pathology department for permanent section analysis and flow cytometry. Permanent sections showed unremarkable squamous mucosa. Flow cytometry revealed mixed inflammatory infiltrate and an increased plasma cell component. Results of stains for infectious organisms were negative. Further immunohistochemical analysis confirmed the diagnosis. A full-body nuclear magnetic resonance positron emission tomography/computed tomography scan was performed to rule out systemic disease. What Is Your Diagnosis?

Laryngeal tuberculosis

Systemic lupus erythematosus

IgG4-related related disease

Churg-Strauss syndrome

C. IgG4-relateddisease

C

IgG4-related related disease

The patient was diagnosed with IgG4-related disease (IgG4-RD), which is a relatively new diagnosis that was first discussed as a unique clinical syndrome in 2003 involving the pancreas.1 The disease has since been characterized as a chronic fibroinflammatory condition with tumefactive lesions that can affect nearly every organ in the body; the exact pathogenesis is not completely understood.2,3 Presentation of the disease will most often occur in an elderly patient with a nonpainful mass.3 In 2010, Zen et al4 performed a cross-sectional analysis and identified the head and neck region as the third most common presentation of IgG4-RD; only systemic and pancreatic hepatobiliary presentations were more prevalent in their study.5 A diagnosis of IgG4-RD has been described within the head and neck region in the salivary glands, lacrimal glands, orbit, sinonasal region, thyroid, pituitary gland, ear, lymph nodes, and less commonly the pharynx.5Because of the masslike clinical presentation of the disease, it is often misdiagnosed as a malignant tumor or some form of granulomatous condition.6 Differential diagnosis of laryngeal masses include benign and malignant lesions such as laryngoceles, granulomatous reaction to tuberculosis, leprosy, syphilis, an autoimmune condition such as relapsing polychondritis, IgG4-RD, rheumatoid arthritis, vascular malformations such as Churg-Strauss syndrome, primary cancer, or metastatic disease. Histopathological analysis remains the criterion standard in obtaining a definitive diagnosis and ruling out other pathologies. Serum IgG4 levels can aid in diagnosis but are normal in roughly one-third of patients with IgG4-RD and therefore should not be used to rule out the disease.2 The hallmarks of the disease at the microscopic level are diffuse lymphoplasmacytic infiltrates, abundant IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia.6,7 Proposed guidelines for definitive diagnosis include: (1) presence of diffuse swelling or organ mass/mass lesion; (2) serum IgG4 levels more than 135 mg/dL (to convert to grams per liter, multiply by 0.01); and (3) positive histology. Treatment of IgG4-RD is most commonly accomplished with systemic corticosteroids but can also include surgical excision, rituximab, or a combination of these options.3 Remission ranges from 68% to 90% based on previous studies.5,8 Obtaining a positron emission tomography scan can be useful to identify systemic disease and monitor treatment response.9The patient was presumed to have an infectious cause but did not respond to antimicrobial therapy. In-office biopsy and culture were nondiagnostic. On return presentation due to increased symptomatology, a definitive diagnosis was sought via representative histological analysis. The hematoxylin-eosin cross-section (Figure 2A) is provided to highlight the characteristic storiform fibrosis, which can be appreciated on the right side of the slide, demonstrating multiple fibroblasts. The left side shows a higher density of the IgG4 secreting plasma cells that are better appreciated by the positive immunohistochemical stain (Figure 2B). Nuclear magnetic resonance positron emission tomography/computed tomography scan was performed to rule out systemic disease, and the patient was noted to have no other systemic disease outside of the supraglottis. The rheumatology department was consulted, and the patient started receiving an oral prednisone taper that improved his symptoms. Serum IgG4 levels were measured and decreased from 133.6 to 57.5 mg/dL over a 6-month period (normal range, 4-86 mg/dL). He was then transitioned to a mycophenolic acid regimen and remains free of symptoms to date.IgG-4–related disease detected on immunohistochemical stain (original magnification ×20) (A) and hematoxylin-eosin (H-E) stain (original magnification ×20) (B).

General

A 29-year-old man with a history of reactive airway disease and eczema presented to the clinic with progressive odynophagia, hoarseness, and dysphagia of solids, liquids, and secretions for the past 6 months. There were no respiratory symptoms, and results of a complete head and neck physical examination were unremarkable. Flexible nasolaryngoscopy was performed and revealed erythema and swelling to the right arytenoid. A 2-week course of doxycycline was completed for presumed infectious supraglottitis without a change in symptoms. A biopsy and culture of the lesion was then collected in the office and revealed inflammatory disease but ultimately was nondiagnostic. The patient chose observation vs further workup at that time.The patient returned 6 months later with worsening symptoms. Repeat flexible nasolaryngoscopy was performed and revealed significant edema of the right arytenoid extending into the aryepiglottic fold, limiting the mobility of the right vocal fold (Figure 1). Microdirect laryngoscopy and biopsy under general anesthesia was performed, and a specimen was sent to the pathology department for permanent section analysis and flow cytometry. Permanent sections showed unremarkable squamous mucosa. Flow cytometry revealed mixed inflammatory infiltrate and an increased plasma cell component. Results of stains for infectious organisms were negative. Further immunohistochemical analysis confirmed the diagnosis. A full-body nuclear magnetic resonance positron emission tomography/computed tomography scan was performed to rule out systemic disease.

what is your diagnosis?

What is your diagnosis?

IgG4-related related disease

Churg-Strauss syndrome

Systemic lupus erythematosus

Laryngeal tuberculosis

a

male

21-30

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2757027

A 31-year-old female patient presented with right nasal pain and radiating facial pain over the previous 3 years. She reported feeling a mass in her right nostril that had not changed in size, as well as associated nasal tenderness to the external nose, worsening pain with exposure to cold temperatures, and frequent sneezing. Prior to presentation, she had been prescribed fluticasone and loratadine for allergic rhinitis without resolution of symptoms. She denied difficulty breathing, epistaxis, rhinorrhea, fever, chills, weight loss, or night sweats. She was a nonsmoker and nondrinker. On physical examination, her external nose had no visible lesions. A rhinoscopy revealed normal mucosa with a submucosal, round, firm, tender lesion, measuring approximately 1 cm and located on the right anterior nasal septum. No drainage was visualized. Her turbinates appeared normal. The patient underwent surgical excision of the septal lesion under general anesthesia for definitive diagnosis. The specimen measured 1.1 × 0.7 × 0.2 cm and was erythematous, soft, vascular, and adherent, with a broad base to the anterior superior nasal septal mucosa just inferior to the upper lateral cartilage (Figure 1A and B). The lesion was excised down through the perichondrium.Endoscopic photographs. A, Intraoperative view and intraoperative photograph of a mucosal lesion on the anterior septum after the initial incision. B, Elevation with a suction shows attachments to the underlying perichondrium. What Is Your Diagnosis?

Glomus tumor

Inverted papilloma

Hemangiopericytoma

Paraganglioma

A. Glomus tumor

A

Glomus tumor

Histopathologic findings showed that no malignant neoplasm was identified (Figure 2A). Results from immunohistochemical analysis were positive for actin (Figure 2B), and stains for the E3 ubiquitin–protein ligase MIB1 protein demonstrated a low proliferation index (Figure 2C). The excised mass was composed of small, round cells arranged around vessels, and Figure 2D highlights this surrounding vasculature with CD31 immunostaining. Histopathological testing confirmed that this lesion was a glomus tumor, specifically a glomangioma. On histological testing, this lesion did not show the characteristic endophytic or inverted growth pattern seen in inverted papillomas, which consists of a markedly thickened squamous epithelial proliferation growing downward into the underlying connective tissue stroma. It also did not express the classic hyalinized, branching, staghorn, thin-walled vessels lined by flattened endothelium commonly seen in hemangiopericytomas.Histological findings. A, Hematoxylin-eosin–stained lesional specimen. Representative low-magnification photomicrograph demonstrated round tumor cells with indistinct borders. B, Immunohistochemical staining for actin, with positive results (arrowheads). C, Stain for E3 ubiquitin–protein ligase MIB1 protein, a marker for cellular proliferation, revealed a very low proliferation index (arrowheads). D, Immunohistochemical staining for CD31 highlighted branching vasculature. A-D, Original magnification ×40.A glomangioma is also not to be confused with a paraganglioma, which is often erroneously called a glomus tumor. Both types of lesions are markedly vascular, but they differ in most other ways. Immunohistochemically, glomus tumors are positive for smooth muscle actin, whereas paragangliomas are positive on staining for neuroendocrine markers, such as synaptophysin and chromogranin. Both of these tests were negative in this patient.1,2 Also, the vasculature in a glomus tumor, although branching, appears normal on histopathological testing compared with the vasculature in a paraganglioma. Glomus tumors are benign perivascular neoplasms that are commonly located in the distal extremities, particularly in the nail bed.3 Paragangliomas are rare, slow-growing neuroendocrine tumors arising from cells of neural-crest origin or paraganglionic tissue.4 They typically originate from the adrenal gland, but occur extra-adrenally in 5% to 10% of cases, including in the head and neck.5 While both lesions are rare in the nasal cavity, clinical and histopathological features differentiate the 2 diagnoses. Glomangiomas are rarely found in the head and neck, let alone the nasal cavity. In a study6 of 85 cases of vascular tumors of the nasal cavity, Fu and Perzin found only 1 glomangioma. Glomangiomas are derived from modified smooth muscle cells of the glomus body, which function as a thermoregulator through arteriovenous shunting of blood.3 Areas rich in glomus bodies include the subungal regions of digits or the deep dermis of the palm, wrist, and forearm; this explains the common occurrence of glomus tumors in these locations.3,7 Paragangliomas usually arise in 3 distinct anatomic locations: the carotid body (a carotid body tumor), jugulotympanic area (glomus jugulare and glomus tympanicum), and vagus nerve (glomus vagale).8 These lesions can arise from glomus cells (not to be confused with glomus bodies) that reside in carotid bodies as chemoreceptors and release catecholamines in response to hypoxic conditions.9 Although common in the head and neck, 1 study4 reported only 2 published cases of paragangliomas in the nasal cavity. The literature has erroneously referenced both types of lesions as glomus tumors, likely because of confusion between glomus bodies and glomus cells. This can complicate a cursory review of the literature. We hope this case clarifies the difference between glomangiomas and paragangliomas while emphasizing the need to broaden differential diagnosis for a nasal cavity mass.Glomangiomas are associated with a triad of symptoms of localized tenderness, cold insensitivity, and paroxysmal pain out of proportion to tumor size. All of these were seen in this patient.3,10 Most glomus tumors are benign. The standard curative treatment is complete surgical excision.7 In this case, the tumor was removed, and the area of lesion had remucosalized at the 3-month postoperative visit, with no evidence of recurrence at 1 year.

General

A 31-year-old female patient presented with right nasal pain and radiating facial pain over the previous 3 years. She reported feeling a mass in her right nostril that had not changed in size, as well as associated nasal tenderness to the external nose, worsening pain with exposure to cold temperatures, and frequent sneezing. Prior to presentation, she had been prescribed fluticasone and loratadine for allergic rhinitis without resolution of symptoms. She denied difficulty breathing, epistaxis, rhinorrhea, fever, chills, weight loss, or night sweats. She was a nonsmoker and nondrinker. On physical examination, her external nose had no visible lesions. A rhinoscopy revealed normal mucosa with a submucosal, round, firm, tender lesion, measuring approximately 1 cm and located on the right anterior nasal septum. No drainage was visualized. Her turbinates appeared normal. The patient underwent surgical excision of the septal lesion under general anesthesia for definitive diagnosis. The specimen measured 1.1 × 0.7 × 0.2 cm and was erythematous, soft, vascular, and adherent, with a broad base to the anterior superior nasal septal mucosa just inferior to the upper lateral cartilage (Figure 1A and B). The lesion was excised down through the perichondrium.Endoscopic photographs. A, Intraoperative view and intraoperative photograph of a mucosal lesion on the anterior septum after the initial incision. B, Elevation with a suction shows attachments to the underlying perichondrium.

what is your diagnosis?

What is your diagnosis?

Hemangiopericytoma

Paraganglioma

Glomus tumor

Inverted papilloma

c

female

31-40

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2758112

A 52-year-old man who had recently emigrated from Guatemala and had a history of asthma presented to the emergency department with exacerbation of long-standing dyspnea along with progressively worsening nasal congestion and dysphonia over the past 2 years. He was diagnosed with asthma 2 years earlier when he first started experiencing shortness of breath and had partial relief with inhaled albuterol treatments only. He had no history of fevers, dysphagia, odynophagia, cough, or allergies.On physical examination, moderately severe dysphonia characterized primarily by roughness with mild breathiness as well as mild inspiratory stridor were noted. Anterior rhinoscopy demonstrated large, bilateral obstructive nasal polyps. Flexible laryngoscopy revealed smooth, lobulated masses involving the epiglottis and right aryepiglottic fold. The epiglottic component extended inferiorly along the petiole, involving and obstructing the anterior glottis. The vocal fold mucosa was thickened, but bilateral mobility was intact with an adequate posterior glottic airway.Computed tomography demonstrated homogenous, isodense, laryngeal lesions that correlated with the previously mentioned laryngoscopy findings, but also showed subglottic stenosis approximately 2 cm in length secondary to the thickened intraluminal soft tissue (Figure, A). The cartilaginous laryngotracheal framework was preserved. The chest radiograph was unremarkable. The patient was taken to the operating room for direct laryngoscopy with endoscopic airway dilation and laryngeal mass biopsy (Figure, B, C, and D).A, Subglottic stenosis was noted on computed tomography (yellow arrowhead). Multifocal laryngeal masses were also observed, with the largest mass involving the epiglottic petiole and extending to obstruct the anterior glottis (black arrowhead). B, The arrowhead points to a smooth, lobulated mass involving the epiglottis and anterior glottis. C, Cotton-Meyer grade II subglottic stenosis was noted. D, Laryngeal mass biopsy results showed vacuolated macrophages with bacilli (yellow arrowhead) and eosinophilic inclusions within plasma cells (black arrowhead) (hematoxylin-eosin). What Is Your Diagnosis?

Amyloidosis

Granulomatosis with polyangiitis

Rhinoscleroma

Sarcoidosis

C. Rhinoscleroma

C

Rhinoscleroma

The patient presented with sinonasal, laryngeal, and tracheal findings suggestive of a systemic disease. The differential diagnosis included infectious disease (rhinoscleroma, tuberculosis, and various mycoses), neoplasm, and rheumatologic/inflammatory causes, such as granulomatosis with polyangiitis, sarcoidosis, and amyloidosis.1,2 Concurrent involvement of the sinonasal cavities and larynx/trachea narrowed the differential. The presence of vacuolated macrophages with bacilli (Mikulicz cells) and large, eosinophilic inclusions within plasma cells (Russell bodies) on the biopsy results confirmed the definitive diagnosis of rhinoscleroma.2Rhinoscleroma is a bacterial infection caused by Klebsiella rhinoscleromatis, which is a gram-negative, facultative anaerobe. Most cases occur in eastern and central Europe, Mexico, Central and South America, Africa, India, and Indonesia. Transmission is postulated to be airborne, requiring long-term close contact.2-4 Patients often have symptoms for approximately 3 years before diagnosis.5 It most commonly affects the nose (≥95% of cases), but may also affect the nasopharynx, paranasal sinuses, larynx, trachea, bronchi, and skin.5,6 Clinical manifestations vary depending on the stage of the disease, which has a slow, progressive course.There are 3 stages of infection: catarrhal, granulomatous, and sclerotic.2 The catarrhal stage is the earliest stage, lasting weeks to months, and is typified by purulent rhinorrhea and nasal obstruction. Examination findings include nasal crusting and mucosal atrophy. Vocal fold edema and/or thickening and more diffuse erythema or exudates may be encountered when the larynx is involved.7 Patients in the granulomatous stage may experience more extensive symptoms such as epistaxis, anosmia, nasal deformity, epiphora, and dysphonia. Granulomas can develop throughout the upper respiratory tract, from the nasal cavities to the subglottis.2,6,7 These lesions may appear tumorlike and are more common in the glottis than the subglottis,7 as was seen in this patient. Transition to the sclerotic stage occurs over months to years and entails dense fibrotic infiltration surrounding granulomatous lesions.2 In the larynx and trachea, this sclerosis could lead to circumferential stenosis and airway compromise, which was also observed in the present case.Diagnosis of rhinoscleroma requires histologic examination and cultures. As previously mentioned, Mikulicz cells (foamy macrophages that failed to phagocytose bacilli) and Russell bodies are indicative of rhinoscleroma (Figure, D).2,5Klebsiella rhinoscleromatis can also be detected on culture in blood agar or MacConkey agar.2 Treatment for rhinoscleroma necessitates a long-term course of antibiotics (3 months of ciprofloxacin, 500 mg, twice daily or a combination of trimethoprim, 80 mg; sulfamethoxazole, 400 mg; and rifampin, 300 mg, twice daily).6 After 3 months, multiple nasal punch biopsies of initially involved areas are performed to assess for residual bacilli; if present, treatment would continue for another 3 months. Clinical improvement occurs at approximately 5 to 6 weeks, but clearance of histopathologic and microbial specimens typically requires 12 to 16 weeks.6 The recurrence rate is approximately 25% to 41% in the 10 years after treatment, possibly owing to incomplete treatment.5,6 Surgical interventions may be indicated to alleviate complications arising from different sites of anatomic involvement.Amyloidosis can affect either the larynx (the most common site in the head and neck region) or sinonasal cavities, but rarely both concurrently. Laryngeal amyloid deposits could have a similar gross appearance as in the present case but have an amorphous eosinophilic appearance on hematoxylin-eosin staining and exhibit apple-green birefringence on Congo red staining. Granulomatosis with polyangiitis frequently causes subglottic stenosis but rarely involves the larynx.8 Histologic signs are characteristic of vasculitis and include granulomas. Sarcoidosis can also demonstrate granulomas on biopsy results but manifests in the larynx as diffuse thickening of the epiglottis, which is different from the mass lesions seen in the present case.With an increasing number of cases of rhinoscleroma reported in the United States,2,7 familiarity with its clinical presentation is important. Diagnosis relies on pathological or microbiological examinations for confirmation. Both medical and surgical treatments are often needed to address the primary infection and its sequelae.

General

A 52-year-old man who had recently emigrated from Guatemala and had a history of asthma presented to the emergency department with exacerbation of long-standing dyspnea along with progressively worsening nasal congestion and dysphonia over the past 2 years. He was diagnosed with asthma 2 years earlier when he first started experiencing shortness of breath and had partial relief with inhaled albuterol treatments only. He had no history of fevers, dysphagia, odynophagia, cough, or allergies.On physical examination, moderately severe dysphonia characterized primarily by roughness with mild breathiness as well as mild inspiratory stridor were noted. Anterior rhinoscopy demonstrated large, bilateral obstructive nasal polyps. Flexible laryngoscopy revealed smooth, lobulated masses involving the epiglottis and right aryepiglottic fold. The epiglottic component extended inferiorly along the petiole, involving and obstructing the anterior glottis. The vocal fold mucosa was thickened, but bilateral mobility was intact with an adequate posterior glottic airway.Computed tomography demonstrated homogenous, isodense, laryngeal lesions that correlated with the previously mentioned laryngoscopy findings, but also showed subglottic stenosis approximately 2 cm in length secondary to the thickened intraluminal soft tissue (Figure, A). The cartilaginous laryngotracheal framework was preserved. The chest radiograph was unremarkable. The patient was taken to the operating room for direct laryngoscopy with endoscopic airway dilation and laryngeal mass biopsy (Figure, B, C, and D).A, Subglottic stenosis was noted on computed tomography (yellow arrowhead). Multifocal laryngeal masses were also observed, with the largest mass involving the epiglottic petiole and extending to obstruct the anterior glottis (black arrowhead). B, The arrowhead points to a smooth, lobulated mass involving the epiglottis and anterior glottis. C, Cotton-Meyer grade II subglottic stenosis was noted. D, Laryngeal mass biopsy results showed vacuolated macrophages with bacilli (yellow arrowhead) and eosinophilic inclusions within plasma cells (black arrowhead) (hematoxylin-eosin).

what is your diagnosis?

What is your diagnosis?

Rhinoscleroma

Amyloidosis

Granulomatosis with polyangiitis

Sarcoidosis

a

male

51-60

Black

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2757852

A healthy woman in her 60s was referred by her dentist to an oral surgeon for evaluation of a palatal swelling of unknown duration. The patient first presented to her dentist with a complaint of “it feels like there is something on the roof of [her] mouth.” She was never aware of the palatal lesion before her initial presentation. She denied any pain or discomfort from the site, and stated that the increasing size of the mass was what first alerted her to its presence.The extraoral examination results were within normal limits, with no evidence of swelling, expansion, trismus, or lymphadenopathy. Intraoral examination revealed a focally ulcerated, fluctuant 2.5 × 2 × 1-cm pink-red submucosal swelling in the right palatal mucosa (Figure, A). The lesion involved almost the entire right side of the hard palatal mucosa and soft palate and terminated at the palatal midline. Imaging studies were unremarkable.A, A clinical image shows a diffuse, right-sided palatal swelling with a focal ulceration. B, A photomicrograph shows sheets of large lymphocytes with a moderate amount of cytoplasm and round to oval nuclei containing vesicular chromatin and 2 to 3 small nucleoli (hematoxylin-eosin, original magnification ×200). The lesional cells stained positively with CD20 (inset) (original magnification, ×400).An incisional biopsy of the lesion was performed and showed fibrous connective tissues infiltrated by inflammatory cells arranged in a diffuse, sheetlike pattern. The cells were large with a moderate amount of cytoplasm and appeared to be round to oval vesicular nuclei with vesicular chromatin and 2 to 3 small nucleoli (Figure, B). The cells stained positively with CD45, CD20 (Figure, B, inset), CD79, CD21, BCL6, and BCL2 antibodies. What Is Your Diagnosis?

Pleomorphic adenoma

Angioleiomyoma

Diffuse large B-cell lymphoma

Mucoepidermoid carcinoma

C. Diffuse large B-cell lymphoma

C

Diffuse large B-cell lymphoma

Non-Hodgkin lymphoma represents a broad spectrum of hematologic malignant neoplasms that may present either with nodal or extranodal sites. The majority of non-Hodgkin lymphoma of the oral cavity present as an extranodal mass. In addition, diffuse large B-cell lymphoma (DLBCL) is the most common type and accounts for 60% of oral cavity lymphomas.1,2 It is defined by the presence of characteristic malignant lymphoid cells that have nuclei equal to or larger than a macrophage nucleus or more than double that of a standard lymphocyte nucleus.3 Although DLBCLs may affect patients of any age, most cases are reported in patients in their sixth to seventh decade of life.3 The cause of DLBCL remains unknown, and it occurs either de novo or represents an aggressive transformation of an indolent lymphoma.3The clinical appearance of DLBCL is often nonspecific, especially intraorally, where it typically presents as a diffuse, nontender swelling involving the palate, gingiva, or buccal mucosa, among other sites.4 The microscopic features of DLBCL are equally as diverse, and it can broadly be divided into 4 morphologic subcategories: centroblastic, immunoblastic, T-cell/histiocyte rich, and anaplastic.5 Although the centroblastic variant is seen most frequently, there is often poor intraobserver and interobserver reproducibility when identifying these subtypes.5 Diffuse large B-cell lymphoma is also classified as either germinal center type (GCB) or activated B-cell type (ABC) based on molecular profiling.6 These subtypes convey different prognoses, and the GCB type often shows improved responses to therapy. Unfortunately, most cases of head and neck DLBCL are of the ABC subtype.7 Because of the nonspecific microscopic features of DLBCL, immunohistochemical studies and genetic testing play critical roles in diagnosis. Diffuse large B-cell lymphoma classically expresses pan-B markers, such as CD19, CD20, CD22, and CD79a; however, the amount of positivity may be limited based on the degree of cellular differentiation.3 Diffuse large B-cell lymphoma may demonstrate clonal rearrangement in both immunoglobulin heavy and light chain genes and show somatic hypermutation in various genes. Translocations of BCL2, BCL6, and MYC genes have all been detected with varying frequencies in cases of DLBCL.6,7Lymphoma staging follows the Ann Arbor classification, which is based on the number and location of nodal and extranodal regions as well as the presence of any systemic symptoms.3 Important prognostic factors for DLBCL include patient age, serum lactate dehydrogenase levels, performance status, and clinical stage.8 These features are used to calculate an International Prognostic Index score, which in turn estimates 5-year survival. Although DLBCL is considered an aggressive malignant tumor, it is potentially curable nowadays with rituximab and multiagent chemotherapy.9Intraoral lymphomas are uncommon, albeit serious, malignant tumors that are often challenging to diagnose owing to their nonspecific clinical presentation. Clinicians should appreciate that palatal swellings, despite their sometimes indolent or subtle clinical appearance, may represent malignant neoplasms such as lymphoma. Early detection and definitive diagnosis are of pivotal importance for prevention of widespread disease and better survival outcomes.

General

A healthy woman in her 60s was referred by her dentist to an oral surgeon for evaluation of a palatal swelling of unknown duration. The patient first presented to her dentist with a complaint of “it feels like there is something on the roof of [her] mouth.” She was never aware of the palatal lesion before her initial presentation. She denied any pain or discomfort from the site, and stated that the increasing size of the mass was what first alerted her to its presence.The extraoral examination results were within normal limits, with no evidence of swelling, expansion, trismus, or lymphadenopathy. Intraoral examination revealed a focally ulcerated, fluctuant 2.5 × 2 × 1-cm pink-red submucosal swelling in the right palatal mucosa (Figure, A). The lesion involved almost the entire right side of the hard palatal mucosa and soft palate and terminated at the palatal midline. Imaging studies were unremarkable.A, A clinical image shows a diffuse, right-sided palatal swelling with a focal ulceration. B, A photomicrograph shows sheets of large lymphocytes with a moderate amount of cytoplasm and round to oval nuclei containing vesicular chromatin and 2 to 3 small nucleoli (hematoxylin-eosin, original magnification ×200). The lesional cells stained positively with CD20 (inset) (original magnification, ×400).An incisional biopsy of the lesion was performed and showed fibrous connective tissues infiltrated by inflammatory cells arranged in a diffuse, sheetlike pattern. The cells were large with a moderate amount of cytoplasm and appeared to be round to oval vesicular nuclei with vesicular chromatin and 2 to 3 small nucleoli (Figure, B). The cells stained positively with CD45, CD20 (Figure, B, inset), CD79, CD21, BCL6, and BCL2 antibodies.

what is your diagnosis?

What is your diagnosis?

Diffuse large B-cell lymphoma

Angioleiomyoma

Mucoepidermoid carcinoma

Pleomorphic adenoma

a

female

61-70

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2759435

A man in his 30s presented to an outside emergency department with left-sided otalgia and periauricular swelling. He was discharged after being prescribed oral antibiotics but continued to have worsening symptoms and returned to the outside facility, where a noncontrasted computed tomographic (CT) scan of the neck and chest showed significant subcutaneous emphysema of the neck and mediastinum (Figure, A and B). He was subsequently transferred to our facility for additional treatment.A. Intraluminal air in the left parotid duct with associated pneumoparotid and dissection of air into the left parapharyngeal and masticator spaces. Pneumoparotid is also noted on the right. B. Inferior dissection of subcutaneous emphysema resulting in pneumomediastinum. Air has dissected around the left common carotid artery near its origin from the aortic arch. C. Frothy air bubbles milked from the parotid duct with external massage of the parotid gland.On evaluation, the patient noted a week of worsening facial swelling, neck pain, dysphagia, and odynophagia. Importantly, the patient noted that he was capable of a “party trick” which involved puffing out his cheeks to force air into his neck with subsequent decompression of air back into his oral cavity by pushing behind his ear. This became a habitual behavior, which the patient performed multiple times per day. On examination, there was a tender, fluctuant pocket of the left neck near the angle of the mandible without significant crepitus (Video). Additional examination findings are demonstrated in the Figure, C. What Is Your Diagnosis?

Esophageal perforation

Necrotizing fasciitis

Spontaneous pneumomediastinum

Pneumoparotid

D. Pneumoparotid

D

Pneumoparotid

Pneumoparotid is characterized by retrograde movement of air through the parotid duct, or Stensen duct, into proximal structures of the parotid gland owing to increased intraoral pressures. Simultaneous parotid inflammation or infection by oral bacteria produces pneumoparotitis. Dissection of air through the parotid capsule can produce subcutaneous emphysema of the head and neck.1 Given its rarity, descriptions of pneumoparotitis and its treatments are limited to case reports and series, which include patients with unilateral or bilateral pneumoparotid from behavioral and iatrogenic causes.2 It occurs in patients who habitually expire against a closed or resisted oral aperture, such as wind instrumentalists and glass blowers.1,3 Multiple cases have been documented in children with psychiatric disorders.4 It has also been described from use of compressed air during dental procedures and positive pressure associated with anesthesia.2,5Pneumoparotid occurs with ingress of air through the parotid papilla and subsequent proximal, retrograde extension during intense or sustained positive pressure from the oral cavity. Diagnosis of pneumoparotid is frequently delayed owing to its rarity and similarity to parotitis on presentation.4,6 Behaviors and risk factors associated with pneumoparotid can be elicited by taking a thorough medical history. On examination crepitus can sometimes be palpated overlying the gland.4 Frothy secretions or bubbles can be milked from the parotid gland, or a patulous duct orifice can be visualized and probed.6 Radiographic workup includes sialography and CT, which is diagnostic.2,7 Sialography shows ductal dilation and beading with filling defects due to intraluminal air. A CT scan demonstrates characteristic presence of air in the parotid duct and parenchyma.2,5,7Increased pneumatic pressure in the parotid architecture can rupture ductal or acinar structures and penetrate the parotid capsule producing subcutaneous emphysema.1,4,6 If dissection proceeds inferiorly along fascial planes, pneumomediastinum can occur.1,8 Association of pneumomediastinum with pneumoparotid is only rarely reported in the literature.Primary treatment of pneumoparotid is conservative and includes gland massage, sialagogues, warm compresses, and antibiotics if pneumoparotitis is suspected. Patients with behavioral pneumoparotid are advised to discontinue causal behaviors,4,6 which is usually curative.2 Children with associated psychiatric disorders have responded to behavioral and psychiatric therapies.4 Wind musicians have responded to embouchure modification by increasing buccinator flexion3 or by no longer playing the instrument.Previous authors have attempted various interventions in patients for whom conservative and behavioral therapy has failed. Fine needle aspiration with decompression of intraparotid air has been used for diagnosis as well as therapy.5 Sialoendoscopy with steroid irrigation may have therapeutic benefit by reducing inflammation and promoting normal anterograde physiology of the duct.9 Modified use of the Wilkie-Brody results in translocation of the parotid duct papilla from its normal anatomic location to the tonsillar fossa to prevent retrograde flow with increased intraoral pressure.6,10 However, the procedure confers relatively considerable postoperative morbidity.10Parotid duct ligation has been proposed by Han et al.7 Ligation confers less surgical morbidity than the Wilkie-Brody procedure, but can result in transient swelling and discomfort of the parotid gland, and in the setting of active infection can lead to worsening parotitis and development of parotid abscess. Following ligation, the parotid gland undergoes acinar atrophy and gland involution.7 In the setting of failed treatments with persistent recurrent pneumoparotitis, most authors advocate for parotidectomy.2,4This patient had no medical history to suggest esophageal perforation, such as recent esophageal procedures, foreign body or caustic ingestion, or severe vomiting. Necrotizing fasciitis would present with severe pain, fever, cellulitis, and leukocytosis. Although spontaneous pneumomediastinum can travel superiorly along fascial planes into the parapharyngeal and masticator spaces, the patient’s medical history was consistent with pneumoparotid as the primary diagnosis. In addition, spontaneous pneumomediastinum would not cause radiologic findings of air in the parotid duct and parenchyma.

General

A man in his 30s presented to an outside emergency department with left-sided otalgia and periauricular swelling. He was discharged after being prescribed oral antibiotics but continued to have worsening symptoms and returned to the outside facility, where a noncontrasted computed tomographic (CT) scan of the neck and chest showed significant subcutaneous emphysema of the neck and mediastinum (Figure, A and B). He was subsequently transferred to our facility for additional treatment.A. Intraluminal air in the left parotid duct with associated pneumoparotid and dissection of air into the left parapharyngeal and masticator spaces. Pneumoparotid is also noted on the right. B. Inferior dissection of subcutaneous emphysema resulting in pneumomediastinum. Air has dissected around the left common carotid artery near its origin from the aortic arch. C. Frothy air bubbles milked from the parotid duct with external massage of the parotid gland.On evaluation, the patient noted a week of worsening facial swelling, neck pain, dysphagia, and odynophagia. Importantly, the patient noted that he was capable of a “party trick” which involved puffing out his cheeks to force air into his neck with subsequent decompression of air back into his oral cavity by pushing behind his ear. This became a habitual behavior, which the patient performed multiple times per day. On examination, there was a tender, fluctuant pocket of the left neck near the angle of the mandible without significant crepitus (Video). Additional examination findings are demonstrated in the Figure, C.

what is your diagnosis?

What is your diagnosis?

Esophageal perforation

Spontaneous pneumomediastinum

Necrotizing fasciitis

Pneumoparotid

d

male

31-40

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2758417

A woman in her 30s was referred for evaluation of corneal opacities. Her medical history was notable for keratoconjunctivitis sicca, Hashimoto thyroiditis, and anti–interferon-γ autoantibody syndrome treated with 6 monthly rituximab infusions (375 mg/m2 with 100 mg of methylprednisolone acetate). Infusions were given weekly for the first 3 weeks and then every 6 to 8 months based on a CD20 count. She had previously been diagnosed with disseminated Mycobacterium avium complex (MAC) infection requiring 2 years of treatment with rifabutin, 300 mg/d; ethambutol hydrochloride, 1000 mg/d; and clarithromycin in a divided dose, 500 mg twice a day. This treatment concluded 2½ years before presentation. In addition, she had a long-standing history of arthralgias with intermittent arthritis treated with hydroxychloroquine, 300 mg/d, that was discontinued 2 years before presentation. On examination, she had no visual concerns. Her visual acuity was 20/20 OU. Conjunctivas were normal, lenses were clear, and anterior chambers were deep and quiet. The results from the slitlamp examination showed numerous bilateral, peripheral light brown corneal opacities. The opacities were located in the far posterior corneae and were present circumferentially (Figure, A). There was no associated keratitis or corneal neovascularization. Anterior segment optical coherence tomographic findings showed focal areas of hyperreflectivity anterior to the Descemet membrane. Confocal microscopy revealed variably shaped, hyperreflective clusters of opacities just anterior to the endothelium (Figure, B).Imaging of the right eye of a patient with rifabutin-related posterior corneal deposits. A, Slitlamp photograph with arrowhead highlighting one of numerous bilateral peripheral, small corneal light brown opacities. B, Confocal microscopic image captured at a slightly oblique angle illustrates normal endothelial cells (yellow arrowhead). Just anterior to the endothelium, the drug deposit appears as variably shaped, hyperreflective clusters of opacities (white arrowhead). What Would You Do Next?

Start treatment with topical corticosteroids

Start treatment with topical antibiotics

Plan a descemetorhexis and posterior cornea biopsy

Reassure the patient and observe

Rifabutin-related posterior corneal deposits

D

Reassure the patient and observe

Treatment with topical corticosteroids (choice A) or antibiotics (choice B) is not the recommended choice because the eyes had no signs of inflammation or infection. The anterior chambers were quiet, and there was no corneal infiltration or vitritis. Biopsy of the posterior cornea (choice C) may help define the underlying abnormality as deposits but would be an invasive and morbid procedure for a benign process. Clinical recognition of these lesions as visually insignificant drug-related deposits is essential to the appropriate decision to reassure the patient and observe (choice D).Rifabutin is a potent antimycobacterial agent used in both the prophylaxis for and treatment of MAC infection. Although uveitis is a well-known toxic effect of rifabutin,1 irreversible corneal deposits have also been reported. Rifabutin-associated corneal deposits are described as having a stellate or polymorphous shape, peripheral location, and yellow-white or yellow-brown color.2 In all reports, including cases with involvement of the central cornea, the deposits are visually insignificant.2 Although most drug-related corneal deposits occur in the epithelium or stroma, rifabutin-associated deposits have been described as endothelial.3 To our knowledge, there is only 1 case report of in vivo confocal microscopy of these lesions in which the authors localized the deposits to the deep stroma.4 The report of the present patient used confocal microscopy to confirm a deposition pattern just anterior to the Descemet membrane.Many medications given for systemic effect can result in drug-related corneal deposits, some of which include amiodarone, indomethacin, tamoxifen, hydroxychloroquine, and gold.5 Notably, this patient had received earlier treatment with hydroxychloroquine. The use of hydroxychloroquine is associated with corneal verticillata, which are whorled salt deposits typically found in the epithelium. In addition, verticillata have been shown to disappear after cessation of drug treatment. In contrast, rifabutin deposits are found in the posterior cornea and are irreversible, persisting and, in some cases, darkening and increasing in density after drug treatment cessation.6,7Deposition appears correlated with the duration of therapy. In a study of children who were HIV positive and taking rifabutin for MAC prophylaxis, treatment duration was associated with a greater likelihood of deposit formation.8 In another case report,2 a patient with recurrent MAC infection developed corneal deposits during his second round of rifabutin therapy. During a third course, the deposits increased in density and appeared centrally. In the patient of the present study, the deposits were first noted by the referring ophthalmologist 19 months after drug initiation in the inferior corneas only. During her 2-year course of rifabutin, they progressed circumferentially to involve the entire peripheral cornea. The lesions persisted after cessation of rifabutin therapy. This pattern of circumferential progression with time may suggest a cumulative dose- or time-dependent risk for the development and density of corneal deposits with rifabutin therapy. However, additional clinical, genetic, or environmental factors are likely involved, since only a subset of patients treated with rifabutin develop these deposits.8,9The cause of rifabutin-associated corneal deposits is not well understood. Most case reports have involved patients with compromised immune systems, either because of HIV infection, pharmacologic immunosuppression for the treatment of autoimmune disease, or, as we now report, anti–interferon-γ autoantibody syndrome.2 While these reports raise the question of an association between the drug deposits and a compromised immune system, MAC infections requiring long-term rifabutin therapy occur nearly exclusively in immunosuppressed individuals.10 Therefore, it is not clear that immunosuppression plays a directly causal role in the development of these deposits.

Ophthalmology

A woman in her 30s was referred for evaluation of corneal opacities. Her medical history was notable for keratoconjunctivitis sicca, Hashimoto thyroiditis, and anti–interferon-γ autoantibody syndrome treated with 6 monthly rituximab infusions (375 mg/m2 with 100 mg of methylprednisolone acetate). Infusions were given weekly for the first 3 weeks and then every 6 to 8 months based on a CD20 count. She had previously been diagnosed with disseminated Mycobacterium avium complex (MAC) infection requiring 2 years of treatment with rifabutin, 300 mg/d; ethambutol hydrochloride, 1000 mg/d; and clarithromycin in a divided dose, 500 mg twice a day. This treatment concluded 2½ years before presentation. In addition, she had a long-standing history of arthralgias with intermittent arthritis treated with hydroxychloroquine, 300 mg/d, that was discontinued 2 years before presentation. On examination, she had no visual concerns. Her visual acuity was 20/20 OU. Conjunctivas were normal, lenses were clear, and anterior chambers were deep and quiet. The results from the slitlamp examination showed numerous bilateral, peripheral light brown corneal opacities. The opacities were located in the far posterior corneae and were present circumferentially (Figure, A). There was no associated keratitis or corneal neovascularization. Anterior segment optical coherence tomographic findings showed focal areas of hyperreflectivity anterior to the Descemet membrane. Confocal microscopy revealed variably shaped, hyperreflective clusters of opacities just anterior to the endothelium (Figure, B).Imaging of the right eye of a patient with rifabutin-related posterior corneal deposits. A, Slitlamp photograph with arrowhead highlighting one of numerous bilateral peripheral, small corneal light brown opacities. B, Confocal microscopic image captured at a slightly oblique angle illustrates normal endothelial cells (yellow arrowhead). Just anterior to the endothelium, the drug deposit appears as variably shaped, hyperreflective clusters of opacities (white arrowhead).

what would you do next?

What would you do next?

Reassure the patient and observe

Plan a descemetorhexis and posterior cornea biopsy

Start treatment with topical corticosteroids

Start treatment with topical antibiotics

a

female

31-40

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2758931

A 41-year-old man presented for evaluation of 2 weeks of blurred vision and pain in the left eye. The onset of vision decrease coincided with muscle pain, joint swelling, and headache. All of the symptoms except blurry vision resolved spontaneously after 3 days. Over the preceding 5 months, he had had approximately monthly similar episodes consisting of a few days of flulike symptoms and blurry vision, with full recovery between episodes. At the time of evaluation, the vision was decreased in the left eye, with pain in both eyes and deep throbbing in the back of the left eye.Visual acuity was 20/20 OD and counting fingers at 1 ft OS, with visual field constriction and a relative afferent pupillary defect in the left eye. The examination of the anterior segment bilaterally was unremarkable, as was the posterior segment examination of his right eye. However, the fundus examination of the left eye showed extensive optic nerve swelling, with nerve fiber layer hemorrhage at the inferior temporal disc margin and peripapillary subretinal fluid extending to the macula (Figure 1). Magnetic resonance imaging (MRI) of the orbits showed anterior swelling of the left optic nerve without masses or hyperintensity of the retrobulbar optic nerve. Brain MRI results were normal.Optic nerve imaging at time of presentation. Optical coherence tomography (A) and fundus photography (B) of the left optic nerve at time of presentation showing broad optic nerve swelling with nerve fiber layer hemorrhage and fluid extending to macula. What Would You Do Next?

Magnetic resonance angiography of the neck

Blood testing for infectious and inflammatory agents

Treatment with oral prednisone

Observation

Bartonella henselae neuroretinitis (cat scratch disease)

B

Blood testing for infectious and inflammatory agents

The differential diagnoses of unilateral anterior swelling of the optic disc in a healthy patient includes optic neuritis, orbital compression, and other inflammatory causes or infection. Nonarteritic anterior ischemic optic neuropathy would be unusual in this age group. Normal MRI excludes orbital compression. This and severity of the disc swelling also make demyelinating or neuromyelitis optica spectrum optic neuritis unlikely. The associated systemic manifestations favor an infectious or inflammatory cause. Therefore, inflammatory and infectious serologic testing (choice B) is the preferred response. Magnetic resonance imaging of the neck (choice A) would not be the preferred answer because the case is not consistent with ischemic vision loss owing to arterial disease. Observation (choice D) is not the preferred choice because some etiologies diagnosed by blood testing may require directed therapy. Oral prednisone (choice C) is not the preferred choice because this is contraindicated as monotherapy in infectious etiologies.Erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, quantiferon gold, HIV, rapid plasma reagin, Lyme IgG/IgM, toxoplasmosis IgG/IgM, B henselae IgG/IgM, and antiphospholipid panel results showed mild elevation of C-reactive protein level, positive B henselae IgG (1:512), and negative IgM. On follow-up examination 3 weeks after symptom onset, macular star was noted (Figure 2).Optic nerve appearance 2 weeks after initial presentation. Optos fundus images show persistent severe optic nerve swelling, macular edema, and macular star.The ocular manifestations of B henselae include neuroretinitis, optic neuropathy, anterior uveitis, choroidal neovascularization, focal retinitis/choroiditis, and/or vitritis. Although neuroretinitis is the most common presentation of posterior segment involvement in cat scratch disease, the presence of isolated disc swelling is the early manifestation of this disease.1,2 The presence of macular star is a characteristic hallmark of B henselae neuroretinitis but may not develop in all patients and is often absent early in the presentation.3 Macular star is not specific for neuroretinitis,4 also occurring in anterior ischemic optic neuropathy, disc tumor, papilledema, and toxic causes. Appropriate serologic tests should be performed to confirm the diagnosis.5 Magnetic resonance imaging can be helpful to exclude inflammatory retrobulbar optic neuropathies such as optic neuritis.6 Although the role of systemic antibiotics in ocular disease is controversial, oral treatment with doxycycline and rifampin for 4 to 6 weeks in conjunction with oral steroid can shorten the disease course and accelerate the visual recovery.7 Long-term visual prognosis is reasonable, typically with minimal sequelae. However, small retinal pigmentary changes and mild postinfectious optic neuropathy may happen in some cases.7Acute B henselae infection is usually self-limited, presenting with lymphadenopathy and fever followed by nontender erythematous papules and pastules at the primary site of scratch or bite and, later, flulike symptoms. In 5% to 14% of patients, disseminated disease may develop, including ocular bartonellosis in 5% to 10% of patients.7,8 Chronic infections with flares have negative IgM and elevated IgG titers.9 Although a positive IgM titer supports the diagnosis of recent Bartonella infection, a negative one does not exclude the diagnosis. Thus, the most helpful diagnostic test remains IgG.10This patient was treated with doxycycline, rifampin, and prednisone for 6 weeks. Three weeks after starting the treatment, visual acuity had improved to 20/200 OS and macular disc swelling improved. Seven weeks after of onset of treatment, the visual acuity was 20/70, and disc swelling had resolved.

Ophthalmology

A 41-year-old man presented for evaluation of 2 weeks of blurred vision and pain in the left eye. The onset of vision decrease coincided with muscle pain, joint swelling, and headache. All of the symptoms except blurry vision resolved spontaneously after 3 days. Over the preceding 5 months, he had had approximately monthly similar episodes consisting of a few days of flulike symptoms and blurry vision, with full recovery between episodes. At the time of evaluation, the vision was decreased in the left eye, with pain in both eyes and deep throbbing in the back of the left eye.Visual acuity was 20/20 OD and counting fingers at 1 ft OS, with visual field constriction and a relative afferent pupillary defect in the left eye. The examination of the anterior segment bilaterally was unremarkable, as was the posterior segment examination of his right eye. However, the fundus examination of the left eye showed extensive optic nerve swelling, with nerve fiber layer hemorrhage at the inferior temporal disc margin and peripapillary subretinal fluid extending to the macula (Figure 1). Magnetic resonance imaging (MRI) of the orbits showed anterior swelling of the left optic nerve without masses or hyperintensity of the retrobulbar optic nerve. Brain MRI results were normal.Optic nerve imaging at time of presentation. Optical coherence tomography (A) and fundus photography (B) of the left optic nerve at time of presentation showing broad optic nerve swelling with nerve fiber layer hemorrhage and fluid extending to macula.

what would you do next?

What would you do next?

Observation

Blood testing for infectious and inflammatory agents

Treatment with oral prednisone

Magnetic resonance angiography of the neck

b

male

41-50

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2759428

A 49-year-old woman presented for evaluation of abnormal retinal pigmentation and concern for cancer-associated retinopathy. The patient reported having difficulty with night driving owing to glare. She reported no other ocular history. The patient’s medical history was significant for type 2 diabetes diagnosed in her 30s and managed with metformin therapy, hypertension, mild hearing loss, and thyroid cancer that was in remission following thyroidectomy and radiotherapy. The patient had been told that radioactive iodine therapy damaged her pancreas and predisposed her to diabetes. The patient denied exposure to retinotoxic drugs.On examination, her best-corrected visual acuity was 20/20 OU. The anterior segment examination findings were unremarkable except for trace nuclear sclerosis in each eye. Dilated fundus examination revealed peripapillary atrophy and scattered macular pigment clumps in each eye. Fundus autofluorescence imaging showed a reticular pattern of hyperautofluorescence with sparing of the central macula (Figure). Optical coherence tomography of the macula demonstrated hyperreflective retinal pigment epithelial (RPE) lesions with no intraretinal or subretinal fluid. Full-field electroretinography (ERG) testing was suggestive of mild cone system dysfunction in each eye.A, Color fundus image of right eye shows scattered deep pigment clumps. B, Fundus autofluorescence image of right eye shows a reticular pattern of hyperautofluorescence with sparing of the central macula.Initiate AREDS (Age-Related Eye Disease Study) nutritional supplement treatment for age-related macular degenerationObtain a family medical history and pursue genetic testingRefer for intensification of oral therapy for type 2 diabetes What Would You Do Next?

Initiate AREDS (Age-Related Eye Disease Study) nutritional supplement treatment for age-related macular degeneration

Monitor retinal pigment abnormalities without further workup

Obtain a family medical history and pursue genetic testing

Refer for intensification of oral therapy for type 2 diabetes

Maternally inherited diabetes and deafness syndrome

C

Obtain a family medical history and pursue genetic testing

On further questioning, the patient noted that her brother had a previous diagnosis of pattern dystrophy as well as early-onset hearing loss. Her mother had received cochlear implants for hearing loss, and her maternal grandmother had hearing loss and early-onset diabetes. In addition, 2 of her 3 maternal aunts and uncles had early-onset hearing loss. The patient’s clinical presentation as well as her maternal family history of diabetes, hearing loss, and retinal disease were suggestive of maternally inherited diabetes and deafness (MIDD). Mitochondrial DNA testing revealed an m.3243A>G mutation in the MT-TL1 gene (OMIM 590050), characteristic of MIDD.Maternally inherited diabetes and deafness syndrome was first described in 1992 in a cohort of patients with the m.3243A>G point mutation.1 This mutation, which is responsible for 85% of cases of MIDD, alters mitochondrial transfer RNA and hinders the mitochondrial respiratory chain, thus leaving highly metabolically active tissues vulnerable to dysfunction.1,2 The mutation may only be inherited maternally, although both male and female children may be affected. Individuals carrying the mutation may exhibit a variety of phenotypes, ranging from isolated diabetes or hearing loss to more extensive disease affecting multiple tissues, including the retina, skeletal muscle, heart, and/or kidneys.2 Individuals within the same family can manifest a wide spectrum of disease, highlighting the variable expressivity of this condition. The same mutation also accounts for most cases of mitochondrial encephalopathy, lactic acidosis, and strokelike episodes and some cases of Leigh syndrome.1,2Although visual symptoms associated with MIDD are uncommon, up to 86% of patients display retinal pigmentary changes.3 When present, visual symptoms may include vision loss, poor night vision, and scotomas.2 On fundus examination, patients with MIDD typically have pigment changes, including pale subretinal deposits, pigment clumps, and patchy RPE atrophy in a perifoveal and peripapillary distribution. Individuals with MIDD are also susceptible to onset and progression of diabetic retinopathy.2 Fundus autofluorescence imaging is helpful in demonstrating the disease extent and typically shows perifoveal areas of speckled or reticular autofluorescence and hypoautofluorescence in areas of RPE atrophy.4-6 As seen in this patient, full-field ERG may show mild cone dysfunction, although multifocal ERG testing is more likely to detect photoreceptor dysfunction.6Because of its heterogeneous presentation, MIDD may be mistaken for age-related macular degeneration (choice A) or other maculopathies such as pattern dystrophy or pentosan polysulfate maculopathy.7,8 These conditions can be distinguished by age at onset, medical history, family history, presence of typical drusen, and distribution of pigmentary abnormalities. Recognition of MIDD is important, as it has health implications for the patient and all maternal family members. For instance, patients typically experience decreased insulin production and require insulin treatment as opposed to metformin therapy and other oral diabetes medications (choice D). In addition, this mutation poses a risk for severe morbidity and mortality from cardiac complications and strokelike episodes. Therefore, suspected cases of MIDD warrant genetic testing and counseling rather than observation (choice B). Although no clear treatment has been identified, coenzyme Q10 therapy may offer some benefit in MIDD, as it may improve mitochondrial function. Results of an open-label randomized study suggested that coenzyme Q10 delays progression of hearing loss and diabetes in patients with MIDD. Further studies are necessary to corroborate this finding.9This patient and her primary care physician were informed of her genetic testing results, and she is undergoing a comprehensive medical evaluation with the guidance of a medical geneticist. The patient will be followed up annually with comprehensive retinal imaging to monitor her macular disease and to screen for diabetic retinopathy.

Ophthalmology

A 49-year-old woman presented for evaluation of abnormal retinal pigmentation and concern for cancer-associated retinopathy. The patient reported having difficulty with night driving owing to glare. She reported no other ocular history. The patient’s medical history was significant for type 2 diabetes diagnosed in her 30s and managed with metformin therapy, hypertension, mild hearing loss, and thyroid cancer that was in remission following thyroidectomy and radiotherapy. The patient had been told that radioactive iodine therapy damaged her pancreas and predisposed her to diabetes. The patient denied exposure to retinotoxic drugs.On examination, her best-corrected visual acuity was 20/20 OU. The anterior segment examination findings were unremarkable except for trace nuclear sclerosis in each eye. Dilated fundus examination revealed peripapillary atrophy and scattered macular pigment clumps in each eye. Fundus autofluorescence imaging showed a reticular pattern of hyperautofluorescence with sparing of the central macula (Figure). Optical coherence tomography of the macula demonstrated hyperreflective retinal pigment epithelial (RPE) lesions with no intraretinal or subretinal fluid. Full-field electroretinography (ERG) testing was suggestive of mild cone system dysfunction in each eye.A, Color fundus image of right eye shows scattered deep pigment clumps. B, Fundus autofluorescence image of right eye shows a reticular pattern of hyperautofluorescence with sparing of the central macula.Initiate AREDS (Age-Related Eye Disease Study) nutritional supplement treatment for age-related macular degenerationObtain a family medical history and pursue genetic testingRefer for intensification of oral therapy for type 2 diabetes

what would you do next?

What would you do next?

Refer for intensification of oral therapy for type 2 diabetes

Obtain a family medical history and pursue genetic testing

Monitor retinal pigment abnormalities without further workup

Initiate AREDS (Age-Related Eye Disease Study) nutritional supplement treatment for age-related macular degeneration

b

female

41-50

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2759801

A 19-year-old man presented with recurrent left eye redness and photophobia for the past year. The patient had previously been treated with topical corticosteroid therapy, which provided temporary relief of his symptoms. Visual acuity was 20/20 OU with normal intraocular pressures. The results from the slitlamp examination of the right eye were within normal limits (Figure 1A). Examination results of the left eye demonstrated 2+ diffuse conjunctival hyperemia, 1+ anterior chamber cell, and a vascularized iris infiltrate (Figure 1B). Results of the dilated fundus examination were within normal limits in both eyes. Ultrasound biomicroscopy of the left eye demonstrated areas of ciliary body thickening 360° and a thickened iris pupillary margin superiorly and nasally. A full review of systems was negative for other abnormalities including skin lesions. Test results for tuberculosis and syphilis were negative.Slitlamp images of both eyes demonstrating a normal right eye (A) and a 2+ conjunctival hyperemia, 1+ anterior chamber cell, and membranous, vascularized iris infiltrate, most prominent superiorly, in the left eye (B).Perform anterior chamber paracentesis for viral polymerase chain reaction What Would You Do Next?

Perform biopsy of the iris lesion

Administer subtenon corticosteroid injection

Perform anterior chamber paracentesis for viral polymerase chain reaction

Screen for antinuclear antibody

Juvenile xanthogranuloma

A

Perform biopsy of the iris lesion

The patient had a unilateral iris infiltrate with recurrent inflammation that was responsive to topical corticosteroid therapy. The differential diagnosis included juvenile xanthogranuloma (JXG), lymphoma, leukemia, sarcoidosis, HLA-B27–associated uveitis, syphilis, and tuberculosis.Of the options above, a biopsy of the lesion seemed most likely to determine the cause and best future treatment modality (choice A). Administration of a subtenon corticosteroid injection (choice B) may be useful in the treatment of inflammation once a diagnosis is made. An anterior chamber (AC) paracentesis for viral polymerase chain reaction (choice C) is unlikely to be helpful, as one would not expect an infiltrative process in a viral uveitis. Screening for lupus with antinuclear antibody testing (choice D) would not be helpful because the presentation as described is not a manifestation of lupus, nor does lupus cause uvetis. Testing for systemic causes such as HLA-B27, syphilis, tuberculosis, lymphoma, leukemia, and sarcoidosis should also be performed but will be less likely to yield a final diagnosis when compared with biopsy results of involved tissue.Juvenile xanthogranuloma is a rare, benign, non–Langerhans cell histiocytosis seen predominantly in young children. Lesions typically appear as reddish yellow cutaneous nodules around the head and neck within the first year of life.1 These lesions can often resolve spontaneously. Cutaneous lesions arise most frequently, with extracutaneous manifestations mostly affecting the eyes and rarely the brain, liver, lungs, spleen, and other internal organs.2-5Ocular involvement occurs in 0.3% to 10% of cases, with conjunctival hyperemia, iris masses, or iris nodules being the most common ophthalmic manifestations.1,6 Hyphema, heterochromia, iris neovascularization, and masses of the conjunctiva, eyelid, orbit, and choroid are other reported ophthalmic manifestations.1 Lesions are typically limited to the anterior segment and rarely appear posteriorly.1,6 Eye disease associated with JXG is responsive to topical, periocular, and systemic corticosteroid therapy in roughly 66% to 100% of patients and rarely has recurrence once fully treated.2,6 Other options for treatment include excisional biopsy.6 There should be close monitoring until inflammation has been resolved for several months. Afterward, the interval between follow-up appointments can be extended as the inflammation remains inactive.The patient underwent an anterior chamber washout and iris biopsy, which revealed granulomatous inflammation consistent with JXG. Other systemic testing results as mentioned previously were negative. On full review of systems and examination, no systemic manifestations of JXG were noted.The patient was prescribed an extended course of topical corticosteroid therapy with a slow taper. This treatment resulted in resolution of the ocular inflammation and iris infiltrate, with residual iris heterochromia (Figure 2). He has continued to remain without signs of ocular inflammation or symptoms of photophobia or redness during follow-up since cessation of topical corticosteroid therapy.Slitlamp image of the left eye at the 6-month follow-up after treatment with topical corticosteroid therapy.

Ophthalmology

A 19-year-old man presented with recurrent left eye redness and photophobia for the past year. The patient had previously been treated with topical corticosteroid therapy, which provided temporary relief of his symptoms. Visual acuity was 20/20 OU with normal intraocular pressures. The results from the slitlamp examination of the right eye were within normal limits (Figure 1A). Examination results of the left eye demonstrated 2+ diffuse conjunctival hyperemia, 1+ anterior chamber cell, and a vascularized iris infiltrate (Figure 1B). Results of the dilated fundus examination were within normal limits in both eyes. Ultrasound biomicroscopy of the left eye demonstrated areas of ciliary body thickening 360° and a thickened iris pupillary margin superiorly and nasally. A full review of systems was negative for other abnormalities including skin lesions. Test results for tuberculosis and syphilis were negative.Slitlamp images of both eyes demonstrating a normal right eye (A) and a 2+ conjunctival hyperemia, 1+ anterior chamber cell, and membranous, vascularized iris infiltrate, most prominent superiorly, in the left eye (B).Perform anterior chamber paracentesis for viral polymerase chain reaction

what would you do next?

What would you do next?

Administer subtenon corticosteroid injection

Perform biopsy of the iris lesion

Perform anterior chamber paracentesis for viral polymerase chain reaction

Screen for antinuclear antibody

b

male

11-20

original

https://jamanetwork.com/journals/jama/fullarticle/2760548

A 34-year-old woman presented with 2 years of progressively worsening intermittent dysphagia, primarily to solids, especially meats, localized retrosternally. She reported no heartburn, nausea, vomiting, abdominal pain, weight loss, or changes in bowel habits. She reported no medications or comorbidities. Physical examination was unremarkable. Results of a recent complete blood cell count were normal. Despite taking ranitidine (150 mg twice daily), she continued to have bothersome daily dysphagia, prompting her primary care clinician to order esophagogastroduodenoscopy (EGD). The EGD showed vertical furrows and circumferential rings in the esophagus (Figure 1A), while the stomach and duodenum appeared normal. Four biopsies each were taken from the proximal and distal esophagus (Figure 1B).Left, Esophagus at initial esophagogastroduodenoscopy (EGD). Right, Esophageal biopsy sample from initial EGD (hematoxylin-eosin, original magnification ×400). What Would You Do Next?

Order barium esophagram

Perform esophageal high-resolution manometry (HRM)

Prescribe omeprazole (40 mg twice daily)

Refer for surgical fundoplication

Eosinophilic esophagitis (EoE)

C

Prescribe omeprazole (40 mg twice daily)

The key to the correct diagnosis is the esophageal mucosal biopsies demonstrating numerous intraepithelial eosinophils, in the setting of dysphagia symptoms and supportive endoscopic findings, and the absence of alternate etiologies for the eosinophilia.1 Other etiologies of esophageal eosinophilia, such as gastroesophageal reflux disease, eosinophilic gastroenteritis, hypereosinophilic syndrome, infections, drug hypersensitivity reaction, Crohn disease, or achalasia, should be carefully considered and excluded based on presenting history, physical examination findings, and diagnostic data.1 Once the diagnosis of EoE was made, the patient was prescribed twice-daily proton pump inhibitor (PPI) therapy, a well-tolerated first-line treatment option.EoE is an allergen-/immune-mediated disorder characterized by esophageal dysfunction due to mucosal eosinophilic infiltration. Diagnosis of EoE has been rapidly increasing, with overall worldwide prevalence estimates of 0.5 per 1000 to 1 per 1000 persons.2 In adults, symptoms may include dysphagia, heartburn, regurgitation, and/or chest pain. Some patients present with food bolus impaction, defined as acute esophageal obstruction by ingested food. In children, symptoms may be less specific (eg, nausea, abdominal pain, failure to thrive).3In the setting of clinical suspicion for EoE based on characteristic symptoms, guidelines recommend obtaining esophageal biopsies at EGD, with a threshold of 15 or more eosinophils in at least 1 high-power field confirming the diagnosis.1,4 Using this threshold, the diagnostic sensitivity of 1 esophageal biopsy for EoE is 73%; of 2 biopsies, 84%; of 3 biopsies, 97%; and of 6 biopsies, 100%.5 Because inflammatory changes may be patchy and may not be present in all biopsy specimens, guidelines recommend obtaining biopsies from both the proximal and distal esophagus, as well as obtaining biopsies of areas of abnormal-appearing mucosa (to maximize diagnostic yield).1,4 Characteristic endoscopic findings of EoE include rings, furrows, and strictures. However, endoscopic findings alone (without biopsies) are only 15% to 48% sensitive for EoE, and up to 17% of patients with EoE may have normal endoscopic findings.4,6Earlier guidelines recommended twice-daily PPI with repeat esophageal biopsies in 8 weeks as the next diagnostic step after EGD documenting esophageal eosinophilia, to exclude PPI-responsive esophageal eosinophilia (PPI-REE).4 PPI-REE, in which eosinophilia and symptoms resolve with PPI treatment, was previously thought to be separate from EoE.4 However, because EoE and PPI-REE share similar clinical, endoscopic, histologic, immunologic, and molecular features, more recent guidelines consider PPI-REE part of the same disease process as EoE and classify PPI as an initial treatment option for EoE, rather than as a diagnostic criterion.1 Other potential therapeutic options for EoE include topical (swallowed oral) corticosteroids (budesonide or fluticasone) or elimination diets, in which common food allergen triggers (wheat, nuts, soy, eggs, milk, seafood) are eliminated and then systematically reintroduced, with monitoring for recurrent eosinophilia.7 Although dietary approaches are more frequently first-line therapies in children, all 3 options should be thoroughly discussed with patients diagnosed with EoE. In many adults, PPIs are typically selected as a reasonable first approach given their convenience, safety profile, and efficacy.1Given its chronic nature, EoE often warrants maintenance therapy to help prevent relapse and limit disease progression.2 If a PPI trial controls symptoms and eliminates eosinophilia, patients should be counseled on potential long-term adverse effects of PPI therapy, such as hypomagnesemia and vitamin B12 deficiency, as part of the discussion of maintenance therapy, and the PPI dose should be titrated to the lowest effective dose and continued long-term to control symptoms and maintain remission. If PPI therapy is unsuccessful, with persistent eosinophilia and symptoms, alternative treatment options (topical corticosteroids or elimination diets) should be prescribed, along with endoscopic dilation of any dominant strictures. Once resolution of eosinophilia is achieved, repeat EGD is not routinely recommended for monitoring in the absence of symptoms.In patients with EoE, barium esophagram may identify subtle or more proximal esophageal strictures or narrow-caliber esophagus that may not be identified at EGD. However, barium esophagram is not sufficient or necessary for diagnosis of EoE.8 Esophageal manometry may demonstrate variable motor patterns in patients with EoE, including abnormal pressurization suggesting impaired adherence, but manometry findings cannot differentiate EoE from other common esophageal disorders.9 While surgical fundoplication is a potential treatment option for gastroesophageal reflux disease, it is not an effective therapy for EoE.10After starting omeprazole (40 mg twice daily), the patient’s dysphagia resolved within 2 weeks. Repeat EGD performed 2 months after initiation of omeprazole demonstrated normal esophageal mucosa (Figure 2), with resolution of eosinophilia on proximal and distal esophageal biopsies. At follow-up 3 months after repeat EGD, the patient remained asymptomatic with omeprazole once daily.Esophagus at follow-up esophagogastroduodenoscopy, 2 months after initiation of omeprazole treatment.

General

A 34-year-old woman presented with 2 years of progressively worsening intermittent dysphagia, primarily to solids, especially meats, localized retrosternally. She reported no heartburn, nausea, vomiting, abdominal pain, weight loss, or changes in bowel habits. She reported no medications or comorbidities. Physical examination was unremarkable. Results of a recent complete blood cell count were normal. Despite taking ranitidine (150 mg twice daily), she continued to have bothersome daily dysphagia, prompting her primary care clinician to order esophagogastroduodenoscopy (EGD). The EGD showed vertical furrows and circumferential rings in the esophagus (Figure 1A), while the stomach and duodenum appeared normal. Four biopsies each were taken from the proximal and distal esophagus (Figure 1B).Left, Esophagus at initial esophagogastroduodenoscopy (EGD). Right, Esophageal biopsy sample from initial EGD (hematoxylin-eosin, original magnification ×400).

what would you do next?

What would you do next?

Order barium esophagram

Prescribe omeprazole (40 mg twice daily)

Perform esophageal high-resolution manometry (HRM)

Refer for surgical fundoplication

b

female

31-40

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2757272

A man in his 60s was referred to our clinic because of a well-demarcated, circular erythematous plaque that had been present at the area of median sternotomy for 3 months. Physical examination findings revealed a 20-cm–diameter plaque that consisted of multiple concentric annular formations with raised erythematous margins and studded with numerous blisters and pustules, some coalescing into lakes of pus (Figure 1A). Nikolsky sign was not elicited, and oral, ocular, and genital mucosa involvement was absent. The patient did not report other symptoms, and findings of the overall physical examination were normal.A, A crusted, focally vesiculating, well-demarcated erythematous plaque at the area of median sternotomy. B, Histopathologic examination of lesional skin (hematoxylin-eosin). C, Histopathologic examination of lesional skin (hematoxylin-eosin).Over the past 5 years, the patient’s medications consisted of metoprolol and acetylsalicylic acid for treatment of established ischemic heart disease. Nine months prior to being referred to our department, he was given oral furosemide and amiloride and then underwent median sternotomy and coronary artery bypass surgery 2 months later. Four days after the operation, he developed a red patch at the area of the incision that was accompanied by mild pruritus. Over the following months, the lesion showed a marked tendency for centrifugal extension over the chest area.Results of routine laboratory studies, Mantoux test, chest radiography, and chest computed tomography of the area were within the normal range. Gram stain, periodic acid–Schiff stain, and tissue culture results were negative (Figure 1B and C). What Is Your Diagnosis?

Annular pustular psoriasis

Bullous tinea

Linear IgA dermatosis

Acute localized exanthematous pustulosis

C. Linear IgA dermatosis

C

Linear IgA dermatosis

A biopsy specimen showed a subepidermal bulla, prominent neutrophilic infiltrate arranged in a linear fashion, and evidence of dermal papillary microabscesses. Direct immunofluorescence (DIF) study results demonstrated linear deposits of IgA along the basement membrane without C3, IgG, or IgM antibody deposition (Figure 2). The diagnosis of linear IgA dermatosis (LAD) was rendered on the basis of clinical, histologic, and DIF findings.Direct immunofluorescence analysis of lesional skin showing high-intensity linear deposition of IgA antibodies at the dermal-epidermal junction.Prior to the patient’s clinical admission, the lesion was treated as a surgical wound infection, and the patient was sequentially prescribed amoxicillin and clavulanic acid, doxycycline, ciprofloxacin and clindamycin, and fluconazole as an add-on therapy, with minimal clinical response. After confirmation of the diagnosis, the furosemide and amiloride were discontinued and replaced by hydrochlorothiazide and valsartan. He started a regimen of dapsone and achieved a short clinical improvement followed by important clinical deterioration.Oral colchicine and a class III topical steroid cream were administered instead of dapsone because the patient was not a candidate for treatment with prednisone owing to severe coronary heart disease. Within 6 weeks, the patient achieved complete remission, and the colchicine and steroid were tapered without any rebound effect.Linear IgA dermatosis is a rare autoimmune subepidermal bullous disease that may be idiopathic or acquired. Acquired LAD is often associated with drug intake, predominantly vancomycin.1 Furosemide has also been implicated in 2 reported cases.2,3 Lesions appear within 1 month of drug initiation, and withdrawal of the agent causes remission within several weeks. Other triggers include systemic autoimmune diseases, infections, and malignant neoplasms.1,4Linear IgA dermatosis is characterized by the specific binding of IgA antibodies to the epidermal basement membrane, which leads to complement activation and neutrophil chemotaxis with release of proteolytic enzymes and blister formation.5 Clinically, considerable variation exists regarding age at disease onset, clinical morphology, and mucosal involvement.1,5 Typical cutaneous manifestations include tense arciform bullae in a cluster-of-jewels configuration or, less commonly, grouped papulovesicles.5,6 Atypical lesions owing to Koebner phenomenon have also been reported in areas where adhesives were previously applied.7,8 This patient developed a lesion on the median sternotomy scar, which was highly suggestive of koebnerization. Although isomorphic response on operation scars has been described in other bullous dermatoses, to our knowledge, only 1 case has been described in LAD.8The histopathologic features are represented by the presence of subepidermal bullae with neutrophil-predominant infiltrate at the dermal-epidermal junction, which are characteristically arranged in a linear array.1,9 The criterion standard for establishing an LAD diagnosis is DIF revealing linear IgA antibody deposition along the basement membrane.5Treatment modalities vary with the degree of involvement and identification of inciting factors.9 Drug-induced LAD is usually self-limiting and gradually resolves after discontinuation of the causative agent. Additional therapy, such as dapsone, sulfonamides, corticosteroids, colchicine, tetracyclines, and nicotinamide, may be required.1,6,10A presumptive clinical diagnosis of annular pustular psoriasis was supported by the annular lesion morphology, formation of pustules, centrifugal expansion, and potential koebnerization; however, pustular psoriasis was unlikely given the DIF positivity and histologic findings. Bullous tinea is a clinical mimicker, and 2 cases have described basement membrane DIF positivity. Nevertheless, the presence of subepidermal rather than intraepidermal bullae, the temporal relationship with medications, and the negative periodic acid–Schiff stain exclude this diagnosis. Acute localized exanthematous pustulosis, a rare localized variant of acute generalized exanthematous pustulosis, may also present with multiple nonfollicular, sterile pustules on a background of edematous erythema in the context of recent drug administration. Distinguishing differences are that in acute localized exanthematous pustulosis, skin reaction occurs within a few hours, is usually accompanied by fever and neutrophilic leukocytosis, and does not exhibit DIF reactivity. Given the potential for koebnerization, this patient’s case emphasizes the importance of including LAD in the differential diagnosis for atypical lesions with an isomorphic response.

Dermatology

A man in his 60s was referred to our clinic because of a well-demarcated, circular erythematous plaque that had been present at the area of median sternotomy for 3 months. Physical examination findings revealed a 20-cm–diameter plaque that consisted of multiple concentric annular formations with raised erythematous margins and studded with numerous blisters and pustules, some coalescing into lakes of pus (Figure 1A). Nikolsky sign was not elicited, and oral, ocular, and genital mucosa involvement was absent. The patient did not report other symptoms, and findings of the overall physical examination were normal.A, A crusted, focally vesiculating, well-demarcated erythematous plaque at the area of median sternotomy. B, Histopathologic examination of lesional skin (hematoxylin-eosin). C, Histopathologic examination of lesional skin (hematoxylin-eosin).Over the past 5 years, the patient’s medications consisted of metoprolol and acetylsalicylic acid for treatment of established ischemic heart disease. Nine months prior to being referred to our department, he was given oral furosemide and amiloride and then underwent median sternotomy and coronary artery bypass surgery 2 months later. Four days after the operation, he developed a red patch at the area of the incision that was accompanied by mild pruritus. Over the following months, the lesion showed a marked tendency for centrifugal extension over the chest area.Results of routine laboratory studies, Mantoux test, chest radiography, and chest computed tomography of the area were within the normal range. Gram stain, periodic acid–Schiff stain, and tissue culture results were negative (Figure 1B and C).

what is your diagnosis?

What is your diagnosis?

Annular pustular psoriasis

Acute localized exanthematous pustulosis

Bullous tinea

Linear IgA dermatosis

d

male

61-70

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2757718

A woman in her 40s presented to the dermatology clinic with a 10-year history of progressive skin thickening and subcutaneous enlargement of the right side of her nose and right cheek. She had been seen by several dermatologists and otolaryngologists and had undergone nondiagnostic skin biopsies. She underwent a septorhinoplasty 6 months prior to presentation because of collapse of her right nasal ala. During the surgical procedure, the surgeon noted a significant amount of submucosal tissue in the right nasal cavity, which was removed; histopathological analysis was performed, and the results were reported as fibroadipose tissue and vascular proliferation. A skin biopsy was performed at the time of the surgical procedure and was interpreted as sebaceous hyperplasia. The patient initially had improvement in her skin, but she again noticed enlargement of the soft tissue with thickening of the overlying skin on her right cheek and right side of her nose several months later.Clinical examination revealed slightly hyperplastic soft tissue with dilated patulous follicles involving the right medial malar cheek and right nasal ala in addition to deviation of the nasal tip (Figure, A). The surgical pathology specimens from her septorhinoplasty were obtained and reviewed.A, Clinical image shows facial asymmetry with deviation of the nasal tip. B, Hematoxylin-eosin stain of an interstitial proliferation of spindle cells within mature adipocytes that extends between bundles of skeletal muscle. C, Hematoxylin-eosin stain of mature adipocytes that are separated by a proliferation of spindle cells associated with fragments of thickened collagen. What Is Your Diagnosis?

Lupus panniculitis (subcutaneous lupus erythematosus)

Spindle cell lipoma

Dermatofibrosarcoma protuberans

Diffuse pattern neurofibroma

B. Spindle cell lipoma

B

Spindle cell lipoma

Histologic examination showed a subcutaneous-based proliferation of spindle cells of varying density associated with thickened and fragmented collagen bundles and mature adipocytes, extending into skeletal tissue (Figure, B and C). The spindle cells had bland cytomorphology with tapered nuclei and ill-defined cytoplasm. No cellular pleomorphism was observed. Based on these findings, a diagnosis of spindle cell lipoma (SCL) with focal intramuscular involvement was made. Immunohistochemical evaluation was deemed unnecessary because this subcutaneous-based lesion showed the classical triad of ropey collagen, tapered spindle cells without atypia, and mature adipocytes.Spindle cell lipoma is a benign tumor that typically occurs on the shoulders of middle-aged or elderly men.1 Histopathologic findings include a proliferation of spindle cells dispersed diffusely or in loose fascicles among ropey, fragmented collagen bundles and with a variable quantity of background mature adipocytes.1 Immunopositivity for CD34 is typically present within lesional cells, and these cells are immunonegative for S100 protein, although mature adiopocytes are positive.2 Although SCL is a common tumor, it is unusual for these tumors to be located outside of the back/shoulder region. There have been 17 case reports of SCL involving the nose and cheek, to our knowledge; of these, 5 occurred in female individuals.2 There has been a single case report of an SCL causing a nasal tip deformity, although it was located in the vestibule of the nose.3The differential diagnosis for an enlarging subcutaneous mass includes subcutaneous lupus erythematosus, dermatofibrosarcoma protuberans (DFSP), and diffuse-type neurofibroma; therefore, histopathologic analysis is critical. Subcutaneous lupus erythematosus is a subtype of chronic cutaneous lupus in which nontender nodules develop within adipose tissue typically on the face, chest, and hips. The overlying skin can be normal, atrophic, indurated, or have concomitant features of discoid lupus.4 This patient did have overlying patulous follicles on physical examination, and lupus panniculitis may present as an isolated finding revealed at the time of biopsy. Histopathologically, there is a lobular pattern panniculitis associated with lymphoplasmacytic infiltrate, hyaline fat necrosis, and mucin deposition. Even in the absence of clinical discoid lupus, vacuolar alteration of the dermal-epidermal interface could be present.4 Dermatofibrosarcoma protuberans is also a mimicker of SCL and presents as a slowly progressive but locally aggressive tumor. Dermatofibrosarcoma protuberans can have a multifaceted clinical presentation from a protuberant indurated plaque/tumor to a subtle infiltrative process involving the subcutaneous compartment resulting in skin thickening.4 On histopathologic analysis, both SCL and DFSP demonstrate a CD34-positive spindle cell proliferation. In a DFSP, these occur diffusely throughout the dermis in a storiform pattern and infiltrate into the subcutaneous tissue in a honeycomblike pattern, whereas the cells in an SCL are generally limited to adipose and lack storiform arrangement. Cytologic atypia and mitotic activity may be present in DFSP as opposed to SCL.1 Dermatofibrosarcoma protuberans also lacks the ropey collagen typical of SCL. Most DFSPs are characterized by chromosomes 17 and 22 rearrangement resulting in the collagen, type 1, alpha 1–platelet-derived growth factor β fusion gene. This abnormality can be detected by fluorescence in situ hybridization analysis in routine practice. Lastly, a diffuse pattern neurofibroma is a rare clinical enigma as it may present as subtle ill-defined soft tissue swelling. Histopathologically, it is the closest mimicker of SCL and shows a population of spindle cells with tapered cytoplasm and wavy nuclei indicating neural origin. They are organized in an infiltrative pattern, extending deep into the adipose and often is associated with increased vascularity. Lesions lack a storiform pattern and are strongly immunopositive for S100 protein and Sry-related HMg-Box gene 10.5 The spindle cells in SCL are negative for S100 and Sry-related HMg-Box gene 10. Expression of CD34 is patchy in neurofibroma as opposed to diffusely positive in SCL.Complete surgical excision of SCL is thought to be curative in its typical location, and small observational data of 8 patients followed up after removal of SCL on the head/neck region also showed no recurrence.2,6 In this patient, the benign tumor recurred and resulted in cosmetic disfigurement. This case highlights an SCL presenting in an unusual location that resulted in initial misdiagnosis and delay in treatment. Spindle cell lipoma is important to consider in the differential for a subcutaneous benign tumor or inflammatory process involving the face.

Dermatology

A woman in her 40s presented to the dermatology clinic with a 10-year history of progressive skin thickening and subcutaneous enlargement of the right side of her nose and right cheek. She had been seen by several dermatologists and otolaryngologists and had undergone nondiagnostic skin biopsies. She underwent a septorhinoplasty 6 months prior to presentation because of collapse of her right nasal ala. During the surgical procedure, the surgeon noted a significant amount of submucosal tissue in the right nasal cavity, which was removed; histopathological analysis was performed, and the results were reported as fibroadipose tissue and vascular proliferation. A skin biopsy was performed at the time of the surgical procedure and was interpreted as sebaceous hyperplasia. The patient initially had improvement in her skin, but she again noticed enlargement of the soft tissue with thickening of the overlying skin on her right cheek and right side of her nose several months later.Clinical examination revealed slightly hyperplastic soft tissue with dilated patulous follicles involving the right medial malar cheek and right nasal ala in addition to deviation of the nasal tip (Figure, A). The surgical pathology specimens from her septorhinoplasty were obtained and reviewed.A, Clinical image shows facial asymmetry with deviation of the nasal tip. B, Hematoxylin-eosin stain of an interstitial proliferation of spindle cells within mature adipocytes that extends between bundles of skeletal muscle. C, Hematoxylin-eosin stain of mature adipocytes that are separated by a proliferation of spindle cells associated with fragments of thickened collagen.

what is your diagnosis?

What is your diagnosis?

Dermatofibrosarcoma protuberans

Spindle cell lipoma

Lupus panniculitis (subcutaneous lupus erythematosus)

Diffuse pattern neurofibroma

b

female

0-10

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2758217

An infant boy, born to a nonconsanguineously wed couple, presented to the dermatology outpatient clinic with recurrent skin blisters since age 2 months. The lesions initially started over the trunk and subsequently progressed to involve the face, hands, and feet. The episodes of skin blisters were accompanied by pruritus and redness all over the body. There was no history of oral erosions or difficulty in feeding. Bowel and bladder movements were normal. The child had an older sibling who had no skin ailments, and none of the other family members were affected.On examination, multiple tense, angulated vesicles and bullae on a background of erythema were seen over the face, trunk, and extremities (Figure, A and B). Few urticated papules and wheals were seen in isolation over the trunk. The ruptured bullae were healing with hypopigmentation with accompanying scarring and discrete milia formation. The mucosae and nails were normal. No contractures or webbing of fingers was noted. There was no organomegaly. A punch biopsy from a vesicle was subsequently performed (Figure, C and D).A, Multiple angulated vesicles and tense bullae over the forehead and chin. Background erythema can be appreciated. B, Tense bullae over the trunk with superficial erosions and postinflammatory hypopigmentation, which are healing with scarring and discrete milia formation. Few urticated papules and plaques can also be appreciated. C, Subepidermal bulla with bandlike mast cell infiltrate in the upper dermis (hematoxylin and eosin stain). D, Higher magnification showing dense infiltrate of mast cells in the upper dermis. Mast cells can be identified by ovoid to spindle-shaped nuclei (hematoxylin and eosin stain). What Is Your Diagnosis?

Dystrophic epidermolysis bullosa

Chronic bullous disease of childhood

Bullous mastocytosis

Congenital erythropoietic porphyria

C. Bullous mastocytosis

C

Bullous mastocytosis

Darier sign, urtication, and erythematous halo produced in response to rubbing and scratching was diffusely positive over the trunk. The skin biopsy from the vesicle revealed clefting at the dermo-epidermal junction containing fibrin. Upper dermis showed bandlike inflammatory infiltrate comprising mast cells that had ovoid- to spindle-shaped nuclei. Some scattered eosinophils were also noted (Figure, C and D). The mast cells stained positive for CD117 and toluidine blue. Results of immunofluorescence studies from perilesional skin were negative. The diagnosis of bullous mastocytosis was thus confirmed.Complete blood cell count and liver function test results were found to be normal. Ultrasonography did not reveal any organomegaly. Owing to lack of any evidence of systemic involvement, bone marrow studies were not done. The child was prescribed hydroxyzine syrup, 0.5 mg/kg, per day with topical fluticasone propionate cream, 0.05%, to be applied twice daily. The episodes were well controlled while the child took antihistamines with mild flare-up during episodes of upper respiratory tract infections. The parents were told the necessary precautionary measures such as avoidance of extreme temperatures, rubbing of the skin, insect bites, and physical trauma and were also provided with a detailed safe drug list that avoided the mast cell–degranulating agents. The possible perioperative complications and instructions were also provided to them.Diffuse cutaneous mastocytosis is a rare entity that occurs exclusively in infants. Two distinct presentations have been described. One is diffuse yellowish orange infiltration of the skin (leathery skin) with papules and nodules, with vesicular lesions noted occasionally. The other less common variant presents with extensive blistering as the initial sign accompanied by generalized erythema as seen in the index case.1,2 Presence of widespread blisters in an infant can lead to a possibility of various other pediatric dermatoses. There are reports of infantile bullous mastocytosis that were initially misdiagnosed as epidermolysis bullosa,1,3 staphylococcal scalded skin syndrome, bullous impetigo, and erythema multiforme.4,5 Because of the early age of onset, recurrent nature, and presence of milia, the possibility of congenital epidermolysis bullosa was considered in the index case. However, blisters in epidermolysis bullosa are noninflammatory, involve the mucosae, and predominantly occur over pressure sites. On histopathology, there is lack of inflammatory infiltrate and the diagnosis can be established by immunofluorescence antigen mapping.3 Chronic bullous disease of childhood usually presents after infancy with pruritic papules and vesicles characteristically arranged in an annular pattern (string of pearl) in the perioral and perineal region. Background erythema is generally present. Histopathology will show a subepidermal bulla with neutrophilic infiltrate, and linear deposition of IgA at basement membrane zone on immunofluorescence is pathognomonic.6 Bullous porphyrias, namely congenital erythropoietic porphyria and rarely type III porphyria cutanea tarda, can present in infancy with generalized blistering over the photo-exposed areas that heals with atrophic scarring. Additional clinical features include hypertrichosis, erythrodontia, and reddish discoloration of urine. Skin biopsy shows subepidermal bulla with festooning of dermal papillae into the floor and periodic acid–Schiff–positive hyaline material in the perivascular areas. Direct immunofluorescence reveals deposits of IgG around the upper dermal vessels. Diagnosis can be confirmed by spectrofluorometry.7Most pediatric cutaneous mastocytosis without systemic involvement are usually benign with spontaneous resolution by adolescence. Systemic involvement can manifest as hepatosplenomegaly and lymphadenopathy. Elevated serum tryptase levels and presence of c-Kit mutations can be used as an indicator for systemic involvement.8 Bone marrow biopsy is indicated in case of recurrent systemic symptoms and evidence of organ involvement.5The mainstay of treatment is parental counseling to avoid the triggering factors. The parents must be provided with a comprehensive list of drugs that are safe and that do not trigger mast cell degranulation. Antihistamines and topical steroids are first-line treatments. Mast cell-stabilizing agents such as sodium cromoglycate and ketotifen can also be used. Phototherapy (psoralen–UV-A) has been used for extensive disease. For systemic mastocytosis, targeted therapies directed against downstream signaling pathways of KIT are the mainstay of treatment.9

Dermatology

An infant boy, born to a nonconsanguineously wed couple, presented to the dermatology outpatient clinic with recurrent skin blisters since age 2 months. The lesions initially started over the trunk and subsequently progressed to involve the face, hands, and feet. The episodes of skin blisters were accompanied by pruritus and redness all over the body. There was no history of oral erosions or difficulty in feeding. Bowel and bladder movements were normal. The child had an older sibling who had no skin ailments, and none of the other family members were affected.On examination, multiple tense, angulated vesicles and bullae on a background of erythema were seen over the face, trunk, and extremities (Figure, A and B). Few urticated papules and wheals were seen in isolation over the trunk. The ruptured bullae were healing with hypopigmentation with accompanying scarring and discrete milia formation. The mucosae and nails were normal. No contractures or webbing of fingers was noted. There was no organomegaly. A punch biopsy from a vesicle was subsequently performed (Figure, C and D).A, Multiple angulated vesicles and tense bullae over the forehead and chin. Background erythema can be appreciated. B, Tense bullae over the trunk with superficial erosions and postinflammatory hypopigmentation, which are healing with scarring and discrete milia formation. Few urticated papules and plaques can also be appreciated. C, Subepidermal bulla with bandlike mast cell infiltrate in the upper dermis (hematoxylin and eosin stain). D, Higher magnification showing dense infiltrate of mast cells in the upper dermis. Mast cells can be identified by ovoid to spindle-shaped nuclei (hematoxylin and eosin stain).

what is your diagnosis?

What is your diagnosis?

Bullous mastocytosis

Congenital erythropoietic porphyria

Chronic bullous disease of childhood

Dystrophic epidermolysis bullosa

a

male

original

https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2753511

A 20-year-old woman was referred by her family physician to a community mental health team in London, United Kingdom. Her mental state had deteriorated progressively over the previous 12 months, following the death of her father. After a period living alone, she had returned to the family home 4 months prior to her presentation and had been noted to be socially withdrawn, preoccupied, and distractible. Her family physician, suspecting a depressive episode, had prescribed citalopram up to a dosage of 40 mg once daily, to no effect. Her family subsequently sought advice from the family physician when the patient was noted to be speaking to herself, expressing concerns about people meaning her harm, and professing the belief that she could hear other peoples’ thoughts.The patient had been born in Sierra Leone after a complicated delivery and had traveled to the United Kingdom as a child with her family, who were fleeing from a civil war. On arrival in the United Kingdom, her family claimed asylum and moved into a small apartment in a high-rise building in central London. Although there was no reported developmental delay, she had struggled academically at school and was bullied for having overweight. She left school without qualifications at age 16 years and worked as a shop assistant. She left this job about a year prior to her referral to psychiatry after a period of sick leave following the death of her father. She was a nonsmoker, did not drink alcohol, and denied illicit drug use. A paternal relative was reported to have a diagnosis of schizophrenia. There was no comorbid physical illness.On review, the patient was kempt and had overweight. Eye contact was fleeting, and she presented as anxious, with a degree of psychomotor agitation. Her speech was normal in rate, volume, and tone, although tangential. There was no other evidence of thought disorder. She denied feeling low in mood or suicidal and was objectively euthymic. There was some sleep disturbance, with the patient reporting being fearful to go to sleep owing to persecutory beliefs regarding her neighbors. She reflected that over the preceding few months, she had experienced a sensation of detachment from her immediate environment, as though it was not real, making her world similar to that of a video game. She reported that in the apartment where she had previously been living, she had realized that something was amiss and had become convinced that the door number of her neighbor’s flat, number 6, signified that they meant her harm. She explained this was because 6 was associated with the number of the devil. She reported hearing her neighbors commenting negatively about her appearance. These distressing experiences prompted her to return to her family home, but she continued to hear her neighbors’ voices making derogatory comments about her appearance and began to hear them commenting on her actions and thoughts in the third person as well. On returning home, her paranoia regarding her previous neighbors worsened, resulting in her rarely leaving the house. The volume and frequency of derogatory auditory hallucinations also worsened, and she reported hearing the thoughts of others as well. There was a degree of insight, and although the patient was convinced of the reality of her experiences, she also saw the stress of losing her father as associated with her experiences and was accepting of input from mental health services.Consider the risk of adverse events and which drugs are approved for use What Would You Do Next?

Consider the risk of adverse events and which drugs are approved for use

Commence treatment with oral olanzapine

Commence treatment with oral clozapine

Commence cognitive behavioral therapy for psychosis

Schizophrenia

A

Consider the risk of adverse events and which drugs are approved for use

There are no clear differences in efficacy between licensed antipsychotic medications in head-to-head trials, although network meta-analyses1,2 suggest that clozapine, olanzapine, and amisulpride are among the most efficacious. Note: Amisulpride is approved for use in the United Kingdom where this patient was treated but is not approved for use in the United States. In addition to the short-term efficacy of antipsychotic medication, there is also evidence that maintenance treatment with antipsychotic drugs lowers the risk of relapse.3In addition to efficacy, the risk of adverse effects should be carefully considered when discussing treatment options (choice A). The patient in this clinical challenge is of African origin and had overweight, both of which increase the likelihood of adverse metabolic effects developing during antipsychotic treatment.4 Furthermore, psychosis itself is associated with an increased risk of metabolic dysfunction.5 Consequently, if efficacy and other risks of adverse effects are equal, treatments with a high risk of adverse metabolic effects, such as olanzapine (choice B), should be avoided if possible. Alternatives to amisulpride with relatively low levels of adverse metabolic effects include haloperidol and aripiprazole.Although clozapine (choice C) has demonstrated superiority compared with other antipsychotic medications, this has not been established for patients experiencing first episodes of psychosis, and it has a high burden of adverse effects and requires regular monitoring of full blood cell counts because of the risk of agranulocytosis. As a result, it is typically not recommended as a first-line treatment. It is, however, the only drug licensed for treatment resistance, and evidence indicates that early use in patients with treatment resistance leads to better outcomes.6Long-acting injectable antipsychotic medications are an underused treatment option and should be considered early in the illness course.7 However, even if a long-acting injectable drug is to be used from the first episode, it is generally preferable to first start with oral medication to allow an estimation of dosage and accommodate the time a drug takes to reach effective plasma levels.8The patient’s mental health team specialized in the management of first-episode psychosis, and dedicated early-intervention services are associated with considerable benefits for the individual patient and also their family.9 These teams provide social and psychological support in addition to pharmacological treatments. Cognitive behavioral therapy (choice D) does not have clear evidence of efficacy when given as a stand-alone treatment, but it shows benefit when given in combination with an antipsychotic drug.10Oral amisulpride in a dosage of 200 mg, twice daily, was prescribed initially (amisulpride is approved for use in the United Kingdom where the patient was treated). At a review 2 weeks later, although auditory hallucinations had reduced in intensity, the patient’s paranoid delusions persisted. She reported good medication concordance, and this was corroborated by the family. The dosage was therefore increased to 400 mg, twice daily, and cognitive behavioral therapy was also commenced. The patient complained of some stiffness, which improved when the morning dosage was reduced back to 200 mg, twice daily. The psychotic symptoms gradually resolved over the next 4 weeks, although she remained socially withdrawn. Her mother was supportive but became increasingly frustrated about her lack of activity and failure to get a new job, and she frequently criticized her for this. Six months after commencing amisulpride, the patient’s positive symptoms returned, and after concerns regarding weight loss secondary to reduced food and fluid intake, she was admitted to a psychiatric hospital. Antipsychotic plasma levels at the time of admission suggested poor compliance with antipsychotic treatment. After discussing this with the patient, she reported finding it difficult to remember to take the treatment regularly, although her family also stated that she had reported to them that she did not feel the need to continue taking her medication. After considering the options, she elected to try treatment with a long-acting injectable formulation of risperidone to avoid the need to remember to take pills. This was started after trying the oral form for a week to check that it suited her.

Psychiatry

A 20-year-old woman was referred by her family physician to a community mental health team in London, United Kingdom. Her mental state had deteriorated progressively over the previous 12 months, following the death of her father. After a period living alone, she had returned to the family home 4 months prior to her presentation and had been noted to be socially withdrawn, preoccupied, and distractible. Her family physician, suspecting a depressive episode, had prescribed citalopram up to a dosage of 40 mg once daily, to no effect. Her family subsequently sought advice from the family physician when the patient was noted to be speaking to herself, expressing concerns about people meaning her harm, and professing the belief that she could hear other peoples’ thoughts.The patient had been born in Sierra Leone after a complicated delivery and had traveled to the United Kingdom as a child with her family, who were fleeing from a civil war. On arrival in the United Kingdom, her family claimed asylum and moved into a small apartment in a high-rise building in central London. Although there was no reported developmental delay, she had struggled academically at school and was bullied for having overweight. She left school without qualifications at age 16 years and worked as a shop assistant. She left this job about a year prior to her referral to psychiatry after a period of sick leave following the death of her father. She was a nonsmoker, did not drink alcohol, and denied illicit drug use. A paternal relative was reported to have a diagnosis of schizophrenia. There was no comorbid physical illness.On review, the patient was kempt and had overweight. Eye contact was fleeting, and she presented as anxious, with a degree of psychomotor agitation. Her speech was normal in rate, volume, and tone, although tangential. There was no other evidence of thought disorder. She denied feeling low in mood or suicidal and was objectively euthymic. There was some sleep disturbance, with the patient reporting being fearful to go to sleep owing to persecutory beliefs regarding her neighbors. She reflected that over the preceding few months, she had experienced a sensation of detachment from her immediate environment, as though it was not real, making her world similar to that of a video game. She reported that in the apartment where she had previously been living, she had realized that something was amiss and had become convinced that the door number of her neighbor’s flat, number 6, signified that they meant her harm. She explained this was because 6 was associated with the number of the devil. She reported hearing her neighbors commenting negatively about her appearance. These distressing experiences prompted her to return to her family home, but she continued to hear her neighbors’ voices making derogatory comments about her appearance and began to hear them commenting on her actions and thoughts in the third person as well. On returning home, her paranoia regarding her previous neighbors worsened, resulting in her rarely leaving the house. The volume and frequency of derogatory auditory hallucinations also worsened, and she reported hearing the thoughts of others as well. There was a degree of insight, and although the patient was convinced of the reality of her experiences, she also saw the stress of losing her father as associated with her experiences and was accepting of input from mental health services.Consider the risk of adverse events and which drugs are approved for use

what would you do next?

What would you do next?

Commence cognitive behavioral therapy for psychosis

Commence treatment with oral clozapine

Consider the risk of adverse events and which drugs are approved for use

Commence treatment with oral olanzapine

c

female

11-20

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2758571

A 71-year-old man had a 3-year history of a recurrent seronegative autoimmune constrictive pericarditis and pleural effusions, which were treated with pericardiectomy and prednisone and azathioprine. The pleural fluid was transudative and sterile, and the pericardium contained focal lymphoplasmacytic aggregates. Attempts to taper immunosuppressive drugs failed because of a recrudescence of the inflammatory syndrome and pericardial effusion. The patient was admitted with fever of unknown origin with a surge of the inflammatory syndrome and pancytopenia. He reported night sweats beginning 3 weeks prior associated with fever and unintentional weight loss. No lymphadenopathy was noted.Laboratory evaluations demonstrated a C-reactive protein level of 133 mg/L (reference range, <10 mg/L); ferritin level of 2607 ng/mL (reference, 30-300 ng/mL); lactate dehydrogenase (LDH) level of 289 U/L (reference, 135-214 U/L); pancytopenia with a hemoglobin level of 9.3 g/dL (reference, 13.3-17.7 g/dL), white blood cell count of 2700/μL (reference, 4000-10 000/μL), and platelet count of 99 ×103/μL (reference, 150-350 ×103/μL); and prerenal acute kidney injury (Acute Kidney Injury Network stage 1) with a serum creatinine level of 1.4 mg/dL (reference, 0.7-1.2 mg/dL). Results of a comprehensive serologic workup were negative. Gastroscopy results showed mycotic distal esophagitis.The patient was readmitted 3 weeks later with fever and hypotension without improvement despite broad-spectrum antibiotics and antifungals. Considering the increase in ferritin and LDH levels and pancytopenia, a hematologic disease was suspected. The patient did not report any bone pain. Computed tomography (CT) results showed a splenomegaly without evidence of metastatic disease or lymph node enlargement. Positron emission tomography (PET)–CT imaging (Figure, A and B) and a bone-marrow biopsy (Figure, C and D) were performed. A rapidly evolving sepsislike syndrome led to the patient’s death.Fluorodeoxyglucose/positron emission tomography–computed tomography imaging results show diffuse hypercaptation in the bone marrow (A) and spleen (B). The entire skeleton is highly metabolic, which suggests advanced bone-marrow involvement. C, Bone-marrow biopsy results show a diffuse infiltrate of large lymphoid cells with scattered residual hematopoietic elements (immunoperoxidase, original magnification ×200). D, Immunostaining shows lymphoid infiltrate strongly positive for paired box protein Pax-5 (immunoperoxidase, original magnification ×200). What Is Your Diagnosis?

Infectious bone-marrow disease

Bone marrow–liver–spleen type of large B-cell lymphoma

Primary bone lymphoma

Hemophagocytic lymphohistiocytosis

B. Bone marrow–liver–spleen type of large B-cell lymphoma

B

Bone marrow–liver–spleen type of large B-cell lymphoma

Fluorodeoxyglucose/PET-CT imaging results (Figure, A and B) showed diffuse medullary hypercaptation of the entire skeleton with splenic activity without lymph node involvement. Bone-marrow biopsy results (Figure, C and D) showed hypercellular marrow with a diffuse interstitial infiltrate of large, centroblasticlike lymphoid cells and no features suggestive of plasmacytic or secretory differentiation. These cells were CD20+, CD5−, and CD30− and accounted for approximately 60% of the global cellularity. The large B cells were CD10−, BCL6+, and MUM-1+, a non-germinal center–like phenotype according to the Hans algorithm. Furthermore, B cells were BCL2+ and negative for MYC expression, and fluorescence in situ hybridization studies showed no rearrangements of the BCL2, BCL6, or MYC genes. Although immunostains for κ and λ light chains highlighted a small population of reactive plasma cells distributed in the marrow spaces, they did not produce specific staining in the lymphoma cells. Residual trilinear hematopoiesis was reduced, with no excess of blasts, and no evidence was found to support a diagnosis of hemophagocytic lymphohistiocytosis. The lymphoma cells were negative for Epstein-Barr virus and human herpesvirus 8.The diagnosis was consistent with the bone marrow–liver–spleen type of large B-cell lymphoma (BLS-type LBCL).1 This subtype of diffuse LBCL (DLBCL) includes bone-marrow involvement with or without involvement of the liver or spleen and is often accompanied by severe anemia (100%), thrombocytopenia, hemophagocytic lymphohistiocytosis (64%), and elevated LDH levels in the absence of lymphadenopathy, other extranodal masses, or a lymphoma history.1Primary bone-marrow lymphoma is restricted to patients with isolated bone-marrow involvement, but this patient also had splenomegaly. Intravascular LBCL may be diagnosed in bone-marrow specimens, but the lymphoma cells were diffusely distributed in the bone-marrow spaces and did not show a distribution restricted to the lumens of small vessels and sinusoids. T-cell/histiocyte-rich LBCL is a rare type of LBCL and commonly involves the liver, spleen, bone marrow, and lymph nodes. In this patient, the T-cell/histiocyte-rich background was missing. A multifocal primary lymphoma of the bone was excluded in the absence of bone lesions.The bone marrow is an unusual site to establish the diagnosis of DLBCL, which typically presents with rapidly enlarging lymph nodes or extranodal masses; secondary bone-marrow involvement occurs in approximately 10% to 16% of patients with DLBCL, not otherwise specified.2,3 Bone marrow–liver–spleen LBCL could be considered an aggressive variant of primary splenic DLBCL that has spread into the bone marrow. However, primary splenic DLBCL usually presents with large splenic masses, or less often as diffuse leukemialike infiltration in the red pulpa,4 and is rarely associated with hemophagocytic syndrome.5 To our knowledge, few cases of BLS-type LBCL have been described. This aggressive lymphoma is characterized by severe clinical presentation and rapid evolution with high mortality and no specific infectious or genetic abnormality.6To our knowledge, this is the first reported case of long-lasting, paraneoplastic-refractory pleuropericarditis associated with BLS-type LBCL. The differential diagnosis of pleuropericarditis is large, including infectious causes, autoimmune and metabolic disorders, chemotherapy or radiation toxic effects, and neoplastic or paraneoplastic conditions. It is most often idiopathic (85%-90%), and only 7% of cases are described as neoplastic or paraneoplastic.7 Pericardial disease as the first manifestation of malignant neoplasm is uncommon and makes diagnosis difficult. In a retrospective study of patients with symptomatic pericardial effusion,8 newly diagnosed cancer accounted for the symptoms in one-fifth of the patients with initially uninformative basic workups. Furthermore, idiopathic inflammatory, refractory pleuropericarditis is often a challenging diagnosis, and malignant neoplasm should be ruled out. When studying the association of acute pericardial disease with malignant neoplasm, Imazio et al8 found an association of the lack of response of pericarditis to steroidal anti-inflammatory drugs and an incessant or recurrent course of pericarditis with the presence of a neoplastic cause of the pericardial disease.In this patient, the initial manifestation of probable paraneoplastic recurrent pleuropericarditis with the absence of lymph node involvement and pancytopenia for more than 3 years made the diagnosis challenging to achieve with an ordinary CT scanner. This case illustrates the growing interest in PET-CT and bone-marrow biopsies in the assessment of idiopathic recurrent pleuropericarditis.

Oncology

A 71-year-old man had a 3-year history of a recurrent seronegative autoimmune constrictive pericarditis and pleural effusions, which were treated with pericardiectomy and prednisone and azathioprine. The pleural fluid was transudative and sterile, and the pericardium contained focal lymphoplasmacytic aggregates. Attempts to taper immunosuppressive drugs failed because of a recrudescence of the inflammatory syndrome and pericardial effusion. The patient was admitted with fever of unknown origin with a surge of the inflammatory syndrome and pancytopenia. He reported night sweats beginning 3 weeks prior associated with fever and unintentional weight loss. No lymphadenopathy was noted.Laboratory evaluations demonstrated a C-reactive protein level of 133 mg/L (reference range, <10 mg/L); ferritin level of 2607 ng/mL (reference, 30-300 ng/mL); lactate dehydrogenase (LDH) level of 289 U/L (reference, 135-214 U/L); pancytopenia with a hemoglobin level of 9.3 g/dL (reference, 13.3-17.7 g/dL), white blood cell count of 2700/μL (reference, 4000-10 000/μL), and platelet count of 99 ×103/μL (reference, 150-350 ×103/μL); and prerenal acute kidney injury (Acute Kidney Injury Network stage 1) with a serum creatinine level of 1.4 mg/dL (reference, 0.7-1.2 mg/dL). Results of a comprehensive serologic workup were negative. Gastroscopy results showed mycotic distal esophagitis.The patient was readmitted 3 weeks later with fever and hypotension without improvement despite broad-spectrum antibiotics and antifungals. Considering the increase in ferritin and LDH levels and pancytopenia, a hematologic disease was suspected. The patient did not report any bone pain. Computed tomography (CT) results showed a splenomegaly without evidence of metastatic disease or lymph node enlargement. Positron emission tomography (PET)–CT imaging (Figure, A and B) and a bone-marrow biopsy (Figure, C and D) were performed. A rapidly evolving sepsislike syndrome led to the patient’s death.Fluorodeoxyglucose/positron emission tomography–computed tomography imaging results show diffuse hypercaptation in the bone marrow (A) and spleen (B). The entire skeleton is highly metabolic, which suggests advanced bone-marrow involvement. C, Bone-marrow biopsy results show a diffuse infiltrate of large lymphoid cells with scattered residual hematopoietic elements (immunoperoxidase, original magnification ×200). D, Immunostaining shows lymphoid infiltrate strongly positive for paired box protein Pax-5 (immunoperoxidase, original magnification ×200).

what is your diagnosis?

What is your diagnosis?

Primary bone lymphoma

Infectious bone-marrow disease

Bone marrow–liver–spleen type of large B-cell lymphoma

Hemophagocytic lymphohistiocytosis

c

male

71-80

White

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2757535

A woman in her 30s with active bulimia was brought by ambulance to the emergency department after a syncopal event that followed 1 hour of palpitations and intermittent lightheadedness. When emergency responders arrived, the patient was responsive but groggy. An electrocardiogram (ECG) in the field demonstrated a regular wide complex tachycardia. En route to the hospital, 6 mg of adenosine followed by 12 mg of adenosine were administered intravenously, without a change in her rhythm.On arrival to the emergency department, she was in a regular wide complex tachycardia with a heart rate of 225 beats per minute (Figure, A), with an initial blood pressure of 108/77 mm Hg. She was oriented but slow to respond. After sedation, a synchronized, biphasic, 200-J shock converted her to sinus rhythm with bigeminy (Figure, B), which settled to normal sinus rhythm. An intravenous amiodarone infusion was administered. Her initial laboratory evaluation revealed hypokalemia (2.8 mEq/L; to convert to millimoles per liter, multiply by 1.0), hypomagnesemia (3.6 mEq/L; to convert to millimoles per liter, multiply by 0.50), and an elevated serum troponin (0.13 nanograms per milliliter; to convert to micrograms per milliliter, multiply by 1.0). Potassium and magnesium replacement was administered orally and intravenously. She reported no family history of sudden cardiac death or unexplained premature death. A transthoracic echocardiogram showed normal biventricular size and function.Twelve-lead electrocardiograms (ECGs) obtained on presentation (A) and immediately after electrical cardioversion (B). What Would You Do Next?

Coronary angiography

Ambulatory cardiac monitoring after electrolyte repletion

Cardiac magnetic resonance imaging

Invasive electrophysiology study

Arrhythmogenic right ventricular cardiomyopathy

C

Cardiac magnetic resonance imaging

The initial and postcardioversion ECGs raise suspicion for an underlying structural abnormality, and further characterization with additional imaging is recommended. The initial ECG (Figure, A) shows a regular wide complex tachycardia with a rate of 225 beats per minute. The inferior axis and left bundle-branch block pattern in the precordial leads with late transition (V5) are consistent with ventricular tachycardia (VT) originating in the right ventricular outflow tract. Once the rhythm was determined to be VT, the initial differential diagnosis for this relatively young woman with electrolyte abnormalities, no cardiac history, and no family history of sudden cardiac death included both structural and nonstructural processes.The first available data were her history of purging behavior and hypokalemia on presentation, and it was initially considered whether this electrolyte derangement might be sufficient to explain her presentation on its own. However, it would be very unusual for sustained monomorphic VT to occur solely as a result of mild hypokalemia (choice B). Furthermore, a review of the ECGs suggests a right ventricular (RV) structural abnormality. While the initial rhythm was consistent with right ventricular outflow tract VT (Figure, A), the subsequent ECG (Figure, B) showed distinct ventricular complexes arising elsewhere in the RV, along with RV repolarization abnormalities with T-wave inversions in V1-V3 on the initial postcardioversion ECG (Figure, B). The multiform ventricular complexes and repolarization abnormalities on the ECG with sinus rhythm raise the suspicion of arrhythmogenic right ventricular cardiomyopathy (ARVC) or its mimics, such as myocarditis or sarcoidosis. These features also suggest against idiopathic right ventricular outflow tract VT, which occurs in the absence of structural heart disease, and tends to be adenosine responsive.1The suspicion for acute coronary syndrome leading to VT was low, based on the absence of chest pain and cardiac risk factors (choice A). While an invasive electrophysiology study would provide further information about the foci and mechanisms of VT, it would not differentiate between the structural processes suggested by the ECG data (choice D).Given the concern for an underlying structural abnormality, further workup, including imaging with multiple modalities, was pursued. A cardiac magnetic resonance imaging study showed borderline reduced RV ejection fraction (47%), borderline increased RV end-diastolic volume, and dyskinesis of the base of the RV (Video). A cardiac positron emission tomography scan showed no evidence of an infiltrative or inflammatory process. On a subsequent electrophysiology study, there were multiple inducible RV VTs of a focal mechanism.The findings of RV dyskinesia and mildly depressed RV ejection fraction on cardiac magnetic resonance imaging, along with the presenting arrhythmia and ECG repolarization abnormalities, met revised task force criteria for the diagnosis of ARVC (1 major and 2 minor criteria).2 Arrhythmogenic right ventricular cardiomyopathy is a heritable disorder characterized by loss of RV myocardium and replacement by fibrofatty tissue, and it is one of the leading causes of arrhythmic cardiac arrest in young people.3 The prevalence of ARVC is approximately 1 in 5000 in the general population and is higher in some European countries.4 The causative mechanism of arrhythmias in ARVC is thought to be multifactorial, with contributions from a scar-associated macroreentry mechanism associated with fibrofatty replacement, as well as changes on the cellular level in proteins important to cell-to-cell adhesion.5,6 For the clinical diagnosis of ARVC, there are guidelines consisting of a qualitative scoring system with major and minor criteria. Patients are evaluated along the criteria of global and regional structural variations and dysfunction, tissue characterization, repolarization abnormalities, depolarization and conduction abnormalities, arrhythmias, and family history.2The patient underwent placement of a subcutaneous implantable cardioverter-defibrillator. She started treatment with an oral β-blocker and was instructed to avoid vigorous exercise. She underwent genetic testing, which did not identify a causal mutation; we note that current generation genetic testing has a yield of approximately 50%.7 In the context of discontinuing β-blockers, she subsequently had recurrence of VT with appropriate implantable cardioverter-defibrillator therapy.

Cardiology

A woman in her 30s with active bulimia was brought by ambulance to the emergency department after a syncopal event that followed 1 hour of palpitations and intermittent lightheadedness. When emergency responders arrived, the patient was responsive but groggy. An electrocardiogram (ECG) in the field demonstrated a regular wide complex tachycardia. En route to the hospital, 6 mg of adenosine followed by 12 mg of adenosine were administered intravenously, without a change in her rhythm.On arrival to the emergency department, she was in a regular wide complex tachycardia with a heart rate of 225 beats per minute (Figure, A), with an initial blood pressure of 108/77 mm Hg. She was oriented but slow to respond. After sedation, a synchronized, biphasic, 200-J shock converted her to sinus rhythm with bigeminy (Figure, B), which settled to normal sinus rhythm. An intravenous amiodarone infusion was administered. Her initial laboratory evaluation revealed hypokalemia (2.8 mEq/L; to convert to millimoles per liter, multiply by 1.0), hypomagnesemia (3.6 mEq/L; to convert to millimoles per liter, multiply by 0.50), and an elevated serum troponin (0.13 nanograms per milliliter; to convert to micrograms per milliliter, multiply by 1.0). Potassium and magnesium replacement was administered orally and intravenously. She reported no family history of sudden cardiac death or unexplained premature death. A transthoracic echocardiogram showed normal biventricular size and function.Twelve-lead electrocardiograms (ECGs) obtained on presentation (A) and immediately after electrical cardioversion (B).

what would you do next?

What would you do next?

Coronary angiography

Invasive electrophysiology study

Cardiac magnetic resonance imaging

Ambulatory cardiac monitoring after electrolyte repletion

c

female

31-40

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2754750

A 0-day-old female neonate exhibited loud stridor and respiratory distress at birth. The pregnancy was uncomplicated, and prenatal ultrasonography results were normal. After spontaneous vaginal delivery at 37 weeks’ gestation, the neonate immediately developed tachypnea, severe retractions, barking cough, hoarse cry, and dusky appearance with oxygen desaturations to 60%, which required continuous positive airway pressure. Despite respiratory support, she was intubated within the first hour of life. The intubating clinician noted a large flesh-colored laryngeal mass and placed a size 3.5 uncuffed endotracheal tube. Ear, nose, and throat evaluation noted that the neonate was intubated and ventilating easily. No craniofacial abnormalities or obvious oral cavity, oropharyngeal, or neck masses were present. Chest radiography was obtained, and results were normal. The patient was subsequently taken to the operating room for direct laryngoscopy and bronchoscopy. Intraoperative evaluation revealed a large submucosal mass involving the left side of the epiglottis, false fold, aryepiglottic fold, and arytenoid that was soft and fluctuant on palpation (Figure 1).Direct laryngoscopy revealed a large mass involving the left side of the epiglottis, false fold, aryepiglottic fold, and arytenoid. What Is Your Diagnosis?

Granular cell tumor

Laryngeal neurofibroma

Lateral saccular cyst

Macrocystic lymphatic malformation

C. Lateral saccular cyst

C

Lateral saccular cyst

Congenital laryngeal cysts are a rare yet important cause of stridor, respiratory distress, and airway obstruction in neonates. Timing of presentation can vary from shortly after birth, to late infancy, to early childhood.1-7 Saccular cysts are fluid-filled submucosal lesions that arise from the laryngeal saccule and often appear in the anterior aspect of the ventricle. These cysts do not communicate with the laryngeal lumen, as opposed to laryngoceles, which typically contain air or air-fluid levels because they are open to the lumen. However, some controversy exists in the nomenclature of these lesions because they are histologically similar. DeSanto et al2 classified laryngeal saccular cysts into 2 types: anterior and lateral. Anterior cysts enlarge medially and posteriorly between the true and false vocal folds. Lateral cysts progress in a posterosuperior direction, which results in distention of the false vocal fold and aryepiglottic fold, as seen in this neonate.Large lateral saccular cysts can present at birth with symptoms of airway compromise that necessitate emergent airway management. Smaller lesions present with coughing, voice changes, cyanotic episodes, poor feeding, and failure to thrive. In nonurgent scenarios, flexible fiberoptic laryngoscopy leads to a suspected diagnosis of lateral saccular cyst. No preoperative radiographic imaging is necessary. The literature emphasizes all patients should be taken to the operating room within 24 hours for endoscopy and surgical management.1In the present patient’s case, on day 1 of life, the cyst was marsupialized. Cold steel instruments were used to incise the mucosa on a posterior and lateral portion of the fluctuant cyst wall in close proximity to the esophageal inlet. A large release of clear mucoid fluid occurred. The opening was expanded by resecting tissue to create a 0.5-cm diameter opening. Three weeks later, the patient showed difficulty maintaining a latch while breastfeeding, and results of follow-up flexible fiberoptic laryngoscopy revealed recurrence of the cyst with 90% obstruction of the supraglottic airway.At 22 days of life, she underwent endoscopic extended ventriculotomy (Figure 2) per the technique described by Kirse et al.1 During direct laryngoscopy, the site of the previous marsupialization was indistinguishable from the surrounding mucosa. The cyst wall was entered on the area of maximal fluctuance above the false fold. The cyst was again decompressed, and the incision was extended anteriorly toward the anterior commissure. Inferiorly, the incision was extended through the false vocal fold and ventricle until it was at the superior limit of the true vocal fold. The resected tissue consisted of the false vocal fold, ventricle, and the redundant mucosa that was medial to the aryepiglottic fold.The medial wall of the cyst was removed along with the false vocal fold and ventricle, marsupializing the cyst and preserving the true vocal fold.The patient was extubated uneventfully in the operating room and transferred to the pediatric intensive care unit for airway monitoring. She breastfed on the day of surgery and demonstrated an immediate improvement in her ability to coordinate breathing and swallowing. She was discharged home on the first postoperative day. She was seen in clinic 1 week after surgery and then every 2 weeks thereafter for 2 months for flexible laryngoscopy to evaluate for recurrence of the cyst. During telephone follow-up 4 months after surgery, no parental concerns were reported.In general, the best choice of surgical approach is debated. Endoscopic marsupialization alone has traditionally been used as the mainstay of treatment; however, recurrence is common, which was seen after the initial drainage procedure in this patient. Mitchell et al3 described 7 of 17 patients (41%) who required further deroofing. Other endoscopic techniques include marsupialization with laser ablation of the cyst lining4 and endoscopic extended ventriculotomy.1 External approaches generally are reserved for endoscopic failures or complex lesions. Because of the rarity of this lesion, it is unlikely that a study of sufficient size would be possible to compare outcomes of different approaches.Lateral saccular cyst is a rare but important cause to include in the differential diagnosis of neonates who present with potentially life-threatening stridor and respiratory distress shortly after birth. When this type of lesion is present, timely operative management is necessary to secure and manage the airway.

General

A 0-day-old female neonate exhibited loud stridor and respiratory distress at birth. The pregnancy was uncomplicated, and prenatal ultrasonography results were normal. After spontaneous vaginal delivery at 37 weeks’ gestation, the neonate immediately developed tachypnea, severe retractions, barking cough, hoarse cry, and dusky appearance with oxygen desaturations to 60%, which required continuous positive airway pressure. Despite respiratory support, she was intubated within the first hour of life. The intubating clinician noted a large flesh-colored laryngeal mass and placed a size 3.5 uncuffed endotracheal tube. Ear, nose, and throat evaluation noted that the neonate was intubated and ventilating easily. No craniofacial abnormalities or obvious oral cavity, oropharyngeal, or neck masses were present. Chest radiography was obtained, and results were normal. The patient was subsequently taken to the operating room for direct laryngoscopy and bronchoscopy. Intraoperative evaluation revealed a large submucosal mass involving the left side of the epiglottis, false fold, aryepiglottic fold, and arytenoid that was soft and fluctuant on palpation (Figure 1).Direct laryngoscopy revealed a large mass involving the left side of the epiglottis, false fold, aryepiglottic fold, and arytenoid.

what is your diagnosis?

What is your diagnosis?

Macrocystic lymphatic malformation

Lateral saccular cyst

Laryngeal neurofibroma

Granular cell tumor

b

female

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2756212

A 69-year-old man with a history of metastatic squamous cell carcinoma in the left parotid gland had undergone left parotidectomy and modified neck dissection followed by adjuvant radiation therapy 12 years previously. Ten years later, he developed a second primary tumor in the hypopharynx requiring total laryngectomy and bilateral neck dissection. He presented with new-onset headaches, left ear pain, and persistent unsteadiness during the previous month. There was no palpable lymphadenopathy, neurological deficits, or mastoid tenderness, and otoscopic examination results of the tympanic membrane appeared normal.Magnetic resonance imaging of the head showed an enhancing lesion in the left infratemporal fossa (3.4 × 3.4 × 2.8 cm) abutting the cerebellum, and subsequent computed tomographic imaging of the head demonstrated osseous destruction of the left temporal bone extending along the left internal jugular vein (Figure, A). Fine-needle aspiration of the left mastoid showed atypical spindle cells. The patient underwent tumor excision with a left infratemporal approach. A large mass with rubbery texture was noted, extending into the jugular foramen and adherent to the dura mater without evidence of intradural invasion. The lower cranial nerves were identified, and the mass was resected to the external wall of the jugular bulb. The patient tolerated the procedure without complications or neurological deficits. Histopathologic assessment demonstrated myogenin-positive spindle cells with no tumor necrosis (Figure, B and C). In addition, the tumor expressed desmin-positive and CD34-positive cells. The tumor focally infiltrated into the fibrous tissue, skeletal muscle, and bone.A, Axial computed tomography of the head and neck demonstrating osseous destruction of the left temporal bone. B and C, Histopathologic test results. B, High-powered view of hematoxylin-eosin stain (original magnification ×40) demonstrating spindle cell morphologic features with admixed fragments of bone (pink-red areas). C, High-powered view of myogenin stain (original magnification ×40) depicting small-cell or spindle cell morphologic features with rare positive results for myogenin (brown cells). What Is Your Diagnosis?

Malignant fibrous histiocytoma

Paraganglioma

Squamous cell carcinoma

Spindle cell rhabdomyosarcoma

D. Spindle cell rhabdomyosarcoma

D

Spindle cell rhabdomyosarcoma

Rhabdomyosarcoma is a rare, aggressive, soft-tissue malignant tumor originating from undifferentiated striated skeletal muscle. Spindle cell/sclerosing rhabdomyosarcoma (SCSR) is one of 4 subtypes of rhabdomyosarcoma (embryonal, alveolar, pleomorphic, and SCSR) classified by the World Health Organization since 2013.1 Because SCSR is a newly classified and rare subtype, there is limited literature addressing risk factors, treatments, and prognosis. Spindle cell/sclerosing rhabdomyosarcoma makes up 5% to 13% of all rhabdomyosarcoma cases and is more common in adults, unlike embryonal and alveolar rhabdomyosarcoma, which are seen predominantly in children.2The head and neck is the most common site of rhabdomyosarcoma, with an incidence rate of fewer than 1 case per 2 million people per year, making up 35% of all rhabdomyosarcoma cases.3 Within the head and neck, rhabdomyosarcoma can be classified into orbital, parameningeal (ie, ear, mastoid, nasal cavity, paranasal sinuses, infratemporal fossa, pterygopalatine fossa), and nonorbital nonparameningeal (ie, palate, parotid, tongue, any other head and neck sites) types.3 Parameningeal tumors, as in this patient, have the worst 5-year relative survival rate (49.1%) of any type and are more likely to present with regional or distant metastases, especially in adults.3 Parameningeal rhabdomyosarcoma, specifically of the infratemporal fossa in adults, has limited literature owing to its rarity.4Previous radiation treatment is a known risk factor for the development of head and neck sarcoma, termed radiation-induced sarcoma of the head and neck (RISHN). The lifetime risk of developing RISHN following head and neck radiation treatment is 0.3%, often with a latency period of more than 15 years.5,6 Fibrous dysplasia is also a risk factor for RISHN following radiation treatment.7 Children have a 9-fold greater risk of radiation-induced sarcoma compared with the general population, and this type of tumor is quite rare in adults.8 The rate of RISHN has been shown to increase with increasing doses of radiation.5 Prognosis in RISHN is poor, with a 30% absolute decrease in overall survival rate compared with de novo sarcomas.6 To our knowledge, no literature to date specifically describes radiation-induced head and neck rhabdomyosarcoma.Spindle cell/sclerosing rhabdomyosarcoma should be considered in the differential diagnosis in patients with destructive lesions who have undergone previous radiation treatment of the head and neck. The differential diagnosis of SCSR is predominantly based on tumor location, aggressiveness, patient age, and histopathologic characteristics with immunohistochemical staining. Fibrosarcoma, leiomyosarcoma, spindle cell carcinoma, and SCSR are all types of malignant tumors that can be found in the head and neck in adults with spindle cells that appear on histopathologic tests.2,9 Immunohistochemical staining can further delineate malignant spindle cell tumors. In most cases, SCSR stains are positive for desmin, vimentin, and myogenin or myoblast determination protein 1 (muscular immunomarkers). Leiomyosarcoma and fibrosarcoma stains are also positive for desmin and vimentin, respectively, but neither stain is positive for muscular immunomarkers.2,9 If SCSR stains are not positive for muscle immunomarkers, delineation between leiomyosarcoma or fibrosarcoma and SCSR can be difficult. Spindle cell carcinoma, a variant of squamous cell carcinoma, is of epithelial origin and exhibits positive results for cytokeratins on immunohistochemical stains, unlike SCSR.9Treatment for rhabdomyosarcoma of the head and neck in adults largely relies on surgical excision when possible, followed by adjuvant radiation or systemic chemotherapy if the residual tumor or metastasis is present.10 Despite aggressive therapy, the 5-year overall survival rate for head and neck rhabdomyosarcoma is 36%.10 A better understanding of the molecular makeup of rhabdomyosarcoma and genetic changes with previous radiation therapy may offer more effective treatment options in the future.

General

A 69-year-old man with a history of metastatic squamous cell carcinoma in the left parotid gland had undergone left parotidectomy and modified neck dissection followed by adjuvant radiation therapy 12 years previously. Ten years later, he developed a second primary tumor in the hypopharynx requiring total laryngectomy and bilateral neck dissection. He presented with new-onset headaches, left ear pain, and persistent unsteadiness during the previous month. There was no palpable lymphadenopathy, neurological deficits, or mastoid tenderness, and otoscopic examination results of the tympanic membrane appeared normal.Magnetic resonance imaging of the head showed an enhancing lesion in the left infratemporal fossa (3.4 × 3.4 × 2.8 cm) abutting the cerebellum, and subsequent computed tomographic imaging of the head demonstrated osseous destruction of the left temporal bone extending along the left internal jugular vein (Figure, A). Fine-needle aspiration of the left mastoid showed atypical spindle cells. The patient underwent tumor excision with a left infratemporal approach. A large mass with rubbery texture was noted, extending into the jugular foramen and adherent to the dura mater without evidence of intradural invasion. The lower cranial nerves were identified, and the mass was resected to the external wall of the jugular bulb. The patient tolerated the procedure without complications or neurological deficits. Histopathologic assessment demonstrated myogenin-positive spindle cells with no tumor necrosis (Figure, B and C). In addition, the tumor expressed desmin-positive and CD34-positive cells. The tumor focally infiltrated into the fibrous tissue, skeletal muscle, and bone.A, Axial computed tomography of the head and neck demonstrating osseous destruction of the left temporal bone. B and C, Histopathologic test results. B, High-powered view of hematoxylin-eosin stain (original magnification ×40) demonstrating spindle cell morphologic features with admixed fragments of bone (pink-red areas). C, High-powered view of myogenin stain (original magnification ×40) depicting small-cell or spindle cell morphologic features with rare positive results for myogenin (brown cells).

what is your diagnosis?

What is your diagnosis?

Paraganglioma

Spindle cell rhabdomyosarcoma

Squamous cell carcinoma

Malignant fibrous histiocytoma

b

male

61-70

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2756213

A 6-month-old infant presented with a congenital papule that had been growing proportionally in size to the infant since birth (Figure 1). No associated pain or pruritus was noted, and the papule had never bled or produced other fluid or debris. The infant had no other congenital anomalies and had been meeting all major developmental milestones. On clinical examination, a superficial, white-yellow papule was identified on the anterior surface of the neck, situated at the midline superior to the sternal notch. It measured 6 mm in diameter and was not associated with overlying surface changes or evident discharge. Dermoscopy results showed scattered telangiectatic vessels over the papule, accentuated peripherally.A smooth, subcutaneous papule with a yellow tint is present above the suprasternal notch and exposed with retraction of skinfolds of the anterior neck.Ultrasonography was performed to further characterize the papule, and imaging results exhibited a superficial cutaneous lesion without evidence of tracking into deeper layers of subcutaneous tissue or fluid collection. Active nonintervention was recommended, but because of continued parental concern, the lesion was shaved off in clinic and sent for histopathologic evaluation to rule out malignant neoplasm and other morbid diagnoses. What Is Your Diagnosis?

Eruptive vellus hair cyst

Thyroglossal duct cyst

Cutaneous bronchogenic cyst

Midline anterior neck inclusion cyst

D. Midline anterior neck inclusion cyst

D

Midline anterior neck inclusion cyst

Hematoxylin-eosin–stained slides demonstrated a single transected dermal cyst lined by stratified squamous epithelium with a confluent granular layer and filled with abundant keratin and few, scattered hair shafts (Figure 2). Rare sebaceous glands were associated with the cyst wall. The diagnosis of midline anterior neck inclusion cyst (MANIC) was made.The dermal cyst, lined by keratinizing squamous epithelium with a granular layer, is filled with keratinous debris and scattered hair shafts. The lightly pigmented skin surface is at the top (hematoxylin-eosin, original magnification ×100).Neck masses, whether congenital, inflammatory, or neoplastic in origin, are common in pediatric patients.1 Congenital defects develop when anatomic structures fail to form properly or regress completely or when embryonic tissues do not fuse appropriately.2 Identifying the location and depth of a neck mass is central to accurate diagnosis and management.3As described by Walsh et al,2MANIC refers to congenital papules that are located at the midline anterior neck at the suprasternal notch and superficially situated within the skin without deeper subcutaneous extension. They clinically and histologically resemble epidermal inclusion cysts or giant milia.2 Histologically, this patient’s MANIC exhibited characteristic squamous epithelial lining with a confluent granular layer and central orthokeratosis but additionally demonstrated few luminal hair shafts and associated pilosebaceous units, akin to a dermoid cyst, expanding the histologic phenotype of MANICs. Although dermoid cysts with classic histologic features can uncommonly be located at the midline neck,4 this patient’s papule was clinically inconsistent with this diagnosis because dermoid cysts are situated more deeply without apposition to the overlying skin.4 Although both MANICs and dermoid cysts occur secondary to improper closure of embryonic fusion planes, typical dermoid cysts mimic other congenital masses more frequently encountered at the midline neck and warrant further radiologic evaluation; definitive treatment requires excision. In contrast, MANICs do not require additional imaging. Although treatment may include surgical removal, these cysts can also spontaneously regress with time, and observation may be appropriate.2Thyroglossal duct cysts represent the most common midline anterior neck anomaly in children.3,5 They form when a segment of the thyroglossal duct persists as the thyroid descends from the foramen cecum of the tongue to the base of the neck during embryonic development. They are most commonly noted at the level of the hyoid bone and may present as asymptomatic nodules or draining sinuses at the midline anterior neck; however, given their predisposition to infection, they may also appear as enlarged, painful subcutaneous masses.3,5 Thyroglossal duct cysts are traditionally situated more deeply than MANICs.1,5 Computed tomography is the preferred imaging modality to evaluate thyroglossal duct cysts, which can be surgically removed via the Sistrunk procedure.1,6Cutaneous bronchogenic cysts are rare congenital developmental anomalies of the embryonic foregut that most frequently present as subcutaneous swellings or draining sinuses at the suprasternal notch or presternal area.7,8 Unlike thyroglossal duct cysts, cutaneous bronchogenic cysts infrequently have overlying skin changes, though associated hyperkeratotic papules have been reported.8 Moreover, cutaneous bronchogenic cysts are often situated in subcutaneous tissue and may enlarge and become productive of mucoid discharge, distinct from MANICs.2 Computed tomography or magnetic resonance imaging can confirm the anomaly and evaluate for deeper extension. Histologically, cutaneous bronchogenic cysts exhibit pseudostratified columnar respiratory epithelium lining the cyst, sometimes accompanied by cartilage or concentric smooth muscle.7,8 Surgical resection is the treatment of choice, though asymptomatic cysts may not require removal.8Eruptive vellus hair cysts (EVHCs) typically appear in individuals younger than 25 years as multiple flesh-colored to hyperpigmented papules on the chest, back, or abdomen.9 These asymptomatic lesions may produce greasy material. Instances of unilesional EVHCs are rare but typically present on the face in young adults. To our knowledge, no congenital cases of unilesional EVHCs have been reported.9 Histologically, EVHCs are characterized by a lining of squamous epithelium with an attenuated granular layer. These cysts are filled with numerous small vellus hair shafts and keratin.9 Epidermal cysts with overlapping histologic features of EVHC have previously been reported,10 which suggests that these cysts may exist on a spectrum of differentiation.In this patient, the congenital onset and distinct location and appearance of the papule support a diagnosis of MANIC. Health care professionals should be aware of this entity to avoid unnecessary and costly imaging and evaluation.

General

A 6-month-old infant presented with a congenital papule that had been growing proportionally in size to the infant since birth (Figure 1). No associated pain or pruritus was noted, and the papule had never bled or produced other fluid or debris. The infant had no other congenital anomalies and had been meeting all major developmental milestones. On clinical examination, a superficial, white-yellow papule was identified on the anterior surface of the neck, situated at the midline superior to the sternal notch. It measured 6 mm in diameter and was not associated with overlying surface changes or evident discharge. Dermoscopy results showed scattered telangiectatic vessels over the papule, accentuated peripherally.A smooth, subcutaneous papule with a yellow tint is present above the suprasternal notch and exposed with retraction of skinfolds of the anterior neck.Ultrasonography was performed to further characterize the papule, and imaging results exhibited a superficial cutaneous lesion without evidence of tracking into deeper layers of subcutaneous tissue or fluid collection. Active nonintervention was recommended, but because of continued parental concern, the lesion was shaved off in clinic and sent for histopathologic evaluation to rule out malignant neoplasm and other morbid diagnoses.

what is your diagnosis?

What is your diagnosis?

Eruptive vellus hair cyst

Cutaneous bronchogenic cyst

Thyroglossal duct cyst

Midline anterior neck inclusion cyst

d

neutral

0-10

White

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2757275

A 25-year-old woman presented with a 6-month history of an enlarging right neck mass. The patient had a history of polycystic ovarian syndrome with insulin resistance and a migraine disorder and reported experiencing 1 to 2 migraine episodes per week since early high school. She believed that the neck mass made these episodes worse than normal. The patient was otherwise previously healthy until she developed an upper respiratory infection. Her physician noted visible swelling in the right neck and clinically interpreted the finding as enlarged lymph nodes associated with the infection. After 2 weeks, the neck swelling persisted despite the resolution of other symptoms. She was subsequently treated with a course of antibiotics, which did not result in any improvement. The mass slowly enlarged over the next 6 months. The patient reported new symptoms, including waxing and waning pain that radiated to the back of her neck, headaches, and intermittent dysphagia. She also noted periods during which the mass would fluctuate in size.Otolaryngologic examination findings were within normal limits except for a single, nontender, compressible right neck mass deep to the sternocleidomastoid muscle and extending into level V. The patient underwent a computed tomography (CT) scan prior to presentation at the Dartmouth-Hitchcock Medical Center’s otolaryngology clinic. The scan showed a fatty-appearing tumor within the right carotid space. The patient underwent surgical excision, and a mass measuring 8.0 × 6.5 × 4.7–cm was removed from the carotid space (Figure, A). Additional material from the mass was excised at the level of the base of the skull. Gross pathologic examination demonstrated yellowish-brown, homogenous, lobular adipose tissue covered by a thin, tan, transparent membrane (Figure, A). Histopathologic examination showed relatively uniform univacuolar and multivacuolated, granular eosinophilic cells with centrally placed nucleoli (Figure, B and C). In addition, several level II and level III lymph nodes were excised, all of which were found to be benign.A, The 8.0 × 6.5 × 4.7–cm mass was surgically excised from the patient’s carotid space. B and C, Histologic results show uniform univacuolar to multivacuolated granular eosinophilic cells with centrally placed nucleoli (hematoxylin-eosin). The cells have a distinct cellular membrane and characteristic small lipid droplets. What Is Your Diagnosis?

Liposarcoma

Hibernoma

Angiolipoma

Lipoma

B. Hibernoma

B

Hibernoma

Hibernomas are rare, painless, slow-growing benign adipocytic tumors that are typically large on initial presentation, with a reported average size of greater than 10 cm.1 Clinically, they are described as well-defined, freely mobile, and asymptomatic. Unusual symptoms, such as dysphagia or difficulty in breathing, are associated with compression or displacement of nearby structures. To our knowledge, no cases of distant metastasis or malignant transformation have been described in the literature.2In 1914, the term hibernoma was proposed owing to the tumor’s similar appearance to brown fat seen in the glands of hibernating mammals.1 In fetuses, brown adipose tissue is thought to play an important role in thermoregulation.3 Brown fat is found in newborns and the amount in the body decreases with age.4Hibernomas mainly occur in adults between the ages of 20 to 40 years, but they can be encountered in a wide age range (2-75 years).5,6 Hibernomas may be misdiagnosed as lipomas. Approximately 100 cases have been reported in the literature, with the affected locations in the body being predominantly in the subcutaneous regions of the axilla, paravertebrally in the back, mediastinum, and shoulders, areas known to harbor vestigial fetal fat. However, hibernomas have also been reported on other anatomical locations such as the popliteal fossa and the thighs.3 Prior literature has described approximately 10 cases of hibernomas in the head and neck region.7 Despite their benign course, hibernomas are difficult to distinguish from malignant tumors solely by their clinical presentation and examination findings.Computed tomography, magnetic resonance imaging, and angiography are helpful imaging modalities for diagnostic evaluation of a potential hibernoma. On CT and magnetic resonance imaging, hibernomas appear as well-circumscribed, heterogeneous masses. In addition, hibernomas are contrast-enhancing masses and have a high signal intensity that is noted to be in the intermediate range between muscle and fat.1 Fat suppression on imaging could be incomplete depending on the variable lipid content of hibernomas. In positron emission tomography-CT, hibernomas typically appear to be metabolically active owing to abundant mitochondria. Positron emission tomography scans may be helpful in distinguishing a hibernoma from a lipoma, but it is not helpful in differentiating a hibernoma from other malignant entities.6On microscopic examination, hibernomas display a lobulated pattern composed of uniform, round, granular, eosinophilic cells to multivacuolated cells with centrally placed nuclei. Intermixed univacuolar cells and peripherally placed nuclei resembling adipocytes are also seen. Four histologic variants have been described, each of which has the same clinical presentation and benign course. The variants include typical, myxoid, lipoma-like, and spindle cells. Cytogenic analysis of hibernomas have revealed structural rearrangements of chromosome 11q13.8 Preliminary data demonstrate that the GARP gene, which codes for a transmembrane protein involved in immune function, may have a role in hibernoma pathogenesis.8The clinical differential diagnosis includes other benign entities such as lipoma, angiolipoma, and hemangioma. Malignant tumors such as liposarcoma, rhabdomyosarcoma, lymphoma, and undifferentiated pleomorphic sarcoma should also be considered. Surgical resection is the recommended course of treatment of hibernoma. No recurrence has been reported after resection.5In the present case, the patient reported intermittent dysphagia, which was likely explained by esophageal compression owing to the location of the hibernoma. In general, hibernomas grow slowly; however, there are reports of rapid growth as well.9 This patient reported waxing and waning growth associated with her symptoms of dysphagia, but we do not have any objective measurements or clinical records demonstrating fluctuating growth, which would explain her symptoms. She has not demonstrated a recurrence since she underwent surgical resection.

General

A 25-year-old woman presented with a 6-month history of an enlarging right neck mass. The patient had a history of polycystic ovarian syndrome with insulin resistance and a migraine disorder and reported experiencing 1 to 2 migraine episodes per week since early high school. She believed that the neck mass made these episodes worse than normal. The patient was otherwise previously healthy until she developed an upper respiratory infection. Her physician noted visible swelling in the right neck and clinically interpreted the finding as enlarged lymph nodes associated with the infection. After 2 weeks, the neck swelling persisted despite the resolution of other symptoms. She was subsequently treated with a course of antibiotics, which did not result in any improvement. The mass slowly enlarged over the next 6 months. The patient reported new symptoms, including waxing and waning pain that radiated to the back of her neck, headaches, and intermittent dysphagia. She also noted periods during which the mass would fluctuate in size.Otolaryngologic examination findings were within normal limits except for a single, nontender, compressible right neck mass deep to the sternocleidomastoid muscle and extending into level V. The patient underwent a computed tomography (CT) scan prior to presentation at the Dartmouth-Hitchcock Medical Center’s otolaryngology clinic. The scan showed a fatty-appearing tumor within the right carotid space. The patient underwent surgical excision, and a mass measuring 8.0 × 6.5 × 4.7–cm was removed from the carotid space (Figure, A). Additional material from the mass was excised at the level of the base of the skull. Gross pathologic examination demonstrated yellowish-brown, homogenous, lobular adipose tissue covered by a thin, tan, transparent membrane (Figure, A). Histopathologic examination showed relatively uniform univacuolar and multivacuolated, granular eosinophilic cells with centrally placed nucleoli (Figure, B and C). In addition, several level II and level III lymph nodes were excised, all of which were found to be benign.A, The 8.0 × 6.5 × 4.7–cm mass was surgically excised from the patient’s carotid space. B and C, Histologic results show uniform univacuolar to multivacuolated granular eosinophilic cells with centrally placed nucleoli (hematoxylin-eosin). The cells have a distinct cellular membrane and characteristic small lipid droplets.

what is your diagnosis?

What is your diagnosis?

Liposarcoma

Lipoma

Hibernoma

Angiolipoma

c

female

21-30

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2755961

A 51-year-old man diagnosed as having acute promyelocytic leukemia, undergoing induction therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide that were started 2 weeks prior, presented with sudden loss of vision. Hospital course was complicated by neutropenic fever, receiving cefepime, acyclovir, vancomycin, and voriconazole for prophylaxis. Laboratory test results were remarkable for pancytopenia. On initial examination, his visual acuity was count fingers at 3 ft in both eyes. Intraocular pressures were 10 mm Hg OD and 11 mm Hg OS. Pupils were round and reactive without a relative afferent pupillary defect. Color plates were 1 of 8 OU, with 50% brightness desaturation in the right eye and no red desaturation. Extraocular movements were full. Slitlamp examination was negative for any signs of inflammation. Dilated fundus examination demonstrated bilateral choroidal effusions with diffuse serous retinal detachments (RD) involving the macula without vitritis as well as white centered intraretinal hemorrhages along peripapillary and superior and inferior arcade distributions in both eyes (Figure, A). Optical coherence tomography demonstrated irregular inner retinal surface and subretinal fluid with septae with loss of the ellipsoid zone (Figure, B). Review of systems was positive for fever, tachycardia, odynophagia, productive cough with wheezing, and marked peripheral edema in upper extremities and negative for headache, nausea, vomiting, dysacusis, meningismus, or skin changes.Fundus photographs and optical coherence tomography 4 days from presentation demonstrating bilateral choroidal effusions with serous retinal detachment and white centered intraretinal hemorrhages. Left eye results shown. A, Left eye color fundus photograph demonstrates peripheral choroidal effusion with areas of stippled subretinal fluid in the macula, areas of intraretinal hemorrhages scattered throughout the posterior pole as well as far temporal periphery. B, Optical coherence tomography of the left eye demonstrating corrugated inner retina with intraretinal and subretinal fluid with septae from further separation of the external limiting membrane and ellipsoid zone as well as some loss of the ellipsoid zone.Order magnetic resonance imaging of brain and orbits with and without contrast and lumbar puncture What Would You Do Next?

Continue chemotherapy therapy and observe

Order magnetic resonance imaging of brain and orbits with and without contrast and lumbar puncture

Stop the ATRA and start steroids

Send HLA-B51 and start steroids

Differentiation syndrome secondary to all-trans-retinoic acid and arsenic trioxide

C

Stop the ATRA and start steroids

Acute promyelocytic leukemia (APL) is an aggressive acute myeloid leukemia characterized by a balanced reciprocal translocation between chromosomes 15 and 17 resulting in a PML-RARα fusion gene; it is also characterized by coagulopathy with lymphocytic blast cell morphology.1 The mainstay of induction therapy for APL is ATRA with arsenic trioxide, with or without anthracycline-based chemotherapy. All-trans-retinoic acid induction therapy leads to terminal differentiation of the malignant blast cell progenitors.Differentiation syndrome (DS) is a well-known, life-threatening complication of induction therapy with ATRA and arsenic trioxide. The incidence of DS after starting induction therapy ranges from 2.5% to 31%.2 Luesink et al2 suggest that DS is caused by excessive systemic inflammation from chemokines inducing a life-threatening capillary leak syndrome. It classically presents with unexplained fever, respiratory distress, hemodynamic instability, peripheral edema, acute kidney injury, and pleuropericardial effusions. Our patient demonstrated fever, wheezing with pulmonary infiltrates, and bilateral upper extremity edema. On literature search, we found 3 other documented cases of DS presenting with bilateral serous RD, manifesting with only subretinal fluid and no intraretinal fluid or choroidal effusions.3,4 In 2 of these 3 cases, ATRA was discontinued and steroids were started, leading to resolution of the subretinal fluid. Our case would represent, to our knowledge, the first reported ophthalmic DS with choroidal effusion and serous RD with intraretinal fluid. Treatment of DS typically entails pausing ATRA and starting systemic steroids.3,4 Given this patient’s constellation of systemic symptoms and prior reports of serous RD in the setting of DS, the patient started receiving intravenous dexamethasone (choice C).The differential diagnosis of choroidal effusions with serous RD includes infectious or inflammatory etiologies (including scleritis and Voyt-Kayanagi-Harada), malignancy, trauma, uveal effusion syndrome, drug reaction, and intraoperative/postoperative complication of intraocular surgery. While rare, leukemia has been known to present with serous RD.5,6 However, this patient was already undergoing treatment for APL at presentation, and the patient had systemic and retinal symptoms of DS similar to 2 prior reports of ophthalmic DS. While observing the patient was a possible option (choice A), because he was hemodynamically stable, starting intravenous steroids prevented systemic deterioration and hastened resolution of the patient’s pleural effusions, peripheral edema, and bilateral choroidal effusions with serous RD.Pseudotumor cerebri is a well-documented complication of ATRA and was the initial concern when the patient presented with sudden vision loss.7 However, the patient denied any symptoms of elevated intracranial pressure, including headache, nausea, vomiting, or tinnitus. Furthermore, fundus examination revealed disc margins that were well defined without disc elevation. Thus, while magnetic resonance imaging of the brain or orbits may later be helpful to rule out cerebral involvement of the APL, lumbar puncture (choice B) would be invasive and unnecessary for the patient.As mentioned, Voyt-Kayanagi-Harada can present with bilateral serous RD. However, this patient does not meet revised diagnostic criteria for Voyt-Kayanagi-Harada; he had clinical evidence suggesting other disease entities and neither neurologic nor integumentary findings.8 Thus, sending for HLA B51 (choice D) would not be indicated.A multidisciplinary team decision was made to hold ATRA for 2 days and start intravenous dexamethasone, 10 mg, twice a day for a total of 7 days. After treatment, the patient’s systemic and visual symptoms improved. Two weeks later, the patient had complete resolution of the bilateral choroidal effusions, intraretinal fluid, and subretinal fluid. Repeated optical coherence tomography 6 weeks later demonstrated a flat retina with persistent disruptions of the ellipsoid zone. Visual acuity improved from count fingers to 20/40 OU.

Ophthalmology

A 51-year-old man diagnosed as having acute promyelocytic leukemia, undergoing induction therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide that were started 2 weeks prior, presented with sudden loss of vision. Hospital course was complicated by neutropenic fever, receiving cefepime, acyclovir, vancomycin, and voriconazole for prophylaxis. Laboratory test results were remarkable for pancytopenia. On initial examination, his visual acuity was count fingers at 3 ft in both eyes. Intraocular pressures were 10 mm Hg OD and 11 mm Hg OS. Pupils were round and reactive without a relative afferent pupillary defect. Color plates were 1 of 8 OU, with 50% brightness desaturation in the right eye and no red desaturation. Extraocular movements were full. Slitlamp examination was negative for any signs of inflammation. Dilated fundus examination demonstrated bilateral choroidal effusions with diffuse serous retinal detachments (RD) involving the macula without vitritis as well as white centered intraretinal hemorrhages along peripapillary and superior and inferior arcade distributions in both eyes (Figure, A). Optical coherence tomography demonstrated irregular inner retinal surface and subretinal fluid with septae with loss of the ellipsoid zone (Figure, B). Review of systems was positive for fever, tachycardia, odynophagia, productive cough with wheezing, and marked peripheral edema in upper extremities and negative for headache, nausea, vomiting, dysacusis, meningismus, or skin changes.Fundus photographs and optical coherence tomography 4 days from presentation demonstrating bilateral choroidal effusions with serous retinal detachment and white centered intraretinal hemorrhages. Left eye results shown. A, Left eye color fundus photograph demonstrates peripheral choroidal effusion with areas of stippled subretinal fluid in the macula, areas of intraretinal hemorrhages scattered throughout the posterior pole as well as far temporal periphery. B, Optical coherence tomography of the left eye demonstrating corrugated inner retina with intraretinal and subretinal fluid with septae from further separation of the external limiting membrane and ellipsoid zone as well as some loss of the ellipsoid zone.Order magnetic resonance imaging of brain and orbits with and without contrast and lumbar puncture

what would you do next?

What would you do next?

Order magnetic resonance imaging of brain and orbits with and without contrast and lumbar puncture

Send HLA-B51 and start steroids

Continue chemotherapy therapy and observe

Stop the ATRA and start steroids

d

male

51-60

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2756332

A 62-year-old man presented with subacute, painless vision loss in the right eye that developed over the course of 1 week. He had a history of well-controlled type 2 diabetes and diffuse large B-cell lymphoma that was diagnosed 3 years earlier. The lymphoma was initially treated with chemotherapy, followed by a relapse that required additional chemotherapy and ultimately autologous bone marrow transplant 3 months before presentation. At the time of presentation, he was taking no immunosuppressive medications and was taking prophylactic acyclovir, 800 mg twice daily, and sulfamethoxazole/trimethoprim (800 mg/160 mg) 3 times weekly.Snellen visual acuity measured 20/40 OD and 20/20 OS. Intraocular pressure (IOP) measured 24 mm Hg OD and 12 mm Hg OS. There was no afferent pupillary defect. Right eye examination results revealed 1+ anterior chamber inflammation, iris neovascularization, keratic precipitates, vitritis, and a granular necrotizing retinitis (Figure, A). Left eye examination results were unremarkable. Fluorescein angiography of the right eye demonstrated panretinal occlusive vasculopathy with severe peripheral nonperfusion (Figure, B). His white blood cell count was moderately low at 3.1 kilos/μL (to convert to ×109/L, multiply by 0.001; reference range, 4.0-10.0 kilos/μL); a complete blood count and serum chemistry panel were otherwise normal. Human immunodeficiency virus (HIV) testing results were negative. An aqueous tap was performed and sent for culture and polymerase chain reaction.A, Wide-field fundus photograph demonstrating vitreous haze, vascular attenuation, macular cotton wool-spots, diffuse intraretinal hemorrhages, and superior granular necrotizing retinitis. B, Late-phase fluorescein angiogram demonstrating disc leakage and marked peripheral nonperfusion.Administer intravitreal foscarnet and admit for intravenous acyclovirAdminister an intravitreal anti–vascular endothelial growth factor agent followed by panretinal photocoagulation What Would You Do Next?

Administer intravitreal clindamycin

Administer intravitreal foscarnet and admit for intravenous acyclovir

Administer intravitreal foscarnet and initiate valganciclovir

Administer an intravitreal anti–vascular endothelial growth factor agent followed by panretinal photocoagulation

Chronic retinal necrosis due to cytomegalovirus

C

Administer intravitreal foscarnet and initiate valganciclovir

Based on the constellation of clinical findings, there was high clinical suspicion for cytomegalovirus (CMV) retinitis, so the patient was treated empirically with intravitreal foscarnet, 2.4 mg, and oral valganciclovir, 900 mg, twice daily. Aqueous tap and polymerase chain reaction analysis results returned 3.5 million copies of CMV DNA, confirming a diagnosis of chronic retinal necrosis (CRN) due to CMV.Cytomegalovirus retinitis typically occurs in patients with severe immunosuppression and has been well described in patients with AIDS.1,2 Cytomegalovirus retinitis often lacks substantial intraocular inflammation and may manifest as either an indolent progressive peripheral granular necrotizing retinitis or as a fulminant posterior hemorrhagic retinitis.1,2The clinical manifestations of CMV retinitis vary according to the patient’s immune status. Increasing levels of immune dysfunction are associated with more severe and extensive CMV retinitis.3 Conversely, limited or partial immune dysfunction (such as with diabetes, advanced age, or immunosuppression with noncytoxic agents) results in a distinct presentation of CMV retinitis with slowly progressive necrotizing retinitis, substantial intraocular inflammation, and extensive occlusive arteritis that is out of proportion to the degree of retinitis.4 Cytomegalovirus retinitis in these patients shares features of classic CMV retinitis and acute retinal necrosis but may be distinguished by the unique combination of a slowly progressive granular retinitis that is more typical of CMV and a severe retinal vasculitis more typical of acute retinal necrosis in the presence of substantial intraocular inflammation.4,5With the advent of highly active retroviral therapy, the incidence of CMV retinitis in patients with HIV is decreasing.6 Despite routine prophylaxis with acyclovir or valacyclovir in patients undergoing immunosuppressive treatment for cancer and bone marrow transplant, CMV retinitis remains a concern in these vulnerable patients.7,8 As demographics shift to include many etiologies of immune dysfunction, early recognition of the protean manifestations of CMV retinitis across a spectrum of immune dysfunction is vital.Timely diagnosis and treatment of CMV usually require clinical recognition before molecular confirmation. Suspected CMV retinitis usually is treated empirically with systemic antiviral medications that are active against CMV (such as oral valganciclovir, intravenous ganciclovir, or a combination thereof) and may be supplemented by intravitreal ganciclovir or foscarnet.9 The necrotizing herpetic retinopathies display occlusive vasculitis and inflammatory reaction similar to CRN but typically exhibit more extensive retinitis that has a confluent (nongranular) appearance and progresses rapidly; these usually are best treated with systemic acyclovir or valacyclovir (which are not active against CMV) and adjunctive intravitreal foscarnet.5 Other opportunistic infections, such as toxoplasmosis (treated with intravitreal clindamycin) may be considered in immunocompromised patients with an infectious retinitis, but early coverage for viral retinitis usually is mandated in patients with necrotizing retinitis and retinal vasculitis. Treatment of neovascularization and retinal nonperfusion is prudent but is no reason to delay antiviral therapy.After initial treatment with intravitreal foscarnet and oral valganciclovir, the patient underwent anti–vascular endothelial growth factor therapy and panretinal photocoagulation for severe retinal nonperfusion with anterior segment neovascularization and was administered topical prednisolone acetate, 4 times daily, and IOP-lowering drops. His CRN was controlled with intravitreal foscarnet injections and long-term oral valganciclovir therapy, 900 mg daily. At latest follow-up 10 months after presentation, the neovascular sequelae had resolved, his visual acuity stabilized at 20/125, and his IOP was well controlled.

Ophthalmology

A 62-year-old man presented with subacute, painless vision loss in the right eye that developed over the course of 1 week. He had a history of well-controlled type 2 diabetes and diffuse large B-cell lymphoma that was diagnosed 3 years earlier. The lymphoma was initially treated with chemotherapy, followed by a relapse that required additional chemotherapy and ultimately autologous bone marrow transplant 3 months before presentation. At the time of presentation, he was taking no immunosuppressive medications and was taking prophylactic acyclovir, 800 mg twice daily, and sulfamethoxazole/trimethoprim (800 mg/160 mg) 3 times weekly.Snellen visual acuity measured 20/40 OD and 20/20 OS. Intraocular pressure (IOP) measured 24 mm Hg OD and 12 mm Hg OS. There was no afferent pupillary defect. Right eye examination results revealed 1+ anterior chamber inflammation, iris neovascularization, keratic precipitates, vitritis, and a granular necrotizing retinitis (Figure, A). Left eye examination results were unremarkable. Fluorescein angiography of the right eye demonstrated panretinal occlusive vasculopathy with severe peripheral nonperfusion (Figure, B). His white blood cell count was moderately low at 3.1 kilos/μL (to convert to ×109/L, multiply by 0.001; reference range, 4.0-10.0 kilos/μL); a complete blood count and serum chemistry panel were otherwise normal. Human immunodeficiency virus (HIV) testing results were negative. An aqueous tap was performed and sent for culture and polymerase chain reaction.A, Wide-field fundus photograph demonstrating vitreous haze, vascular attenuation, macular cotton wool-spots, diffuse intraretinal hemorrhages, and superior granular necrotizing retinitis. B, Late-phase fluorescein angiogram demonstrating disc leakage and marked peripheral nonperfusion.Administer intravitreal foscarnet and admit for intravenous acyclovirAdminister an intravitreal anti–vascular endothelial growth factor agent followed by panretinal photocoagulation

what would you do next?

What would you do next?

Administer an intravitreal anti–vascular endothelial growth factor agent followed by panretinal photocoagulation

Administer intravitreal foscarnet and initiate valganciclovir

Administer intravitreal foscarnet and admit for intravenous acyclovir

Administer intravitreal clindamycin

b

male

61-70

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2757263

A white man in his 70s was referred for evaluation of a rapidly enlarging fleshy nodule of the right nasal conjunctiva. The patient noted redness, pain, and a foreign body sensation on his right eye for 2 weeks. The general ophthalmologist prescribed a 3-week course of oral prednisone, 20 mg/d, that reduced surrounding inflammation and pain, but the lesion did not change in appearance. The chest radiographic findings and blood work results were unremarkable. The lack of response to oral prednisone therapy led to suspicion of a possible malignant neoplasm, and the patient was referred for our opinion.The patient’s medical history was notable for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with transformation to large B-cell lymphoma that was treated with rituximab, adriamycin, vincristine sulfate, and prednisone chemotherapy 4 years earlier. Two years before referral, bladder cancer was diagnosed and was treated surgically and with multiple rounds of intravesical BCG immunotherapy. The most recent BCG treatment was 5 months before presentation to the Ocular Oncology Service at Wills Eye Hospital, Philadelphia, Pennsylvania.On examination, visual acuity was 20/25 OD and 20/40 OS. Anterior segment examination findings were remarkable for a limbal-based amelanotic lesion of the nasal conjunctiva measuring 5 mm in basal diameter and 1.5 mm thick and fed by large dilated conjunctival and episcleral vessels (Figure 1). Ocular ultrasonography revealed no intraocular involvement. The remainder of the eye examination was unremarkable.External photograph depicting a perilimbal erythematous conjunctival nodule with dilated episcleral vessels.Perform a complete excisional biopsy of the lesionObtain magnetic resonance imaging of the brain and orbits What Would You Do Next?

Administer intralesional corticosteroids

Perform a complete excisional biopsy of the lesion

Administer topical antibiotics

Obtain magnetic resonance imaging of the brain and orbits

Nodular episcleritis unresponsive to corticosteroids

B

Perform a complete excisional biopsy of the lesion

The differential diagnosis of a rapidly growing amelanotic conjunctival and episcleral nodule includes various benign and malignant lesions. A rapidly enlarging mass raises concern for a malignant process, and evaluation by an ocular oncologist can be considered. Nodular episcleritis is typically responsive to anti-inflammatory agents.1 However, recurrence or failure to completely respond to treatment requires further workup. Although episcleritis is usually idiopathic, up to one-third of patients have an associated systemic disorder, including collagen-vascular, inflammatory bowel, and dermatologic disorders; metabolic diseases; medication toxic effects; and hematolymphoid malignant neoplasms.1,2 This patient’s history of CLL/SLL and lack of response to oral prednisone therapy raised concern for possible conjunctival involvement by CLL/SLL. Although excisional biopsy is not typically performed for nodular episcleritis, it was necessary to rule out malignancy (choice B). Intralesional corticosteroid injection (choice A) is not recommended because of the patient’s poor response to prior corticosteroid treatment. Topical antibiotics (choice C) should not be administered until the etiology of the mass is determined. Obtaining a magnetic resonance image of the brain and orbits (choice D) would be an appropriate step if the lesion was determined to be lymphoma.Histopathologic evaluation of the excised lesion showed dilated lymphatic channels with intralymphatic and extralymphatic nonnecrotizing granulomas composed of epithelioid histiocytes and lymphocytes (Figure 2). The results of acid-fast bacilli and Gomori methenamine silver stains, performed to evaluate for mycobacterial and fungal infections, were negative. Other causes of intralymphatic nonnecrotizing granulomas, including granulomatous cheilitis and idiopathic inflammatory bowel disease, were not supported by the patient’s clinical history and examination findings. In light of the patient’s history of BCG therapy, systemic involvement by intravesical bacille Calmette-Guérin was the presumed cause of the intralymphatic and extralymphatic conjunctival and episcleral granulomas. In the literature, the only other cases of mycobacterium-related nodular episcleritis have been from underlying Mycobacterium tuberculosis infection.3,4An aggregate of epithelioid macrophages and lymphocytes is present inside a dilated lymphatic channel of the conjunctival substantia propria (hematoxylin-eosin, original magnification ×100).Intravesical BCG is an immunotherapy containing a live strain of Mycobacterium bovis. It is well tolerated in 95% of patients but can produce an array of local and systemic complications ranging from hematuria to disseminated mycobacterial disease.5-10 Most systemic toxic effects are believed to result from hematogenous spread of bacille Calmett-Guérin through disrupted urothelial epithelium, such as from traumatic urinary catheterization or an open-wound, posttransurethral bladder tumor resection.5 Toxic effects can be due to frank M bovis infection, a type IV hypersensitivity reaction, or a combination of both.5Mycobacterium bovis infection requires antituberculosis treatment (ATT), whereas hypersensitivity reactions, such as reactive arthritis, are treated with anti-inflammatory agents.5 Similar to other systemic toxic effects, ocular complications can be either infectious or immune mediated.5,8 Differentiation presents a clinical challenge because the identification of M bovis through the use of acid-fast bacilli stain, polymerase chain reaction, and cultures have shown positive results in only 25%, 41%, and 42% of cases, respectively.5 Thus, the diagnosis requires high clinical suspicion, especially since complications can arise years after treatment.9 Owing to the challenging nature of the diagnosis, it must be determined which patients require antituberculosis treatment because of possible M bovis dissemination and which require immunosuppression for an autoimmune process.This patient underwent complete excision without complications. He will be examined by infectious disease consultants for disseminated M bovis infection and monitored for local recurrence.

Ophthalmology

A white man in his 70s was referred for evaluation of a rapidly enlarging fleshy nodule of the right nasal conjunctiva. The patient noted redness, pain, and a foreign body sensation on his right eye for 2 weeks. The general ophthalmologist prescribed a 3-week course of oral prednisone, 20 mg/d, that reduced surrounding inflammation and pain, but the lesion did not change in appearance. The chest radiographic findings and blood work results were unremarkable. The lack of response to oral prednisone therapy led to suspicion of a possible malignant neoplasm, and the patient was referred for our opinion.The patient’s medical history was notable for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with transformation to large B-cell lymphoma that was treated with rituximab, adriamycin, vincristine sulfate, and prednisone chemotherapy 4 years earlier. Two years before referral, bladder cancer was diagnosed and was treated surgically and with multiple rounds of intravesical BCG immunotherapy. The most recent BCG treatment was 5 months before presentation to the Ocular Oncology Service at Wills Eye Hospital, Philadelphia, Pennsylvania.On examination, visual acuity was 20/25 OD and 20/40 OS. Anterior segment examination findings were remarkable for a limbal-based amelanotic lesion of the nasal conjunctiva measuring 5 mm in basal diameter and 1.5 mm thick and fed by large dilated conjunctival and episcleral vessels (Figure 1). Ocular ultrasonography revealed no intraocular involvement. The remainder of the eye examination was unremarkable.External photograph depicting a perilimbal erythematous conjunctival nodule with dilated episcleral vessels.Perform a complete excisional biopsy of the lesionObtain magnetic resonance imaging of the brain and orbits

what would you do next?

What would you do next?

Administer intralesional corticosteroids

Perform a complete excisional biopsy of the lesion

Administer topical antibiotics

Obtain magnetic resonance imaging of the brain and orbits

b

male

71-80

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2757593

A 23-year-old white man with Netherton syndrome, a skin condition of ichthyosiform erythroderma, presented to the clinic with what he described as “pressure behind the eye” and visual acuity “going in and out” in his left eye. The patient had an ocular history of herpes simplex (HSV) keratitis with a previous perforation of the right eye repaired with a patch graft, advanced open-angle glaucoma in the right eye, and ocular hypertension of the left eye, and he was receiving brimonidine 3 times a day in both eyes and acetazolamide, 250 mg, 3 times a day.On examination, his visual acuity without correction was 20/200 OD and 20/50 OS, with pinhole acuity measured at 20/80 OD and 20/40 OS. His intraocular pressure was 9 mm Hg OD and 42 mm Hg OS. An external examination revealed severe eczematous skin changes and thinning of the eyebrows and eyelashes. A slitlamp examination showed madarosis, mild eyelid edema, and conjunctival injection, which were greater in the left eye than the right eye. The right cornea had inferior pannus, scarring, and neovascularization. The left cornea revealed microcystic edema and central ulceration (Figure 1). The anterior chambers of both eyes were quiet. A fundus examination was notable for cup-disc ratios of 0.8 OD and 0.4 OS.Examination at presentation. External photograph of the right eye with neurotrophic cornea with neovascularization and scarring (A) and external photograph of the left eye with epithelial dendritic lesion with corneal edema (B).Bacterial cultures, a viral polymerase chain reaction, and potassium hydroxide preparations were obtained from the ulcer of the left cornea. The results of the viral polymerase chain reaction and potassium hydroxide tests were negative, while bacterial cultures had positive results for methicillin-resistant Staphylococcus aureus and Escherichia coli. What Would You Do Next?

Start topical antibiotics

Start oral antiviral therapy

Start oral antiviral and topical antibiotic therapy

Admit patient for intravenous antiviral therapy

Herpes simplex keratitis with bacterial superinfection

C

Start oral antiviral and topical antibiotic therapy

Netherton syndrome is an autosomal-recessive condition. It causes excessive shedding of skin, atopic eczema, pruritus, and fragile hair, including eyelashes and eyebrows.1The clinical manifestations of Netherton syndrome may necessitate consideration of causes of dendritic corneal lesions, including HSV, epithelial regeneration lines, neurotrophic keratopathy, varicella zoster virus, iatrogenic causes, and infestations with Acanthamoeba species. Given this patient’s history and presentation, HSV was most likely.While, to our knowledge, the association of Netherton syndrome and HSV has not been documented previously, there is a well-established connection between atopy and ophthalmic HSV. Patients with atopy have been shown to be twice as likely to develop ophthalmic HSV as control individuals.2 Severe primary, recurrent, and bilateral disease are more common in patients with atopy than unaffected patients.3,4 Similarly, in patients with ocular HSV, the odds ratio of having atopic disease is 1.5 to 4.8 compared with control individuals.5 Patients with atopy have been reported to have more episodes of infectious HSV than inflammatory episodes compared with those without atopy.6The diagnosis of HSV keratitis is typically clinical. However, diagnostic testing, such as cultures or polymerase chain reaction testing, can be taken from conjunctival, corneal, or skin lesions to confirm the diagnosis. It is important to remember that such tests are limited, because the sensitivity of viral cultures is less than 50% and polymerase chain reaction sensitivity ranges from 55% to 88%, while tests identifying recurrent disease may demonstrate lower sensitivity.7-9While antibiotic therapy is indicated, given bacterial superinfection, the high clinical suspicion of HSV renders antibiotics alone insufficient (choice A). Antiviral therapy should be started in patients with classic findings or high clinical suspicion of HSV, even when culture and polymerase chain reaction test results are negative (choice B); however, if cultures indicate superinfection, antibiotics are also necessary (choice C). Intravenous therapy is only rarely considered (choice D).Four years after his initial presentation, the patient developed a geographic ulcer in his left eye despite receiving 500 mg of valacyclovir daily. Treatment was changed to valacyclovir, 500 mg, 3 times a day, topical ganciclovir 5 times daily, and moxifloxacin 4 times a day. The ulcer persisted, and he developed a hypopyon, which was believed to be inflammatory, given the absence of corneal infiltrate. He was switched to 400 mg of acyclovir 5 times daily and topical prednisolone 4 times a day, but his condition continued to worsen. The patient was admitted to the hospital for treatment with intravenous acyclovir at a dosage of 10 mg per kg every 8 hours, and administration of prednisolone was stopped. A culture had concerning results for acyclovir-resistant HSV, and therapy was switched to intravenous foscarnet at a dosage of 40 mg per kg every 8 hours. The patient underwent multiple corneal gluings for perforations, amniotic membrane graft placement, and finally penetrating keratoplasty. Pathological and immunohistochemical evaluations confirmed an HSV infection (Figure 2).Pathology specimen. Photomicrograph of the cornea with acute keratitis and viral inclusion in the epithelial nuclei (hematoxylin-eosin; original magnification ×40).Postoperatively, he was admitted to the hospital for intravenous acyclovir at 10 mg per kg every 8 hours and fortified topical vancomycin 4 times a day to maximize success in this high-risk transplant. Shortly after discharge, he required readmission for an enlarging epithelial defect. The defect improved, but the cornea became neurotrophic and the graft failed.This case highlights the important link between atopy and HSV keratitis, the limitations of diagnostic testing, and the potentially difficult course of HSV in patients with severe atopic disease. Clinicians should consider the influence of atopy when evaluating and treating HSV in such patients.

Ophthalmology

A 23-year-old white man with Netherton syndrome, a skin condition of ichthyosiform erythroderma, presented to the clinic with what he described as “pressure behind the eye” and visual acuity “going in and out” in his left eye. The patient had an ocular history of herpes simplex (HSV) keratitis with a previous perforation of the right eye repaired with a patch graft, advanced open-angle glaucoma in the right eye, and ocular hypertension of the left eye, and he was receiving brimonidine 3 times a day in both eyes and acetazolamide, 250 mg, 3 times a day.On examination, his visual acuity without correction was 20/200 OD and 20/50 OS, with pinhole acuity measured at 20/80 OD and 20/40 OS. His intraocular pressure was 9 mm Hg OD and 42 mm Hg OS. An external examination revealed severe eczematous skin changes and thinning of the eyebrows and eyelashes. A slitlamp examination showed madarosis, mild eyelid edema, and conjunctival injection, which were greater in the left eye than the right eye. The right cornea had inferior pannus, scarring, and neovascularization. The left cornea revealed microcystic edema and central ulceration (Figure 1). The anterior chambers of both eyes were quiet. A fundus examination was notable for cup-disc ratios of 0.8 OD and 0.4 OS.Examination at presentation. External photograph of the right eye with neurotrophic cornea with neovascularization and scarring (A) and external photograph of the left eye with epithelial dendritic lesion with corneal edema (B).Bacterial cultures, a viral polymerase chain reaction, and potassium hydroxide preparations were obtained from the ulcer of the left cornea. The results of the viral polymerase chain reaction and potassium hydroxide tests were negative, while bacterial cultures had positive results for methicillin-resistant Staphylococcus aureus and Escherichia coli.

what would you do next?

What would you do next?

Start topical antibiotics

Start oral antiviral therapy

Start oral antiviral and topical antibiotic therapy

Admit patient for intravenous antiviral therapy

c

male

21-30

White

original

https://jamanetwork.com/journals/jama/fullarticle/2758611

A 61-year-old white man with seronegative rheumatoid arthritis presented with hand and wrist pain. Over 2 years, he was prescribed various therapies including prednisone, methotrexate, tumor necrosis factor inhibitors, abatacept, and anakinra; he experienced intermittent improvement in his joint pain but had persistently elevated levels of inflammatory markers. He continued to experience asymmetric small- and large-joint polyarthralgias and later developed intermittent fevers (temperatures up to 38.3°C [101°F]) along with a 50-lb (22.7-kg) unintentional weight loss over the course of a few months.On examination, there was subtle synovitis in bilateral metacarpophalangeal joints. Findings on cardiac, pulmonary, and neurologic examinations were unremarkable. Laboratory evaluation was notable for a normocytic anemia and elevated C-reactive protein level (7.7 mg/dL [73.3 nmol/L]). Results of esophagogastroduodenoscopy with gastric biopsies and bone marrow biopsy were unremarkable. Findings on further workup including transthoracic echocardiography to assess for endocarditis, carotid magnetic resonance angiography to assess for vasculitis, and abdominal fat pad biopsy for amyloidosis were also unremarkable. Tocilizumab was initiated. Over the next several months, he developed intermittent abdominal pain, steatorrhea, protein-losing enteropathy, and symmetric bilateral lower extremity edema requiring diuresis. Results of infectious stool studies, celiac serology, and fecal elastase testing were normal. Repeat esophagogastroduodenoscopy (Figure, panel A) was performed, with gastric and duodenal biopsies (Figure, panels B and C).A, Duodenal segment on esophagogastroduodenoscopy. B, Histologic examination of duodenal mucosa (hematoxylin-eosin, original magnification ×100; sample obtained using cold forceps). C, Histologic examination of duodenal lamina propria (periodic acid–Schiff, original magnification ×100; sample obtained using cold forceps).Perform genetic analysis for evaluation of hematologic malignancyRefer to a nutritionist for education on gluten-free diet What Would You Do Next?

Begin antimicrobial therapy

Initiate intravenous immunoglobulin therapy

Perform genetic analysis for evaluation of hematologic malignancy

Refer to a nutritionist for education on gluten-free diet

Whipple disease

A

Begin antimicrobial therapy

The keys to the correct diagnosis are the endoscopic and histologic abnormalities. The endoscopic duodenal image (Figure, panel A) highlights the whitish plaques characteristic of Whipple disease. Biopsies revealed small-bowel mucosa with foamy macrophages (Figure, panel B) and periodic acid–Schiff–positive macrophages in the lamina propria (Figure, panel C), all consistent with Whipple disease. Results of polymerase chain reaction assay for Tropheryma whipplei were also positive. Intravenous immunoglobulin therapy (choice B) is appropriate for common variable immune deficiency, which manifests as chronic, opportunistic infections and absence of plasma cells on small bowel biopsy, neither of which occurred in this patient. While the patient manifested multiple symptoms, genetic evaluation for hematologic malignancy (choice C) is incorrect given no evidence of malignancy on laboratory, imaging, and tissue evaluations. Referral to a nutritionist for education on a gluten-free diet (choice D) is incorrect given the absence of positive results from celiac serologic testing (which has 99% sensitivity) and absence of typical changes on biopsy such as villous blunting and intraepithelial lymphocytosis.1Whipple disease is an infectious condition due to T whipplei. It was first described by George H. Whipple in 1907 in a 36-year-old clinician with “gradual loss of weight and strength, stools consisting chiefly of neutral fat and fatty acids, indefinite abdominal signs, and a peculiar multiple arthritis.”2 It was considered a fatal illness until the first reported efficacy of antibiotic treatment nearly 50 years later (1952), with significant advances in understanding made in 2000 when the causative organism, T whipplei, was ultimately cultured.3,4T whipplei is a ubiquitous environmental organism, thought to be acquired by fecal-oral transmission.Whipple disease is rare, with a reported annual incidence of less than 1 per 1 000 000 people.5 However, it might be more prevalent than previously thought, and T whipplei was the most commonly found pathogen associated with culture-negative infective endocarditis in a large observational cohort of German patients.6 In that study, heart valves from 1135 patients between 2000-2007 were cultured; 255 valves showed growth of bacteria, with 6% of these growing T whipplei. Whipple disease appears more frequently in people of European ancestry, and 80% of cases affect men, typically middle age.7 Because it may present with an inflammatory polyarthritis mimicking seronegative rheumatoid arthritis, Whipple disease should be suspected in patients diagnosed with a seronegative rheumatoid arthritis, particularly those with prolonged disease course, insufficient response to treatment, or both.Whipple disease affects multiple organ systems and thereby has a broad spectrum of signs and symptoms. “Classic” Whipple disease presents with weight loss (92%), steatorrhea (91%), hypoalbuminemia (91%), anemia (85%), diarrhea (76%), lymphadenopathy (60%), arthralgia (67%), abdominal pain (55%), or fever (38%).5 The typical presentation—as in this case—is a prodrome of arthritis followed by persistent diarrhea and weight loss. The arthritis can precede the gastrointestinal symptoms by many years, with a median of 5.5 years.8 Whipple disease can also manifest with endocarditis (30%) or central nervous system disease (10%-40%). Central nervous system disease may be asymptomatic; thus, lumbar puncture is mandatory. This patient had normal lumbar puncture findings. Neurologic manifestations include cognitive change, supranuclear ophthalmoplegia, altered level of consciousness, cranial nerve abnormalities, seizures, ataxia, and sensory deficits, which may be irreversible despite treatment.9The diagnosis can be made with small-bowel biopsy with periodic–acid Schiff staining along with polymerase chain reaction assay of blood or tissue (eg, duodenum, synovial fluid, cerebrospinal fluid, or lymph node).Treatment is with antibiotics, which typically involves induction with intravenous ceftriaxone for 2 weeks (or 4 weeks if endocardial involvement is present), followed by maintenance therapy with trimethoprim-sulfamethoxazole for 1 year.9The patient received intravenous ceftriaxone for 2 weeks; this resulted in prompt improvement in diarrhea, fevers, and arthralgias. He then began trimethoprim-sulfamethoxazole for 12 months. After several months of antimicrobial therapy, he regained the previously lost weight and ultimately made a full recovery.

General

A 61-year-old white man with seronegative rheumatoid arthritis presented with hand and wrist pain. Over 2 years, he was prescribed various therapies including prednisone, methotrexate, tumor necrosis factor inhibitors, abatacept, and anakinra; he experienced intermittent improvement in his joint pain but had persistently elevated levels of inflammatory markers. He continued to experience asymmetric small- and large-joint polyarthralgias and later developed intermittent fevers (temperatures up to 38.3°C [101°F]) along with a 50-lb (22.7-kg) unintentional weight loss over the course of a few months.On examination, there was subtle synovitis in bilateral metacarpophalangeal joints. Findings on cardiac, pulmonary, and neurologic examinations were unremarkable. Laboratory evaluation was notable for a normocytic anemia and elevated C-reactive protein level (7.7 mg/dL [73.3 nmol/L]). Results of esophagogastroduodenoscopy with gastric biopsies and bone marrow biopsy were unremarkable. Findings on further workup including transthoracic echocardiography to assess for endocarditis, carotid magnetic resonance angiography to assess for vasculitis, and abdominal fat pad biopsy for amyloidosis were also unremarkable. Tocilizumab was initiated. Over the next several months, he developed intermittent abdominal pain, steatorrhea, protein-losing enteropathy, and symmetric bilateral lower extremity edema requiring diuresis. Results of infectious stool studies, celiac serology, and fecal elastase testing were normal. Repeat esophagogastroduodenoscopy (Figure, panel A) was performed, with gastric and duodenal biopsies (Figure, panels B and C).A, Duodenal segment on esophagogastroduodenoscopy. B, Histologic examination of duodenal mucosa (hematoxylin-eosin, original magnification ×100; sample obtained using cold forceps). C, Histologic examination of duodenal lamina propria (periodic acid–Schiff, original magnification ×100; sample obtained using cold forceps).Perform genetic analysis for evaluation of hematologic malignancyRefer to a nutritionist for education on gluten-free diet

what would you do next?

What would you do next?

Begin antimicrobial therapy

Refer to a nutritionist for education on gluten-free diet

Initiate intravenous immunoglobulin therapy

Perform genetic analysis for evaluation of hematologic malignancy

a

male

61-70

White

original

https://jamanetwork.com/journals/jama/fullarticle/2757849

A 61-year-old woman with a history of uncontrolled type 2 diabetes mellitus presented with progressive right upper quadrant abdominal pain of 1 month’s duration. The pain was sharp, intermittent without radiation, and not exacerbated by eating. She had no subjective fevers, nausea, vomiting, diarrhea, or weight loss. She had immigrated from Chuuk, Micronesia, to Hawaii 10 years ago and had not traveled overseas since. She denied alcohol use or contact with animals such as pigs.On examination, her temperature was 38.5°C (101.3°F); pulse rate, 104/min; blood pressure, 205/92 mm Hg; and respiratory rate, 33/min with normal saturation. Mild conjunctival icterus and a positive Murphy sign were noted. Laboratory evaluation showed a white blood cell count of 16.4 × 109/L (neutrophils, 87.4%; eosinophils, 0.5% [absolute count, 82/μL]); hemoglobin level, 14.9 g/dL; platelet count, 254 × 109/L; aspartate aminotransferase level, 514 U/L; alanine aminotransferase level, 236 U/L; alkaline phosphatase level, 208 IU/L; total bilirubin level, 2.5 mg/dL; direct bilirubin level, 1.1 mg/dL; and lipase level, 247 U/L. Results of serologic testing for hepatitis A, B, and C were negative. Abdominal ultrasound showed no cholecystitis or pancreatohepatobiliary abnormalities. Magnetic resonance cholangiopancreatography was notable for a linear filling defect within the common bile duct extending through the left hepatic duct (Figure, left panel). During endoscopic retrograde cholangiopancreatography (ERCP), numerous worms were discovered within the biliary trees, with 1 visible outside the ampulla of Vater (Figure, right panel).Left, Findings on magnetic resonance cholangiopancreatography. Right, Findings on endoscopic retrograde cholangiopancreatography.Order polymerase chain reaction (PCR) assay for Ascaris What Would You Do Next?

Prescribe anthelminthic therapy alone

Prescribe antibiotics followed by anthelminthic therapy

Order polymerase chain reaction (PCR) assay for Ascaris

Order serum serologic testing for Ascaris

Acute cholangitis due to Ascaris lumbricoides

B

Prescribe antibiotics followed by anthelminthic therapy

The key to the correct diagnosis is the round-shaped worm seen on ERCP; this is most consistent with A lumbricoides. When cholangitis is concomitant, antibiotics should be administered first, as mortality is increased with a superimposed bacterial infection. Once acute symptoms have improved, anthelminthics are typically given for parasitic eradication. Oral albendazole is the preferred agent, as it can achieve a 96% cure rate with a single 400-mg dose in ascariasis.1 The sensitivities of PCR assay and serologic testing are superior to that of stool microscopy for diagnosing infection but are mainly used for research purposes.Helminthic infestation of the hepatobiliary system occurs primarily with A lumbricoides, Echinococcus granulosus, Clonorchis sinensis, Opisthorchis felineus, O viverrini, and Fasciola hepatica. Globally, ascariasis is the most common human parasitic disease, with an estimated 819 million people infected in 2010.2 It is endemic in regions where poor sanitation predisposes to contamination of soil and where human or pig feces are used as fertilizers.Although this patient immigrated from the Western Pacific where ascariasis is highly prevalent, she had no history of travel in the past 10 years. Adult Ascaris worms live for 1 to 2 years3; thus, it is unlikely that she was infected before her immigration and remained asymptomatic. Ascariasis transmits via a fecal-oral route with no person-to-person transmission reported. Continuous cycles of reinfection within the United States are improbable, as this requires ingestion of embryonated eggs found in stool-contaminated soil. Therefore, it was presumed that family members who traveled between Hawaii and Micronesia had imported the infectious eggs via contaminated food or goods.Most infected hosts remain asymptomatic. A high worm burden causes gastrointestinal obstructive symptoms including abdominal distension, bloating, nausea, vomiting, diarrhea, and weight loss.4 When the pancreatobiliary system is inhabited by a mass of worms, obstructive cholangitis and pancreatitis can occur. A retrospective study of 77 inpatients with ascariasis showed acute cholangitis in 15.6%, followed by obstructive jaundice (9.1%), acute pancreatitis (6.5%), acute cholecystitis (6.5%), choledocholithiasis (6.5%), and liver abscess (2.6%).5 Rarely, pulmonary manifestations occur when larvae invade lung tissue (Löffler syndrome); in these cases, peripheral eosinophilia is more likely observed.6The diagnosis should be suspected in patients with exposure to an endemic area. Stool microscopy generally confirms the infection but can be negative in early stages of infection. PCR assay and serologic testing are usually not performed. For symptomatic patients, imaging studies are often diagnostic. In intestinal ascariasis, abdominal barium study shows cylindrical and often coiled radiolucent filling defects within the barium-filled intestinal lumen. Abdominal ultrasound may be a more sensitive modality for diagnosing intestinal and hepatobiliary ascariasis (sensitivity, 25%-91%7); typically, echogenic long structures without acoustic shadowing are seen. Computed tomography or magnetic resonance imaging may be useful for supplemental imaging, with characteristic findings being elongated filling defects within the gastrointestinal tract or biliary duct.Similar to other cases of ascending cholangitis, early administration of broad-spectrum antibiotics is paramount in pyogenic cholangitis associated with biliary ascariasis. Parasitic eradication, however, is key in preventing recurrent cholangitis.8 Anthelminthics alone may be ineffective for pure biliary ascariasis because of poor systemic absorption and low concentrations in bile.7 ERCP allows direct visualization of worms and, if applicable, enables worm extraction, which facilitates biliary decompression, parasite eradication, and parasite identification.9 Endoscopic worm extraction may also be associated with rapid relief of symptoms.10Worm extraction with occlusion balloon and biliary contrast injection was performed during ERCP. Intravenous fluid and broad-spectrum antibiotics were given, followed by oral albendazole. Pathological examination of adult worms confirmed A lumbricoides. Screening stool microscopy for asymptomatic helminthic infection was recommended to the patient’s family members.

General

A 61-year-old woman with a history of uncontrolled type 2 diabetes mellitus presented with progressive right upper quadrant abdominal pain of 1 month’s duration. The pain was sharp, intermittent without radiation, and not exacerbated by eating. She had no subjective fevers, nausea, vomiting, diarrhea, or weight loss. She had immigrated from Chuuk, Micronesia, to Hawaii 10 years ago and had not traveled overseas since. She denied alcohol use or contact with animals such as pigs.On examination, her temperature was 38.5°C (101.3°F); pulse rate, 104/min; blood pressure, 205/92 mm Hg; and respiratory rate, 33/min with normal saturation. Mild conjunctival icterus and a positive Murphy sign were noted. Laboratory evaluation showed a white blood cell count of 16.4 × 109/L (neutrophils, 87.4%; eosinophils, 0.5% [absolute count, 82/μL]); hemoglobin level, 14.9 g/dL; platelet count, 254 × 109/L; aspartate aminotransferase level, 514 U/L; alanine aminotransferase level, 236 U/L; alkaline phosphatase level, 208 IU/L; total bilirubin level, 2.5 mg/dL; direct bilirubin level, 1.1 mg/dL; and lipase level, 247 U/L. Results of serologic testing for hepatitis A, B, and C were negative. Abdominal ultrasound showed no cholecystitis or pancreatohepatobiliary abnormalities. Magnetic resonance cholangiopancreatography was notable for a linear filling defect within the common bile duct extending through the left hepatic duct (Figure, left panel). During endoscopic retrograde cholangiopancreatography (ERCP), numerous worms were discovered within the biliary trees, with 1 visible outside the ampulla of Vater (Figure, right panel).Left, Findings on magnetic resonance cholangiopancreatography. Right, Findings on endoscopic retrograde cholangiopancreatography.Order polymerase chain reaction (PCR) assay for Ascaris

what would you do next?

What would you do next?

Prescribe anthelminthic therapy alone

Order polymerase chain reaction (PCR) assay for Ascaris

Order serum serologic testing for Ascaris

Prescribe antibiotics followed by anthelminthic therapy

d

female

61-70

White

original

https://jamanetwork.com/journals/jama/fullarticle/2757729

A 41-year-old woman presented with a 2-day history of burning, stinging, itchy blisters on the lower lip. She had experienced a similar eruption at the same site with spontaneous resolution 1 year previously, after she had taken a cold medication containing ibuprofen. Her medical history was otherwise unremarkable. She took no prescription medications; however, she did occasionally take over-the-counter ibuprofen. On examination, she was well-appearing and afebrile. There were tense confluent blisters in a 4-cm area on and around the lower lip (Figure 1) and no other skin or mucosal lesions.Tense confluent blisters on the lower lip area. What Would You Do Next?

Administer valacyclovir

Discontinue all cosmetics

Discontinue ibuprofen

Administer antibiotics

Bullous nonpigmenting fixed drug eruption

C

Discontinue ibuprofen

The key to the correct diagnosis in this case is the recurrence of local blisters at the same anatomical site after ibuprofen administration. A fixed drug eruption is a skin or mucosal adverse drug reaction that occurs at the same site each time the causative drug is taken.1 Common sites include the hands, feet, lips, and genitals.2,3 The lesion typically appears as solitary or multiple oval erythemas, which can evolve to become blisters (bullous fixed drug eruption). This sometimes causes residual postinflammatory hyperpigmentation; however, there sometimes may be cases without pigmentary change (nonpigmenting fixed drug eruption), as in this instance.Labial herpes (choice A) usually presents as grouped vesicles of uniform size and tends to include pustules or hemorrhagic crusts, with larger blisters being uncommon in the lesion. Contact dermatitis (choice B) presents as erythema, papules, and papulovesicles with intense itching. Impetigo (choice D) presents with flaccid blisters or erosions that quickly ooze and then form yellow crusts.Fixed drug eruption accounts for up to 39% of all drug eruptions.4 It is most common in adults, particularly those aged 40 to 80 years.2 Various causative drugs have been reported, including nonsteroidal anti-inflammatory drugs, acetaminophen, cotrimoxazole, tetracyclines, amoxicillin, and carbocysteine.2 Sensitization usually occurs a few weeks after initial medication exposure, though in some cases occurs over the course of several years (eg, in the case of sporadic use of analgesic drugs).5 The pathophysiology behind why lesions recur in the exact same anatomical site has not been clearly elucidated; however, it is thought that fixed drug eruption is a cytotoxic T-cell–mediated immune reaction and that skin-resident effector/memory T cells are the key mediators. At the end of the immune response in a fixed drug eruption, most of activated cytotoxic T cells in the lesion are removed by apoptosis, but a small population of cytotoxic T cells evades apoptosis as a result of keratinocyte-derived IL-15 and other factors. This population remains as skin-resident T cells in the lesional site, and an immunologic “resting fixed drug eruption lesion” is formed after clinical resolution. On reexposure to the drug antigen, there is activation and expansion of these resident T cells, and the recurrent fixed drug eruption develops, usually within 30 minutes to 8 hours after intake of a causative agent.6The histology of an early lesion shows the epidermal immigration of lymphocytes, apoptotic keratinocytes, and the vacuolar degeneration of basal keratinocytes that can lead to subepidermal blistering. Those histologic features of fixed drug eruption resemble erythema multiforme or Stevens-Johnson syndrome; therefore, definitive distinction among them based on skin biopsy alone is not always possible.7An oral provocation test using the implicated drug is the gold standard for confirming the causative drug in fixed drug eruption. It should be carefully performed, especially in patients with multiple lesions, because of the risk of severe reactions and new lesions with repeated exposure to the causative drug.8 It should not be performed for a generalized bullous fixed drug eruption. The protocol involves administration of very small doses of the implicated drug with a gradual increase in dose (eg, 1/10, 1/8, 1/4, 1/2, and full therapeutic dose) until reaction is observed at the site of fixed drug eruption.5 The observation time depends on the specific drug and patient history. For instance, carbocysteine-induced fixed drug eruption requires more than 2 days to elicit the eruption, as the hypersensitivity is usually to a metabolite.8Patch testing, in which the results are positive on previously lesional skin and negative on nonlesional skin, has been suggested as an alternative diagnostic method; however, positive responses occur in only about 40% of fixed drug eruption cases. The false-negative result might be attributable to the fact that the hypersensitivity reaction is not to the drug but rather to a metabolite, which would only form after oral ingestion.9The majority of fixed drug eruptions are self-limiting. Topical corticosteroids are used to reduce symptoms, and systemic corticosteroids may be necessary in patients with multiple lesions. Severe generalized bullous fixed drug eruption should be treated in an intensive care setting, similar to Stevens-Johnson syndrome and toxic epidermal necrolysis.10 Patients must be advised to avoid further use of the causative drug.The patient was told to avoid ibuprofen. The eruption resolved in 2 weeks with topical 0.12% betamethasone, without residual hyperpigmentation. A patch test with 10% ibuprofen in petrolatum was conducted on the lesional site (perioral skin just inferior to the vermilion border) and showed a positive result (Figure 2), confirming the diagnosis of ibuprofen-induced fixed drug eruption.Result of a patch test for ibuprofen after 48 hours, showing erythema and vesicles occurring on the previously involved site.

General

A 41-year-old woman presented with a 2-day history of burning, stinging, itchy blisters on the lower lip. She had experienced a similar eruption at the same site with spontaneous resolution 1 year previously, after she had taken a cold medication containing ibuprofen. Her medical history was otherwise unremarkable. She took no prescription medications; however, she did occasionally take over-the-counter ibuprofen. On examination, she was well-appearing and afebrile. There were tense confluent blisters in a 4-cm area on and around the lower lip (Figure 1) and no other skin or mucosal lesions.Tense confluent blisters on the lower lip area.

what would you do next?

What would you do next?

Discontinue ibuprofen

Administer valacyclovir

Discontinue all cosmetics

Administer antibiotics

a

female

41-50

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2755288

A girl in her teens presented with a unilateral itchy nodule on her right labium majus of 4 months’ duration. The patient was born and lived in a rural village in Malawi. Her medical and family history were unremarkable. She did not report fever or malaise. Physical examination revealed a polypoid, rubbery tumor measuring 1.5 cm located on her right labium majus, which obliterated the right labium minus (Figure, A). She did not present with enlarged lymph nodes, and results of the physical examination were otherwise unremarkable. An incisional lesional biopsy was taken (Figure, B and C).A, Polypoid nodule on the right labium majus obliterating the labium minus. B-D, Hematoxylin-eosin–stained lesional specimens. B, Histopathologic analysis of the nodule showed pseudoepitheliomatous hyperplasia with transepidermal elimination of basophilic oval-shaped structures in the epidermis and a dense acute and chronic dermal infiltrate in the dermis. C, Numerous dermal structures surrounded by a dense acute and chronic inflammatory cell infiltrate with granuloma formation. D, High-power magnification of the oval parasitic structures with a typical terminal spine. What Is Your Diagnosis?

Onchocerciasis

Late cutaneous bilharziasis

Periorificial cutaneous tuberculosis

Granuloma inguinale

B. Late cutaneous bilharziasis

B

Late cutaneous bilharziasis

Histopathologic examination showed pseudoepitheliomatous epidermal hyperplasia and transepidermal elimination of basophilic oval-shaped structures. A dense acute and chronic inflammatory cell infiltrate composed of neutrophils, eosinophils, lymphocytes, and macrophages with granuloma formation was identified in the dermis. Numerous parasitic structures were observed in the granulomas (Figure, B and C). At high-power magnification, basophilic oval-shaped parasites with a terminal spine characteristic of Schistosoma haematobium were identified in the dermis (Figure, D).Given these histopathologic findings, the diagnosis of late cutaneous bilharziasis (LCB) was made. However, the patient was lost to follow-up. Therefore, no additional tests could be performed to exclude complications (urine or fecal analyses, abdominal imaging), nor treatment given.Late cutaneous bilharziasis, or late cutaneous schistosomiasis, is a chronic cutaneous infection caused by trematodes of the Schistosoma genus. It is the second most common parasitic infection in the world and is more frequent in freshwater-rich areas of the African continent. However, with migratory flows, cases can be observed worldwide.1Schistosoma hematobium is the most common causative agent. However, infections by Schistosoma mansoni and Schistosoma japonicum have also been reported.2 The genitalia are the most common location of LCB, even if extragenital location can also occur. Vulvar involvement, considered to be rare in genital LCB (about 7%-17%),2 is more frequent in prepuberal age, although it may be underreported.3There are different clinical forms of cutaneous schistosomiasis according to the immune status of the patient and time of presentation after exposure: swimmer’s itch, Katayama fever, and LCB. Late cutaneous bilharziasis is produced by deposition of the parasite eggs in the dermis by retrograde migration through portal, perivesical, and mesenteric venules from previous systemic infection. Granuloma formation and transepidermal elimination subsequently occur to eliminate the parasites.4 Eventually, granulomatous reactions produce clinical manifestations, such as itchy papules, nodular lesions and polypoid tumors. Urinary (in S hematobium infection) and fecal (in S mansoni and S japonicum infection) parasitic discharge and the corresponding signs and symptoms can occur concomitantly.2 Possible complications of S hematobium infection are the development of vesical squamous cell carcinoma, hydronephrosis, infertility, increased transmission of sexually transmitted diseases, and pseudoelephantiasis, among others.1-3,5,6Confirmation of LCB diagnosis requires microscopic detection of eggs in urine, feces or skin; S hematobium has a terminal spine, while S mansoni has a lateral spine. Enzyme-linked immunosorbent assays for IgG, IgM, and IgE are available and distinguish acute from chronic infection. Onchocerciasis, periorificial cutaneous tuberculosis, cutaneous amoebiasis, and granuloma inguinale are the main differential diagnoses of LCB.Onchocerciasis is a nematode infection by Onchocerca volvulus. It can present with atrophic hypopigmented macules, blindness, and skin nodules called onchocercomas. However, no vulvar onchocercomas have been reported to our knowledge. Biopsy specimens show microfilaria in the dermis. Vulvar periorificial cutaneous tuberculosis is very rare, and is caused by hematogenous or urinary inoculation of Mycobacterium tuberculosis. Cases clinically similar to the present one have been described,7 but histopathological findings were different, showing granulomas with caseation. Cutaneous amoebiasis is an infection by Entamoeba histolytica. Vulvar cases are extremely rare and present with verrucous and/or ulcerated plaques through contiguous infection from amoebiasis colitis. Entamoeba trophozoites can be observed in biopsy specimens, and they are CD59 positive (N-acetyl-galactosamine positive). Granuloma inguinale or donovanosis is a rare infection by Klebsiella granulomatis. A hypertrophic form exists, presenting with clinical features very similar to those of the present case. However, Donovan bodies may be found in pathologic studies.The treatment of choice in LCB is praziquantel, 40 mg/kg, 2 or 3 doses.8 When fibrotic tissue remains after praziquantel treatment, surgery is indicated.In conclusion, we present a rare case of vulvar bilharziasis. Early diagnosis requires adequate clinicopathological correlation to prevent complications.

Dermatology

A girl in her teens presented with a unilateral itchy nodule on her right labium majus of 4 months’ duration. The patient was born and lived in a rural village in Malawi. Her medical and family history were unremarkable. She did not report fever or malaise. Physical examination revealed a polypoid, rubbery tumor measuring 1.5 cm located on her right labium majus, which obliterated the right labium minus (Figure, A). She did not present with enlarged lymph nodes, and results of the physical examination were otherwise unremarkable. An incisional lesional biopsy was taken (Figure, B and C).A, Polypoid nodule on the right labium majus obliterating the labium minus. B-D, Hematoxylin-eosin–stained lesional specimens. B, Histopathologic analysis of the nodule showed pseudoepitheliomatous hyperplasia with transepidermal elimination of basophilic oval-shaped structures in the epidermis and a dense acute and chronic dermal infiltrate in the dermis. C, Numerous dermal structures surrounded by a dense acute and chronic inflammatory cell infiltrate with granuloma formation. D, High-power magnification of the oval parasitic structures with a typical terminal spine.

what is your diagnosis?

What is your diagnosis?

Onchocerciasis

Late cutaneous bilharziasis

Granuloma inguinale

Periorificial cutaneous tuberculosis

b

female

11-20

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2755537

A man in his 30s presented with a 3-month history of gradual growth of a pruriginous, reddish nodule on the left ear. He had no relevant medical history. On medical examination, a reddish, smooth, superficial nodule with small dimples and a soft consistency that measured approximately 1.5 cm in diameter was seen on the left earlobe (Figure, A). It was not painful to the touch. The patient reported no history of lesions or foreign bodies at this location. A biopsy specimen was obtained for histopathologic analysis (Figure, B and C).A, Clinical photograph of a pruriginous, reddish tumor on the earlobe. B and C, Histopathologic findings reveal mixed diffuse dermatitis involving the reticular dermis, with small-vessel vasculitis, characteristic sparing of a superficial dermal grenz zone as well as the dilated vessel luminal, and mixed leukocytic infiltrate with eosinophils, lymphocytes, and neutrophils involving the full thickness of the vessel wall (hematoxylin-eosin). What Is Your Diagnosis?

Sweet syndrome

Extrafacial granuloma faciale

Angiolymphoid hyperplasia with eosinophilia

Leishmaniasis

B. Extrafacial granuloma faciale

B

Extrafacial granuloma faciale

The biopsy results revealed a mixed dermal infiltrate with eosinophils, neutrophils, and plasma cells, and a nonleukocytoclastic vasculitic component without epidermal changes. The histologic appearance was compatible with extrafacial granuloma faciale (GF).Granuloma faciale is a chronic, benign, and infrequent inflammatory skin disease of unknown origin. It usually manifests as a solitary reddish-violet plaque on the face, and extrafacial involvement may occur; other potential locations include the ears, scalp, trunk, and limbs.1,2 Lesion size varies from several millimeters to several centimeters in diameter. The lesions are usually smooth on the surface and can often present with superficial telangiectasias and prominent follicular orifices, which sometimes show an orange peel appearance.3 Granuloma faciale can be divided into plaque or nodular types, with the latter being generally resistant to therapy.4In a retrospective analysis of 66 patients with GF, i27 (41.5%) patients presented with a nodule, 25 (38%) had multiple lesions, 6 (9%) had extrafacial involvement alone, and 1 (1.5%) had facial and extrafacial involvement.5 Some studies have included GF in the spectrum of IgG4-related diseases.1-4 Although the precise pathogenesis remains unknown, interferon-γ and increased local production of interleukin 5 may be important mediators.1Granuloma faciale is characterized by a diffuse polymorphous inflammatory infiltrate that mainly affects the upper half of the dermis.5,6 The histologic characteristics of leukocytoclastic vasculitis are more prominent in the beginning, with older lesions tending to have fewer neutrophils and more eosinophils and plasma cells, as well as fibrosis.1 The clinical appearance of GF is distinctive, but the differential diagnosis may include lymphoma, persistent arthropod bite reactions, angiolymphoid hyperplasia with eosinophilia, tumid lupus erythematosus, erythema elevatum diutinum, and various granulomatous disorders.Treatment for this condition is limited. First-line therapies include corticosteroids (intralesional injection or topical), topical use of tacrolimus, or complete surgical removal.Sweet syndrome is characterized by a constellation of clinical symptoms that include high fever and sensitive erythematous cutaneous lesions that are usually painful. Histopathologic results reveal a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis. In this case, the patient did not comply with the necessary criteria.7 In contrast, angiolymphoid hyperplasia with eosinophilia is characterized by papules or nodules with an angiomatoid aspect and that are predominantly located on the head, especially around the ears. The histopathologic characteristics of angiolymphoid hyperplasia with eosinophilia include abnormal vascular proliferation formed by capillaries grouped around arterial or venous vessels, with lymphocytic infiltrates with eosinophils instead of a mixed dermal infiltrate.8Localized cutaneous leishmaniasis tends to occur in exposed areas of the skin and begins as a pink papule which gets bigger and becomes a nodule or a lesion similar to a plaque. The distinctive differences between GF and leishmaniasis are its clinical presentation and the evolution of the lesion; treatment for leishmaniasis can take months or years. In addition, the histopathologic results include a granulomatous infiltrate in the dermis and the presence of amastigotes in the acute phase of infection.9,10Herein, we present a rare case of nodular extrafacial GF. The patient underwent surgical excision of the lesion, with no recurrence reported. This condition should be included in the differential diagnosis of chronic plaques or nodules in the ears, scalp, trunk, and/or extremities, particularly in middle-aged men.

Dermatology

A man in his 30s presented with a 3-month history of gradual growth of a pruriginous, reddish nodule on the left ear. He had no relevant medical history. On medical examination, a reddish, smooth, superficial nodule with small dimples and a soft consistency that measured approximately 1.5 cm in diameter was seen on the left earlobe (Figure, A). It was not painful to the touch. The patient reported no history of lesions or foreign bodies at this location. A biopsy specimen was obtained for histopathologic analysis (Figure, B and C).A, Clinical photograph of a pruriginous, reddish tumor on the earlobe. B and C, Histopathologic findings reveal mixed diffuse dermatitis involving the reticular dermis, with small-vessel vasculitis, characteristic sparing of a superficial dermal grenz zone as well as the dilated vessel luminal, and mixed leukocytic infiltrate with eosinophils, lymphocytes, and neutrophils involving the full thickness of the vessel wall (hematoxylin-eosin).

what is your diagnosis?

What is your diagnosis?

Angiolymphoid hyperplasia with eosinophilia

Leishmaniasis

Extrafacial granuloma faciale

Sweet syndrome

c

male

31-40

original

https://jamanetwork.com/journals/jamaneurology/fullarticle/2752282

A 34-year-old man presented with headache, double vision, and seizures for 1 month and altered consciousness for 1 week. He had had 2 episodes of seizures that were characterized by tonic head and eye deviation to the left, followed by a brief period of tonic-clonic activity of all 4 limbs and postictal confusion for 10 to 15 minutes. He denied a history of fever, head trauma, limb weakness, or vomiting. He was a vegetarian, nonsmoker, and nondrinker. He denied a history of drug addiction.On examination, he was confused. He had facial flushing and grade III clubbing in his fingers and toes. His chest and cardiovascular examination results were normal. He had ptosis in his right eye. The right eye was deviated laterally secondary to right-medial rectus palsy. His pupil size and pupillary light reactions were normal. He also had grade II papilledema. His motor and sensory examination results were normal; however, he had brisk deep-tendon jerks and extensor planter responses. There were no meningeal signs.His cranial magnetic resonance image showed 2 ring-enhancing lesions in the right frontal and left parietal cortexes, along with surrounding brain edema and mass effects. Both lesions showed a thin-walled, contrast-enhancing rim with a central liquefaction (Figure, A). The central liquefaction showed restricted diffusion on diffusion-weighted magnetic resonance images.A, Cranial T1-weighted postcontrast magnetic resonance image showing ring-enhancing lesions in the right frontal and left parietal lobes. B, Chest radiography showing a radiolucent nodular shadow in left middle lung field.His hemoglobin level was 19.3 grams per deciliter (to convert to grams per liter, multiply by 10.0), his total leukocyte count was 13 500/μL (to convert to cells × 109/L, multiply by 0.001), his hematocrit was 62.4% (to convert to a proportion of 1.0, multiply by 10), and his platelet count was 210 000/μL (to convert to cells × 109/L, multiply by 0.001). He had normal liver and renal function test results. An enzyme-linked immunosorbent assay for HIV was nonreactive. A radiograph of his chest showed a nodular shadow in the left middle field of the lung (Figure, B). The 2-dimensional echocardiogram did not show any evidence of congenital heart disease. An arterial blood gas test result showed an oxygen saturation level of 80%. His blood cultures were found to be sterile. What Is Your Diagnosis?

Encysted empyema thoracis

Lung abscess

Pulmonary arteriovenous shunt

Bronchogenic carcinoma

C. Pulmonary arteriovenous shunt

C

Pulmonary arteriovenous shunt

A pyogenic brain abscess can occur because of purulent spread from infections in the middle ear, meninges, paranasal sinuses, mastoids, lungs (in cases of empyema, bronchiactesis, and pulmonary abscess), heart (in cases of infective endocarditis or cyanotic congenital heart diseases), gastrointestinal tract, or mouth (in cases of dental infection). A brain abscess can also occur after head trauma and neurosurgical procedures.1 Among the pulmonary causes, digital clubbing and pyogenic brain abscess can be seen in empyema thoracis, lung abscess, bronchiactesis, interstitial lung disease, and pulmonary arteriovenous shunts.2 Symptoms of pulmonary arteriovenous shunt depend on the size of the shunt. A patient with a pulmonary arteriovenous shunt may remain asymptomatic, whereas patients with empyema thoracis and lung abscess present with acute fever, chest pain, cough, and dyspnea on exertion or at rest.3With high suspicion of a pulmonary arteriovenous shunt, we performed bubble echocardiography testing with agitated saline infused through the left antecubital vein. During the fifth cardiac cycle, a large number of bubbles appeared in the left atria, suggesting a right-to-left shunt. There was no evidence of a patent foramen ovale. A contrast-enhanced computed tomographic scan of the chest showed a large pulmonary arteriovenous shunt in the left lung. The arterial feeder of the shunt arose from the pulmonary artery of the left upper lobe. The shunt drained into the left atrium via a dilated pulmonary vein.Pulmonary arteriovenous shunts can be histologically characterized as pulmonary arteriovenous fistulae (PAVF) or arteriovenous malformations. Pulmonary arteriovenous fistulae are abnormal dilated vessels that provide right-to-left shunts between the pulmonary artery and veins, whereas arteriovenous malformations are tumorous hemangiomas with localized overgrowth of thick vessels.4 Only 9% of patients with PAVF develop pyogenic brain abscesses5; in these cases, PAVF can produce paradoxical septic emboli to brain and brain abscesses. The other postulated mechanism is the formation of focal cerebral ischemia attributable to high blood viscosity, which forms a nidus for cerebral infections.6Pulmonary arteriovenous fistulae can be hereditary or acquired. Approximately 70% cases of PAVF are associated with hereditary hemorrhagic telangiectasia syndrome (Osler-Weber-Rendu syndrome).7 Epistaxis, hemoptysis, or peripheral telangiectasias are characteristic manifestations of hereditary hemorrhagic telangiectasia; these were not seen in this patient.Pulmonary arteriovenous fistulae occur twice often in women as in men.7 Nearly 50% patients may have associated peripheral arteriovenous fistulae.3 Because of right-to-left shunting, a state of chronic hypoxemia develops, and it continues to progress if the PAVF is left untreated.The clinical features of a PAVF depend on its size. Up to 55% of patients may remain asymptomatic.3 Common presenting features are dyspnea on exertion, chest pain, and cough. The complications of PAVF occur because of chronic hypoxemia, and they include polycythemia, recurrent syncopal attacks, cyanosis, and clubbing.3 The central nervous system complications of PAVF are transient ischemic attacks, migraine, stroke, brain abscess, and seizures.3 A contrast computed tomographic scan of the chest is a noninvasive way to diagnose PAVF. However, pulmonary angiography is required for the precise localization of feeder and draining vessels and embolization of the arterial feeder.Intravascular embolization of the pulmonary shunt remains a preferred treatment.3 Surgery is considered in patients with allergies to contrast material and those with very large shunts that are not amenable to embolization.In this patient, we closed the pulmonary shunt with an intravascular approach. Shunt closure produced a considerable improvement in oxygen saturation and hematocrit levels. To treat the patient’s brain abscesses, we used injectable ceftriaxone, vancomycin, and metronidazole on an empirical basis. After 6 weeks of antibiotic treatment, the brain abscesses healed completely.The present case highlights that a combination of features, such as digital clubbing, poor oxygen saturation, a raised hematocrit level, and the absence of congenital heart disease on echocardiography, should prompt clinicians to look for PAVF in a patient with a pyogenic brain abscess. Intravascular or surgical management of PAVF is essential to prevent further complications.

Neurology

A 34-year-old man presented with headache, double vision, and seizures for 1 month and altered consciousness for 1 week. He had had 2 episodes of seizures that were characterized by tonic head and eye deviation to the left, followed by a brief period of tonic-clonic activity of all 4 limbs and postictal confusion for 10 to 15 minutes. He denied a history of fever, head trauma, limb weakness, or vomiting. He was a vegetarian, nonsmoker, and nondrinker. He denied a history of drug addiction.On examination, he was confused. He had facial flushing and grade III clubbing in his fingers and toes. His chest and cardiovascular examination results were normal. He had ptosis in his right eye. The right eye was deviated laterally secondary to right-medial rectus palsy. His pupil size and pupillary light reactions were normal. He also had grade II papilledema. His motor and sensory examination results were normal; however, he had brisk deep-tendon jerks and extensor planter responses. There were no meningeal signs.His cranial magnetic resonance image showed 2 ring-enhancing lesions in the right frontal and left parietal cortexes, along with surrounding brain edema and mass effects. Both lesions showed a thin-walled, contrast-enhancing rim with a central liquefaction (Figure, A). The central liquefaction showed restricted diffusion on diffusion-weighted magnetic resonance images.A, Cranial T1-weighted postcontrast magnetic resonance image showing ring-enhancing lesions in the right frontal and left parietal lobes. B, Chest radiography showing a radiolucent nodular shadow in left middle lung field.His hemoglobin level was 19.3 grams per deciliter (to convert to grams per liter, multiply by 10.0), his total leukocyte count was 13 500/μL (to convert to cells × 109/L, multiply by 0.001), his hematocrit was 62.4% (to convert to a proportion of 1.0, multiply by 10), and his platelet count was 210 000/μL (to convert to cells × 109/L, multiply by 0.001). He had normal liver and renal function test results. An enzyme-linked immunosorbent assay for HIV was nonreactive. A radiograph of his chest showed a nodular shadow in the left middle field of the lung (Figure, B). The 2-dimensional echocardiogram did not show any evidence of congenital heart disease. An arterial blood gas test result showed an oxygen saturation level of 80%. His blood cultures were found to be sterile.

what is your diagnosis?

What is your diagnosis?

Bronchogenic carcinoma

Encysted empyema thoracis

Lung abscess

Pulmonary arteriovenous shunt

d

male

31-40

original

https://jamanetwork.com/journals/jamaneurology/fullarticle/2752667

A 27-year-old Asian man was found with painless masses of about 5.1 cm in diameter that appeared on both Achilles tendons 10 years ago. Two years prior, he had no obvious inducement and gradually developed indifference, glassy eyes, lethargy, and poor memory. One year prior, the patient’s personality changed dramatically, with notably decreased memory formation but intact short-term memory. He was short-tempered, irritable, hyperactive, and exhibited slight balance instability while walking. On admission, physical examination showed unstable balance while walking in a straight line, positive ankle clonus bilaterally, positive Babinski sign bilaterally, positive Chaddock sign bilaterally, positive Romberg sign, and painless lumps of about 8.2 cm in diameter in both Achilles tendons. Routine laboratory test results showed that the patient’s triglyceride level was elevated at 342.48 mg/dL (to convert to millimoles per liter, multiply by 0.0013 mg/dL; normal levels are considered to be 30.97-150.44 mg/dL). A brain magnetic resonance imaging (MRI) indicated multiple bilateral, symmetric abnormal signals in the genus of the internal capsules, posterior limbs of internal capsules, cerebral peduncles, pons, and cerebellar dentate nuclei (Figure, A). Genetic testing indicated a known pathogenic mutation c.1214G>A (p.Arg405Gln; Hom) in the CYP27A1 gene. An MRI of the ankle joints revealed an enlargement of the left Achilles tendon with abnormal signal, and the right Achilles tendon was circumscribed by a fusiform enlargement with abnormal signal (Figure, B).A, Brain magnetic resonance imaging (MRI) suggested multiple symmetrical abnormal signals (bilateral genus of internal capsule and posterior limbs of internal capsule, bilateral cerebral peduncles, pons, and cerebellar dentate nucleus). B, Right ankle joint MRI suggested right Achilles tendon circumscribed and a fusiform enlargement with abnormal signal (arrowhead). What Is Your Diagnosis?

Frontotemporal dementia

Wilson disease

Cerebrotendinous xanthomatosis

Autoimmune encephalitis

C. Cerebrotendinous xanthomatosis

C

Cerebrotendinous xanthomatosis

The brain MRI indicated multiple symmetrical strips and slightly longer T1 and T2 signals in the indicated regions. Fluid-attenuated inversion recovery indicated high signal (Figure, A) but enhanced MRI did not show enhanced signal. The N-acetylaspartate to creatine ratio decreased, and the chlorine to creatine ratio increased. There were no hemorrhagic foci or hemosiderin deposits in susceptibility-weighted imaging. The patient underwent CYP27A1 gene detection because the patient presented with encephalopathy with bilateral Achilles masses, suggesting a possible mutation of c.1214G>A (p.Arg405Gln; Hom). The patient’s various clinical manifestations and abnormal intracranial signals could not be explained as only frontotemporal dementia. Furthermore, there were no Kayser-Fleischer rings in the fundus of the eyes, and a normal serum copper blue protein test result excluded Wilson disease. All autoimmune antibodies tested negative, which did not support autoimmune encephalitis. As a result, a diagnosis of cerebrotendinous xanthomatosis (CTX) was made.Cerebrotendinous xanthomatosis is a rare clinical disease, with a worldwide incidence of fewer than 5 in every 100 000 individuals.1 It is an autosomal recessive, hereditary disease of lipid metabolism often caused by mutation of the CYP27A1 gene. The CYP27A1 gene-coded sterol 27-hydroxylase enzyme catalyzes the initial oxidation of cholesterol to bile acid. Thus, CYP27A1 mutation results in the ineffective conversion of cholesterol to bile acid. Excess cholesterol and cholestanol accumulate in the body. It is hypothesized that a large amount of cholesterol and cholestanol damage the blood-brain barrier, leading to the central nervous system deficits.The clinical manifestations of CTX in patients are diverse. Although the initial symptoms and signs occur in infancy or early childhood, the diagnosis is often incorrect or delayed by 17 to 25 years.2-4 Cholestasis jaundice and idiopathic stubborn diarrhea are often the first symptoms in the neonatal period. Cataracts can be seen in childhood. Tendon xanthoma exists in 70% of patients with CTX. Neurologic symptoms appear relatively late and the symptoms are diverse, including dementia, behavioral disorders, pyramidal tract signs, ataxia, dystonia, epilepsy, spinal cord lesions, and peripheral neuropathy. It has been reported that abnormal MRI signal in the dentate nucleus may be a specific marker of CTX. The abnormal elevation of plasma cholestanol and urinary bile alcohols is usually a laboratory indicator of CTX, but the level of blood cholesterol may not increase or can even decrease.1,5 Worldwide, 49 gene mutation sites have been reported. About 50% of these mutations are located in exon 6-8 of the CYP27A1 gene.1,5,6The treatment of CTX mainly includes a low-fat diet and pharmaceutical treatments such as bile acid replacement therapy, HMG-CoA reductase inhibitors, and statins. Bile acid replacement therapy can inhibit the production of cholesterol and its precursors. The HMG-CoA reductase inhibitors directly metabolize cholesterol and its precursors, reducing their accumulation. Statins may have some therapeutic effect on CTX. Chenodexycholic acid (CDCA) is the choice for treating neurologic and nonneurologic symptoms in patients with CTX.7 Some studies have found that supplementary treatment of CDCA can restore the level of plasma cholestanol and urinary bile alcohols to normal, but improvements to the neurologic deficits are not obvious. After 1 year of treatment with CDCA, 60% of patients’ neurologic symptoms still worsened progressively, and 20% of patients died. The survival rate of patients with CTX is only related to the age at diagnosis.3In this case, follow-up with the patient occurred after 18 months of oral administration of CDCA. The patient’s glassy eyes improved, whereas the symptoms of agitation and hyperactivity did not. A brain MRI showed that the size of cranial lesions was slightly decreased; however, the patient is now bedridden and unable to care for himself. Early diagnosis and intervention are key factors for the prognosis of CTX.

Neurology

A 27-year-old Asian man was found with painless masses of about 5.1 cm in diameter that appeared on both Achilles tendons 10 years ago. Two years prior, he had no obvious inducement and gradually developed indifference, glassy eyes, lethargy, and poor memory. One year prior, the patient’s personality changed dramatically, with notably decreased memory formation but intact short-term memory. He was short-tempered, irritable, hyperactive, and exhibited slight balance instability while walking. On admission, physical examination showed unstable balance while walking in a straight line, positive ankle clonus bilaterally, positive Babinski sign bilaterally, positive Chaddock sign bilaterally, positive Romberg sign, and painless lumps of about 8.2 cm in diameter in both Achilles tendons. Routine laboratory test results showed that the patient’s triglyceride level was elevated at 342.48 mg/dL (to convert to millimoles per liter, multiply by 0.0013 mg/dL; normal levels are considered to be 30.97-150.44 mg/dL). A brain magnetic resonance imaging (MRI) indicated multiple bilateral, symmetric abnormal signals in the genus of the internal capsules, posterior limbs of internal capsules, cerebral peduncles, pons, and cerebellar dentate nuclei (Figure, A). Genetic testing indicated a known pathogenic mutation c.1214G>A (p.Arg405Gln; Hom) in the CYP27A1 gene. An MRI of the ankle joints revealed an enlargement of the left Achilles tendon with abnormal signal, and the right Achilles tendon was circumscribed by a fusiform enlargement with abnormal signal (Figure, B).A, Brain magnetic resonance imaging (MRI) suggested multiple symmetrical abnormal signals (bilateral genus of internal capsule and posterior limbs of internal capsule, bilateral cerebral peduncles, pons, and cerebellar dentate nucleus). B, Right ankle joint MRI suggested right Achilles tendon circumscribed and a fusiform enlargement with abnormal signal (arrowhead).

what is your diagnosis?

What is your diagnosis?

Frontotemporal dementia

Autoimmune encephalitis

Cerebrotendinous xanthomatosis

Wilson disease

c

male

21-30

Asian

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2755966

A man in his mid-60s with a history significant for hereditary spherocytosis, polycythemia vera, hemochromatosis, hypereosinophilia, and asymptomatic paroxysmal supraventricular tachycardia presented to the emergency department because of dyspnea. Over a 4-week period, he developed dyspnea with moderate levels of physical activity that were occasionally associated with brief episodes of lightheadedness. He also reported orthopnea but no paroxysmal nocturnal dyspnea or leg edema. There was no chest pain, palpitations, cough, fever, or hemoptysis. He had tachypnea with a respiratory rate of 24 breaths per minute with a normal oxygen saturation, temperature, heart rate, and blood pressure. A soft (I/VI) systolic murmur with a brief diastolic component was appreciated over the apex. Jugular venous distension was present; there were no pulmonary rales, abdominal distention, or leg edema. Workup results demonstrated leukocytosis (white blood cell count, 39 800/μL [to convert to ×109 L, multiply by 0.001]; 15920/μL eosinophils [44%]), with a hemoglobin level of 12.4 g/dL (to convert to grams per liter, multiply by 10) and a platelet count of 153 ×103/μL (to convert to ×109 L, multiply by 1). A basic metabolic panel yielded normal results and troponin was undetectable. His chest radiography results were suggestive of pulmonary vascular congestion. The echocardiogram results demonstrated a normal left ventricular ejection fraction with no substantial wall motion abnormalities. There was an echogenic band traversing the apical portion of the left ventricle with increased echogenicity compared with the adjacent myocardium (Video). Representative frames of the echocardiogram are shown in Figure 1.Representative apical 4-chamber view in diastole (A) and systole (B) demonstrating an echogenic band traversing the apical portion of the left ventricle with increased echogenicity compared with the adjacent myocardium. What Would You Do Next?

Endomyocardial biopsy

Cardiac magnetic resonance imaging (MRI)

A whole-body positron emission tomography/computed tomography scan

Genetic testing for noncompaction

Loeffler syndrome with a left ventricular thrombus

B

Cardiac magnetic resonance imaging (MRI)

Loeffler syndrome is a progressive, restrictive heart failure syndrome with inflammatory endocardial fibrosis in the setting of hypereosinophilia. In hypereosinophilic syndromes (HES), eosinophils infiltrate, disrupt, and progressively destroy tissues through the deposition of enzymatic, granular, cationic, and proinflammatory proteins.1,2 Hypereosinophilic syndromes are rare with an incidence of approximately 0.036 per 100 000.1 Cardiac involvement is present in approximately 50% of patients with HES; the resultant fibroplastic endocarditis and eventual endomyocardial fibrosis may cause a restrictive cardiomyopathy. The damaged endocardium and prothrombotic milieu provide a nidus for mural thrombus formation.1-3 A new cardiac mass in the setting of hypereosinophilia should immediately cause concern for a thrombus.Oral anticoagulation is the standard therapy for patients with left ventricular (LV) thrombi.4,5 Warfarin is guideline recommended for LV thrombi in the setting of ST-elevation myocardial infarction; novel anticoagulants are still being studied. Although not specifically studied for the management of thrombi in Loeffler syndrome, the use of warfarin has been extrapolated to this patient population. Bridging with parenteral anticoagulation until a therapeutic international normalized ratio is achieved is needed.Cardiac MRI is considered the criterion standard for diagnosing LV thrombi. It is also the criterion standard for the noninvasive evaluation for Loeffler syndrome. A demonstration of patchy endomyocardial fibrosis in the setting of eosinophilia is essentially diagnostic of this pathology. While a definitive diagnosis requires endomyocardial biopsy with a demonstration of characteristic hypereosinophilic infiltration and tissue destruction, this procedure is deferred in the setting of mural thrombi.Other cardiac manifestations of HES include valvular disease, supraventricular tachyarrhythmias (as seen in this patient’s history), pericarditis with effusion, eosinophilic coronary periarteritis, and acute necrotizing eosinophilic myocarditis.1 In keeping with the management of HES, the treatment of Loeffler syndrome depends on the presence or absence of secondary causes or genetic abnormalities. Corticosteroids are often used, with nearly 85% of patients showing at least a partial response to corticosteroids within 1 month. Maintenance therapy is often required. Treatments with hydroxyurea, interferon-alpha, and imatinib have shown promise as well.6 Hematology should help cotreat patients with Loeffler syndrome. Surgical endocardial decortication is occasionally performed. During the preimmunomodulatory era, survival rates were about 50% over 10 years.7Anticoagulation was initiated. Cardiac MRI was performed, demonstrating extensive, circumferential subendocardial late gadolinium enhancement in the distal and apical LV segments that was consistent with the endomyocardial fibrosis seen in Loeffler syndrome. The large, distal LV mass was again detected (Figure 2). This was heterogeneous in character and did not enhance on perfusion or early and late postcontrast imaging sequences. In the setting of eosinophilic myocarditis, this mass was consistent with an LV thrombus. The hematology service was consulted for comanagement. About 6 months before this hospitalization, the patient had undergone a prolonged oral steroid taper for his eosinophilia with some efficacy. Oral prednisone was readministered. One month later, his eosinophil level remained elevated and the steroid therapy was increased. Five months after the hospitalization, he sustained critical limb ischemia from a thromboembolism to the lower extremities, requiring emergent surgical thrombectomy. His goal international normalized ratio was increased and he was subsequently administered mepolizumab, an immunomodulator used to treat eosinophilic asthma.In this cardiac magnetic resonance imaging study, a large left ventricular mass is demonstrated extending across the distal left ventricular cavity. The mass is heterogeneous in character but primarily nonenhancing on perfusion as well as early and late postcontrast imaging sequences. Late postcontrast enhancement of the apical subendocardium is suggestive of subendocardial fibrosis, consistent with eosinophilic myocarditis with associated left ventricular thrombus.

Cardiology

A man in his mid-60s with a history significant for hereditary spherocytosis, polycythemia vera, hemochromatosis, hypereosinophilia, and asymptomatic paroxysmal supraventricular tachycardia presented to the emergency department because of dyspnea. Over a 4-week period, he developed dyspnea with moderate levels of physical activity that were occasionally associated with brief episodes of lightheadedness. He also reported orthopnea but no paroxysmal nocturnal dyspnea or leg edema. There was no chest pain, palpitations, cough, fever, or hemoptysis. He had tachypnea with a respiratory rate of 24 breaths per minute with a normal oxygen saturation, temperature, heart rate, and blood pressure. A soft (I/VI) systolic murmur with a brief diastolic component was appreciated over the apex. Jugular venous distension was present; there were no pulmonary rales, abdominal distention, or leg edema. Workup results demonstrated leukocytosis (white blood cell count, 39 800/μL [to convert to ×109 L, multiply by 0.001]; 15920/μL eosinophils [44%]), with a hemoglobin level of 12.4 g/dL (to convert to grams per liter, multiply by 10) and a platelet count of 153 ×103/μL (to convert to ×109 L, multiply by 1). A basic metabolic panel yielded normal results and troponin was undetectable. His chest radiography results were suggestive of pulmonary vascular congestion. The echocardiogram results demonstrated a normal left ventricular ejection fraction with no substantial wall motion abnormalities. There was an echogenic band traversing the apical portion of the left ventricle with increased echogenicity compared with the adjacent myocardium (Video). Representative frames of the echocardiogram are shown in Figure 1.Representative apical 4-chamber view in diastole (A) and systole (B) demonstrating an echogenic band traversing the apical portion of the left ventricle with increased echogenicity compared with the adjacent myocardium.

what would you do next?

What would you do next?

Cardiac magnetic resonance imaging (MRI)

A whole-body positron emission tomography/computed tomography scan

Genetic testing for noncompaction

Endomyocardial biopsy

a

male

61-70

White

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2752947

A 45-year-old woman was referred to a tertiary care center for hoarseness. She had a left vocal fold polyp that was removed 2 months earlier at an outside institution, with benign pathology reported. Subsequent stroboscopy revealed a hemorrhagic-appearing polyp (2-3 mm). She was sent for preoperative voice therapy, with plans for excision. However, her voice worsened with therapy, and she returned to the otolaryngology clinic after a few weeks. A larger, 6- to 7-mm, irregular, left vocal fold mass was noted. Preoperative imaging was nonspecific, revealing a small soft-tissue density along the true vocal fold. The patient was taken to the operating room for excision (Figure, A). After the final pathology results were obtained, the patient was taken back to the operating room for cordectomy with negative margins.A, The left vocal fold lesion has a hemorrhagic exophytic mass that has prolapsed into the subglottis. B, Lesional spindled, fibroblastic-myofibroblastic, and inflammatory cells (both plasma cells and lymphocytes) appear in a myxoid background with abundant blood vessels. Even within this field, the denser collagenized stroma interrupts looser edematous areas. The overlying squamous epithelium demonstrates only minimal reactivity with some acanthosis and parakeratosis. C, Neoplastic, spindled, fibroblastic-myofibroblastic cells have diffuse, strong, granular cytoplasmic staining with the ALK1 (D5F3 clone). The intralesional blood vessels and inflammatory cells and overlying epithelium do not stain.Pathologic results revealed spindle-shaped cells with variable atypia noted and inflammatory cells, including lymphocytes and plasma cells (Figure, B). Cellular proliferation was present in a myxomatous and focally fibrous-appearing stroma. Immunohistochemical analysis revealed that the lesional cells were negative for desmin, S100, P63, and cytokeratin (Figure, C). They were reactive for vimentin and anaplastic lymphoma kinase 1 (ALK1). These findings were confirmed at the time of the initial excision. She has had no recurrent disease for the past 3 years. What Is Your Diagnosis?

Spindle cell carcinoma

Inflammatory myofibroblastic tumor

Laryngeal granuloma

Plasmacytoma of the larynx

B. Inflammatory myofibroblastic tumor

B

Inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumors (IMTs) are rare, neoplastic lesions that commonly involve the lungs or abdominopelvic region.1,2 Head and neck involvement is very uncommon, with the larynx most frequently affected.3 Laryngeal IMTs has a predilection for the true vocal cords, subglottis, and aryepiglottic folds.2,3 Although persons of any age may be affected, IMTs tend to occur in the fifth decade of life.2 Symptoms are secondary to mass effect, with 74% of patients presenting with hoarseness or dysphonia, dyspnea, dysphagia, globus sensation, otalgia, cough, and stridor.2,3Laryngeal IMT accounts for less than 1% of all respiratory tract tumors and remains poorly understood.4 The cause of laryngeal IMT has yet to be completely elucidated; however, predisposing factors may include smoking, trauma, infection (Epstein-Barr virus and human herpesvirus-8), and immunologic factors.1-3 Up to 70% of IMT cases have overexpression of the ALK protein, secondary to genetic abnormalities involving chromosome 2p23, a finding that supports its neoplastic nature.1,4,5 Aberrations in the ALK protein have been demonstrated in several other tumors, including rhabdomyosarcoma, renal cell carcinoma, non–small cell lung cancer, glioblastoma, and its namesake, anaplastic large-cell lymphoma.5Radiologic investigation is frequently included in the evaluation of patients with IMTs. Although magnetic resonance imaging and computed tomographic studies can reveal the size of the lesion, there is no characteristic imaging finding to differentiate an IMT from other airway masses.1,2 Diagnosis relies on immunohistopathologic evaluation of a biopsy specimen typically obtained from direct laryngoscopy. The lesions are composed of myofibroblastic spindle cells in the setting of a chronic inflammatory infiltrate of eosinophils and a chronic inflammatory infiltrate of lymphocytes and plasma cells (Figure, B).1,3,4,6 These inconclusive histologic findings should prompt consideration for laryngeal IMT.6 Immunohistochemical staining is used to confirm the diagnosis. With IMT, there is expression of vimentin, smooth muscle actin, and often ALK.1,3 In cases of ALK-negative IMTs, there have been a number of alternative genetic abnormalities implicated, most notably the ROS1 protein–tyrosine kinase fusion protein. Cases of IMTs that are positive for both ALK and ROS1 protein–tyrosine kinase may be targeted by crizotinib therapy.7,8 In this case, the specific immunohistochemical findings were key in the diagnosis of inflammatory myofibroblastic tumor.Complete surgical excision remains the mainstay of treatment.4 Depending on the extent of disease, surgical excision with negative margins can usually be accomplished endoscopically, with open approaches reserved for cases with inadequate endoscopic visualization, recurrence, or extensive disease.2 Inflammatory myofibroblastic tumors are aggressive, tend to recur locally, and have the potential to spread distally.1,2,4 The rate of local recurrence and distant metastasis has been reported to be 25% and less than 5%, respectively.1 Recurrence is most commonly secondary to incomplete excision and tends to occur within the first postoperative year.2 In addition to surgery, radiotherapy may be used for treatment of local recurrences.2 Surveillance with flexible laryngoscopy is necessary to promptly detect any recurrence.2

General

A 45-year-old woman was referred to a tertiary care center for hoarseness. She had a left vocal fold polyp that was removed 2 months earlier at an outside institution, with benign pathology reported. Subsequent stroboscopy revealed a hemorrhagic-appearing polyp (2-3 mm). She was sent for preoperative voice therapy, with plans for excision. However, her voice worsened with therapy, and she returned to the otolaryngology clinic after a few weeks. A larger, 6- to 7-mm, irregular, left vocal fold mass was noted. Preoperative imaging was nonspecific, revealing a small soft-tissue density along the true vocal fold. The patient was taken to the operating room for excision (Figure, A). After the final pathology results were obtained, the patient was taken back to the operating room for cordectomy with negative margins.A, The left vocal fold lesion has a hemorrhagic exophytic mass that has prolapsed into the subglottis. B, Lesional spindled, fibroblastic-myofibroblastic, and inflammatory cells (both plasma cells and lymphocytes) appear in a myxoid background with abundant blood vessels. Even within this field, the denser collagenized stroma interrupts looser edematous areas. The overlying squamous epithelium demonstrates only minimal reactivity with some acanthosis and parakeratosis. C, Neoplastic, spindled, fibroblastic-myofibroblastic cells have diffuse, strong, granular cytoplasmic staining with the ALK1 (D5F3 clone). The intralesional blood vessels and inflammatory cells and overlying epithelium do not stain.Pathologic results revealed spindle-shaped cells with variable atypia noted and inflammatory cells, including lymphocytes and plasma cells (Figure, B). Cellular proliferation was present in a myxomatous and focally fibrous-appearing stroma. Immunohistochemical analysis revealed that the lesional cells were negative for desmin, S100, P63, and cytokeratin (Figure, C). They were reactive for vimentin and anaplastic lymphoma kinase 1 (ALK1). These findings were confirmed at the time of the initial excision. She has had no recurrent disease for the past 3 years.

what is your diagnosis?

What is your diagnosis?

Inflammatory myofibroblastic tumor

Spindle cell carcinoma

Laryngeal granuloma

Plasmacytoma of the larynx

a

female

41-50

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2753324

A full-term, 7-month-old male infant presented to an outpatient pediatric otolaryngology clinic with a firm, irregularly shaped posterior neck mass. He had been diagnosed prenatally with cerebellar hypoplasia, so a magnetic resonance imaging study of the brain was performed at 1 month of age. This study demonstrated an incidental solid, homogenous mass in the subcutaneous fat of the right occiput with irregular borders and infiltration into the paraspinal musculature (Figure, A). On examination, the upper posterior neck mass was deep to palpation without overlying skin changes. The patient had no discomfort, and neck movement was not restricted.A, Axial T2-weighted magnetic resonance imaging of the neck without contrast. The arrowhead points to a 1.1-cm × 0.8-cm × 1.7-cm right occipital soft tissue mass with irregular borders and infiltration into the deep paraspinal musculature. B and C, Hematoxylin-eosin–stained images demonstrating cells with oval nuclei and multiple small nucleoli surrounded by a pale eosinophilic and slightly fibrillary stroma.At 7 months of age, the patient underwent ultrasonography to assess interval change of the lesion, which confirmed a 3.4-cm × 1.6-cm × 3.7-cm mass that had grown proportionally with the patient and was relatively avascular. Shortly thereafter, the mass was excised en bloc along with a cuff of adjacent posterior neck muscle and subcutaneous tissue. Grossly, the lesion was firm, round, and white in color with a smooth intact border but no discrete capsule. Histologic examination revealed cells with oval nuclei and multiple small nucleoli surrounded by a pale eosinophilic and slightly fibrillary stroma (Figure, B and C). Immunohistochemical studies were diffusely positive for glial fibrillary acidic protein and vimentin, and focally positive for S100, NeuN, and synaptophysin. What Is Your Diagnosis?

Lipoma

Rhabdomyosarcoma

Infantile hemangioma

Glial heterotopia

D. Glial heterotopia

D

Glial heterotopia

Glial heterotopia occurs when normal glial tissue abnormally appears at a location distant from the central nervous system (CNS). These lesions arise when fragments of embryonic neuroglial tissue become separated from the developing CNS.1 Although glial heterotopia lesions may be connected to the cranium via a fibrous stalk, complete separation (rather than herniation or invagination) from the CNS is what differentiates lesions such as glial heterotopia from meningoceles, encephaloceles, or meningoencephaloceles. While glial heterotopia in the head and neck area often presents in the nasal region (frequently referred to as nasal glioma), these masses may occur in other locations along the developing nervous system, including the paranasal sinuses, orbits, nasopharynx, scalp, face, neck, lungs, and gluteal regions.1,2 In many cases, glial heterotopia is asymptomatic and discovered incidentally.3 The incidence of nasal glioma is 1 in 20 000 to 40 000 births, with nonnasal glial heterotopia presenting even less commonly.4 Glial heterotopia may be associated with other congenital abnormalities, including cleft palate, congenital heart defects, Pierre Robin sequence, or posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies syndrome.5,6On Doppler ultrasound, glial heterotopia demonstrates a low or absent vascular flow velocity during the end-diastolic phase.6 On magnetic resonance imaging, these lesions demonstrate intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-weighted images owing to the presence of gliosis.6 In comparison, lipoma is characterized by homogenously high signal intensity on T1-weighted images. Hemangioma, in its proliferative phase, is hypointense to isointense on T1-weighted images and hyperintense on T2-weighted images.7 Rhabdomyosarcoma is isointense on T1-weighted images and hyperintense on T2-weighted images. If there is any concern about bony defects associated with the mass, computed tomography imaging is recommended.3Histologically, glial heterotopia is a neuroectoderm-derived tissue within a fibrovascular stroma. The cells may vary in complexity, with some being simply neurons and astrocytes, and others showing differentiation to the point of forming a functioning choroid plexus (meaning that lesions may be surrounded by their own cerebrospinal fluid).4 In contrast, infantile hemangioma is an unencapsulated mass of capillaries lined by plump endothelial cells, pericytes, and smooth muscle cells. Lipoma consists of mature adipocytes with interspersed fibrous connective tissue.7,8 Rhabdomyosarcoma may present with a variety of morphological and architectural characteristics depending on the histologic subtype of the tumor. Nevertheless, tumor cells in rhabdomyosarcoma usually display skeletal muscle differentiation histomorphologically and have features concerning for cancer, such as atypia and a high mitotic index.9The histological distinction between glial heterotopia and encephalocele is more subtle. Similar to glial heterotopia, encephalocele contains varying components of neural tissue. Depending on the degree of herniation, encephalocele may also contain meninges, which is a distinguishing factor from glial heterotopia.2 However, distinction between the 2 is most often based clinically on whether the lesion retains any connection to the CNS.Complete surgical resection is the recommended course of treatment for glial heterotopia because it can eventually lead to aesthetic deformities or functional impairment if left untreated. In the present case, the patient underwent successful complete excision of the mass without complication and has demonstrated no sign of recurrence or untoward events related to surgery at the 3-year interval.

General

A full-term, 7-month-old male infant presented to an outpatient pediatric otolaryngology clinic with a firm, irregularly shaped posterior neck mass. He had been diagnosed prenatally with cerebellar hypoplasia, so a magnetic resonance imaging study of the brain was performed at 1 month of age. This study demonstrated an incidental solid, homogenous mass in the subcutaneous fat of the right occiput with irregular borders and infiltration into the paraspinal musculature (Figure, A). On examination, the upper posterior neck mass was deep to palpation without overlying skin changes. The patient had no discomfort, and neck movement was not restricted.A, Axial T2-weighted magnetic resonance imaging of the neck without contrast. The arrowhead points to a 1.1-cm × 0.8-cm × 1.7-cm right occipital soft tissue mass with irregular borders and infiltration into the deep paraspinal musculature. B and C, Hematoxylin-eosin–stained images demonstrating cells with oval nuclei and multiple small nucleoli surrounded by a pale eosinophilic and slightly fibrillary stroma.At 7 months of age, the patient underwent ultrasonography to assess interval change of the lesion, which confirmed a 3.4-cm × 1.6-cm × 3.7-cm mass that had grown proportionally with the patient and was relatively avascular. Shortly thereafter, the mass was excised en bloc along with a cuff of adjacent posterior neck muscle and subcutaneous tissue. Grossly, the lesion was firm, round, and white in color with a smooth intact border but no discrete capsule. Histologic examination revealed cells with oval nuclei and multiple small nucleoli surrounded by a pale eosinophilic and slightly fibrillary stroma (Figure, B and C). Immunohistochemical studies were diffusely positive for glial fibrillary acidic protein and vimentin, and focally positive for S100, NeuN, and synaptophysin.

what is your diagnosis?

What is your diagnosis?

Infantile hemangioma

Glial heterotopia

Lipoma

Rhabdomyosarcoma

b

male

0-10

White

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2753563

A woman in her 30s with a medical history of epilepsy and alcohol use disorder who was taking lamotrigine presented with severe head trauma. Her Glasgow Coma Score (GCS) was 11 M5V4E2 on admission, and a computed tomographic (CT) scan showed a right frontal epidural hematoma with a maximum thickness of 19 mm and a volume of 30 cm3 (Figure 1A). The hematoma was evacuated by neurosurgery, and her GCS improved to 14 postoperatively. On postoperative day 2, she developed isolated dysphagia and dysphonia. Laryngoscopic examination revealed right vocal cord paralysis (Figure 1B).A, Computed tomographic (CT) image of the head shows a right frontal epidural hematoma. B, Clinical laryngoscopic image at day 2 shows right vocal cord palsy. C and D, Computed tomographic images with contrast show a thrombosis of the right sigmoid-jugular complex (yellow arrowheads), which causes acute compression of the recurrent nerve as it follows the course of the cranial accessory nerve then the vagus nerve. What Is Your Diagnosis?

Carotid artery dissection

Cerebral vein thrombosis

Posttraumatic central motor impairment

Postoperative laryngeal paralysis

B. Cerebral vein thrombosis

B

Cerebral vein thrombosis

A CT scan of the patient’s neck with contrast showed venous thrombosis of the right sigmoid-jugular complex (Figure 1, C and D), and she was diagnosed with incomplete posttraumatic Collet-Sicard syndrome (CSS) with compression of the vagus nerve (CN [cranial nerve] X).The jugular foramen is divided into 2 portions, separated by a temporal intrajugular process that continues with a fibrous intrajugular septum (Figure 2).1 The anteromedial petrous part (historically pars nervosa) contains the glossopharyngeal nerve (CN IX) and the inferior petrosal sinus (IPS). The IPS crosses CN IX inferiorly, then CN X superiorly before flowing into the jugular bulb (JB). The posterolateral sigmoid part (historically pars vascularis) contains CN X and the accessory nerve (CN XI) anteriorly, which are closely connected during their course through the jugular foramen, and the JB posteriorly, which is the junction between the sigmoid sinus and the internal jugular vein (IJV). The CN X and XI pass through a dura-matter duplication attached to the intrajugular process, which defines the intrajugular compartment; the ascending pharyngeal artery provides a posterior meningeal artery, which also passes through this compartment. As it exits the jugular foramen, the CN IX is tethered to the internal carotid artery and the JB by dense connective tissue,2 and thus is vulnerable to vessel injuries. The cranial accessory nerve (cXI) separates from the spinal accessory nerve (sXI) to rejoin the middle ganglion of the vagus nerve, to further become the recurrent laryngeal nerve. Finally, the hypoglossal nerve (CN XII) exits from the hypoglossal canal medially to the jugular foramen, then descends between the IJV and the internal carotid artery (ICA) before crossing the ICA laterally while heading forward. Hence, the last 4 CNs share close relations to neck vessels as they exit the skull base.Artistic view of the posterior facet of petrous bone and the jugular foramen, which illustrates the relations between cranial nerves (CNs) IX to XI and venous sinus as they enter the bone canal. Below this are shown the complex relations between major neck vessels and CNs IX to XII. CL indicates clivus; cXI, cranial accessory nerve; FM, foramen magnum; ICA, internal carotid artery; IJV, internal jugular vein; IPS, inferior petrosal sinus; SS, sigmoid sinus; sXI, spinal accessory nerve.Many of the CN eponymous compressive syndromes arise from the complex path of the last 4 CNs through the skull base and in the upper neck; therefore, careful clinical examination is necessary to elucidate the underlying pathology.3 Glossopharyngeal nerve palsy (CN IX) results in soft palate anesthesia and loss of the gag reflex. Vagus nerve palsy (CN X) results in vocal cord paralysis. Accessory nerve palsy (CN XI) causes a drooping shoulder, and difficulty turning the head to the contralateral side. Hypoglossal nerve palsy results in ipsilateral tongue wasting. Palsy of these 4 nerves defines CSS.4,5 Villaret syndrome is defined as ipsilateral Horner syndrome in addition to these 4 CN lesions indicating sympathetic tract involvement in the carotid sheath.These syndromes are typically associated with skull base metastasis, trauma to the skull base, or vascular injury (carotid artery dissection, jugular vein thrombosis). Other less common causes of CSS include primary intracranial tumors (meningioma, schwannomas, gliomas), extracranial cancers (myelomas), and inflammatory diseases.6Internal jugular vein thrombosis is one of the leading causes of CSS, mainly owing to incorrect placement of central venous catheters.7 To our knowledge, CSS from posttraumatic jugular venous thrombosis has never been reported. The patient’s complete coagulopathy work-up (including factor V Leiden, prothrombin G20210A mutation, antithrombin III, activated protein C resistance, protein S resistance, and antiphospholipid syndrome) revealed negative results. There were no evident risk factors for sigmoid-jugular thrombosis to occur, aside from the head trauma and the subsequent hematoma evacuation.Collet-Sicard syndrome from sigmoid-jugular thrombosis is treated with anticoagulation, just as other cerebral venous thromboses. This patient’s recovery supports that early diagnosis and anticoagulant therapy8 may lead to significant clinical improvement.

General

A woman in her 30s with a medical history of epilepsy and alcohol use disorder who was taking lamotrigine presented with severe head trauma. Her Glasgow Coma Score (GCS) was 11 M5V4E2 on admission, and a computed tomographic (CT) scan showed a right frontal epidural hematoma with a maximum thickness of 19 mm and a volume of 30 cm3 (Figure 1A). The hematoma was evacuated by neurosurgery, and her GCS improved to 14 postoperatively. On postoperative day 2, she developed isolated dysphagia and dysphonia. Laryngoscopic examination revealed right vocal cord paralysis (Figure 1B).A, Computed tomographic (CT) image of the head shows a right frontal epidural hematoma. B, Clinical laryngoscopic image at day 2 shows right vocal cord palsy. C and D, Computed tomographic images with contrast show a thrombosis of the right sigmoid-jugular complex (yellow arrowheads), which causes acute compression of the recurrent nerve as it follows the course of the cranial accessory nerve then the vagus nerve.

what is your diagnosis?

What is your diagnosis?

Posttraumatic central motor impairment

Postoperative laryngeal paralysis

Cerebral vein thrombosis

Carotid artery dissection

c

female

31-40

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2753763

A 31-year-old Hispanic woman had a 3-year history of a steadily growing, increasingly pruritic, painless mass behind the right ear. The patient denied bleeding from the mass, ear pain, trauma, fever, fatigue, night sweats, or recent illnesses. Her medical history included eczema treated with triamcinolone acetonide cream. Otherwise, the patient had no family history or exposure to tobacco or alcohol.On physical examination, a 2-cm, nontender, mobile retroauricular mass with superficial excoriations was palpable over the right mastoid cortex. The patient had no hearing deficits and no fistula into the external auditory canal. There was no palpable head and neck lymphadenopathy. Serologic studies revealed an elevated absolute eosinophil count of 790/μL (reference range, <700/μL; to convert to ×109 per liter, multiply by 0.001) and an eosinophilia percentage of 9.7% (reference range, <6.0%). The T1-weighted postcontrast magnetic resonance imaging of the head and neck showed a heterogeneously enhancing mass with irregular borders in the right retroauricular space, with a tract coursing anteriorly toward the parotid gland (Figure, A).A, Axial T1-weighted postcontrast magnetic resonance image of the head and neck. B, Lesional specimen of the excised mass (original magnification ×10).The excised mass was an enlarged, 2.2 × 1.5 × 2.2-cm lymph node with a smooth, pale core and no hemorrhage or necrosis. The capsule was moderately thickened by collagen fibrosis with focal areas of interstitial fibrosis. Reactive follicular hyperplasia was present with prominent eosinophilia in the interfollicular areas and within follicles, forming eosinophilic microabscesses and follicular cysts (Figure, B). A few small and ill-defined granulomas were present. Results of Gomori methenamine silver and acid-fast stains were negative. What Is Your Diagnosis?

Hodgkin lymphoma

Mastoiditis

Kimura disease

Brachial cleft cyst

C. Kimura disease

C

Kimura disease

Kimura disease (KD) is a chronic inflammatory disorder of the salivary glands or lymph nodes of the head and neck. Recognized in 1948 as a distinct clinicopathologic entity, much of our knowledge of this disease comes from a collection of sporadic case reports and small case series. It is characterized clinically by unilateral, painless cervical lymphadenopathy and deep subcutaneous masses of the head and neck, systemic eosinophilia, and elevated serum immunoglobulin E levels. This disease typically occurs in young Asian male patients in their second to fourth decades of life, although rare cases in other races and ethnicities have also been seen.1 We report a case of KD in an adult Hispanic woman in the United States.Although benign, KD can mimic infectious processes, such as tuberculosis infection or mastoiditis, brachial cleft cysts, drug reactions, and dermatopathic lymphadenopathy.2 In distinguishing nodular sclerosing Hodgkin lymphoma from KD, it is important to note the patient’s clinical course. Initial pathologic markers of Hodgkin lymphoma, such as CD30 positivity or presence of Reed-Sternberg cells, may be absent, and features found in KD, such as stromal fibrosis and eosinophilia, may be present in the former disease.2 Proper diagnosis is essential to avoid unnecessary tests and undue harm to the patient. In particular, KD has been historically misidentified as other lymphogranulomatous disorders, namely angiolymphoid hyperplasia with eosinophilia. Both have similar clinical features, including painless head and neck nodules, and were thought to be closely related on a spectrum of reactive disorders. However, angiolymphoid hyperplasia with eosinophilia is a vascular tumor that presents as small erythematous dermal nodules that bleed easily and is histologically characterized by endothelial proliferation without eosinophilic proliferation.3 There is marked fibrosis present at all stages of KD, but it is usually absent in angiolymphoid hyperplasia with eosinophilia.4Diagnosis is made by biopsy and histologic analysis of the mass. Microscopically, KD has characteristic pathologic features in the affected tissue, namely a dense lymphoid infiltrate rich in eosinophils with follicular hyperplasia as well as stromal fibrosis and increased vascularity.1 In addition, multinucleate giant cells called Warthin-Finkeldey cells may be observed. Computed tomography and magnetic resonance imaging typically reveal moderately enhancing masses with irregular borders within and around the parotid gland, with associated regional lymphadenopathy.1,5 Although not diagnostic, imaging may assist in surgical planning and determining the extent of tumor involvement. A unique feature of KD is the finding of serum eosinophilia, which may be confused with other disease entities that can cause systemic eosinophilia, such as parasitic infection. The pathophysiologic features of marked eosinophilia are thought to be due to abnormal activation of lymphocytes, leading to the release of eosinophil-activating cytokines.6 There is typically a concomitant increase in immunoglobulin E levels on the results of quantitative immunoglobulin tests.Given its indolent and self-limiting course, treatment of KD is mainly symptomatic.7 However, there is an important known association of KD with renal disease in the form of nephrotic syndrome.8 Masses may be excised, although there is a high probability of recurrence even after complete excision. Some reports support the effectiveness of nonsurgical treatment, including steroid therapy, chemotherapy, cyclosporine, thalidomide, and radiation.9,10

General

A 31-year-old Hispanic woman had a 3-year history of a steadily growing, increasingly pruritic, painless mass behind the right ear. The patient denied bleeding from the mass, ear pain, trauma, fever, fatigue, night sweats, or recent illnesses. Her medical history included eczema treated with triamcinolone acetonide cream. Otherwise, the patient had no family history or exposure to tobacco or alcohol.On physical examination, a 2-cm, nontender, mobile retroauricular mass with superficial excoriations was palpable over the right mastoid cortex. The patient had no hearing deficits and no fistula into the external auditory canal. There was no palpable head and neck lymphadenopathy. Serologic studies revealed an elevated absolute eosinophil count of 790/μL (reference range, <700/μL; to convert to ×109 per liter, multiply by 0.001) and an eosinophilia percentage of 9.7% (reference range, <6.0%). The T1-weighted postcontrast magnetic resonance imaging of the head and neck showed a heterogeneously enhancing mass with irregular borders in the right retroauricular space, with a tract coursing anteriorly toward the parotid gland (Figure, A).A, Axial T1-weighted postcontrast magnetic resonance image of the head and neck. B, Lesional specimen of the excised mass (original magnification ×10).The excised mass was an enlarged, 2.2 × 1.5 × 2.2-cm lymph node with a smooth, pale core and no hemorrhage or necrosis. The capsule was moderately thickened by collagen fibrosis with focal areas of interstitial fibrosis. Reactive follicular hyperplasia was present with prominent eosinophilia in the interfollicular areas and within follicles, forming eosinophilic microabscesses and follicular cysts (Figure, B). A few small and ill-defined granulomas were present. Results of Gomori methenamine silver and acid-fast stains were negative.

what is your diagnosis?

What is your diagnosis?

Brachial cleft cyst

Mastoiditis

Hodgkin lymphoma

Kimura disease

d

female

31-40

Hispanic

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2753928

A 55-year-old white woman presented with 1 week of decreased visual acuity and ache on abduction in the right eye. She had decreased right-sided hearing and tinnitus, a moderate right-sided frontal headache, and an unsteady gait. She did not have diplopia, facial numbness, or paresthesias. She had a history of stage IV breast cancer treated with letrozole after a mastectomy 5 years prior. On an initial examination, her best-corrected visual acuity was 20/50 OD and 20/25 OS, with dyschromatopsia, relative afferent pupillary defect, and visual-field defects on the right side. Her extraocular movements were full. A dilated fundus examination demonstrated a pale right optic nerve. Magnetic resonance imaging (MRI) of the brain was reported to have normal results, but on review, we noted thickening and enhancement of both optic nerves (with the right eye larger than the left eye) (Figure 1A), cranial nerve III in the right eye, cranial nerve V bilaterally, the pituitary infundibulum, and the hypothalamus, as well as adjacent cavernous sinuses. Leptomeningeal thickening over the convexities of the anterior frontal lobes was also evident (Figure 1B). The patient’s cerebrospinal fluid contained a small population of polyclonal CD19+ B cells and CD4+ and CD8+ T cells. An extensive laboratory workup, including tests for HIV, antinuclear antibodies, anti–double-stranded DNA, antineutrophil cytoplasmic antibodies, serum protein electrophoresis, erythrocyte sedimentation rate, C-reactive protein, complete blood cell count, antiganglioside antibodies, anti–myelin-associated glycoprotein antibodies, and angiotensin-converting enzyme, gave normal results. A computed tomographic (CT) scan of the thorax and a whole-body positron emission tomography (PET)/CT scan revealed no abnormalities.Initial magnetic resonance imaging of the brain. A, Thickening and enlargement of both optic nerves (with greater intensity in the right eye than the left eye). B, Leptomeningeal thickening over the convexities of anterior frontal lobes was also evident.Clinically, she initially responded to corticosteroids. Over the ensuing 5 years, she had multiple similar presentations that also included facial pain and paresthesias. She also developed a chronic small-fiber peripheral neuropathy and was treated with mycophenolate mofetil, cyclophosphamide, and intravenous immunoglobulin at various points. She remained clinically stable for 4 years and returned with similar symptoms.Repeat the magnetic resonance imaging of the brainRepeat the testing for angiotensin-converting enzyme in serum and cerebrospinal fluid What Would You Do Next?

Administer high-dose corticosteroids

Repeat the magnetic resonance imaging of the brain

Repeat the whole-body positron emission tomography scan

Repeat the testing for angiotensin-converting enzyme in serum and cerebrospinal fluid

Neurosarcoidosis presenting with relapsing optic neuropathy and multiple cranial neuropathies

C

Repeat the whole-body positron emission tomography scan

Although the findings of an initial MRI of the brain were described as normal, the symptoms and clinical findings of the neuro-ophthalmologist in conjunction with the findings on review of the MRI raised suspicion for sarcoidosis involving the central nervous system. Neurosarcoidosis can present a diagnostic challenge in indolent, relapsing cases, and the clinician should maintain a high index of suspicion despite a negative workup. Given the rarity of central nervous system involvement in sarcoidosis and the low chance of false-negative results on PET, repeating the testing is essential with disease evolution as well (choice C).1,2 A repeated PET/CT scan showed fluorodeoxyglucose-avid cervical, mediastinal, and hilar lymphadenopathy in a pattern suggestive of sarcoidosis (Figure 2), and a tissue biopsy of a hilar lymph node was characterized by noncaseating granulomas with proliferation of epithelioid cells.A repeated positron emission tomography/computed tomography scan 9 years after initial presentation revealed fluorodeoxyglucose-avid cervical, mediastinal, and hilar lymphadenopathy in a pattern suggestive of sarcoidosis.Neither corticosteroids (choice A) nor other immunomodulator medications would reveal the causative mechanism of this relapsing optic neuropathy and the cranial neuropathies. However, these medications can provide control of symptoms and should be administered to patients with definite neurosarcoidosis.The MRI findings in the central nervous system (choice B) in patients with neurosarcoidosis are nonspecific, overlapping with numerous inflammatory, infectious, and neoplastic processes.3 Given the history of breast carcinoma, clinicians should always include leptomeningeal metastasis in the differential diagnosis. However, that would be less likely, given the multiple responses to steroids, the absence of other symptoms, and the poor prognosis associated with leptomeningeal metastasis. A repeated MRI (9 years after initial presentation) showed new enhancement of the left cranial nerve III in a T1 image, before and after contrast. Primary central nervous system lymphoma was also included in the differential diagnosis. The patient’s cerebrospinal fluid was characterized by lymphocytosis of an unclear causative mechanism. Additionally, neither unusual cells in flow cytometry nor malignant cells by cytologic testing were detected.It has been demonstrated that serum angiotensin-converting enzyme levels are elevated only in 30% to 40% of patients with isolated neurosarcoidosis, compared with 60% in those with systemic disease (choice D). In addition, cerebrospinal fluid angiotensin-converting enzyme levels are estimated to be elevated in only 28% of affected individuals.4 Furthermore, while elevated protein and pleocytosis in the cerebrospinal fluid are consistent with neurosarcoidosis, they are not considered pathognomonic.5Targeted immunomodulatory therapy was started after the establishment of the diagnosis. The patient reported feeling better overall. Her neuro-ophthalmic examination results have been stable since then, and she continued to have decreased visual acuity with dyschromatopsia (with greater intensity in the right eye than the left eye), with a relative afferent pupillary defect on the right eye and right-sided hearing loss. The patient has followed up with autoimmune neurology and neuro-ophthalmology.

Ophthalmology

A 55-year-old white woman presented with 1 week of decreased visual acuity and ache on abduction in the right eye. She had decreased right-sided hearing and tinnitus, a moderate right-sided frontal headache, and an unsteady gait. She did not have diplopia, facial numbness, or paresthesias. She had a history of stage IV breast cancer treated with letrozole after a mastectomy 5 years prior. On an initial examination, her best-corrected visual acuity was 20/50 OD and 20/25 OS, with dyschromatopsia, relative afferent pupillary defect, and visual-field defects on the right side. Her extraocular movements were full. A dilated fundus examination demonstrated a pale right optic nerve. Magnetic resonance imaging (MRI) of the brain was reported to have normal results, but on review, we noted thickening and enhancement of both optic nerves (with the right eye larger than the left eye) (Figure 1A), cranial nerve III in the right eye, cranial nerve V bilaterally, the pituitary infundibulum, and the hypothalamus, as well as adjacent cavernous sinuses. Leptomeningeal thickening over the convexities of the anterior frontal lobes was also evident (Figure 1B). The patient’s cerebrospinal fluid contained a small population of polyclonal CD19+ B cells and CD4+ and CD8+ T cells. An extensive laboratory workup, including tests for HIV, antinuclear antibodies, anti–double-stranded DNA, antineutrophil cytoplasmic antibodies, serum protein electrophoresis, erythrocyte sedimentation rate, C-reactive protein, complete blood cell count, antiganglioside antibodies, anti–myelin-associated glycoprotein antibodies, and angiotensin-converting enzyme, gave normal results. A computed tomographic (CT) scan of the thorax and a whole-body positron emission tomography (PET)/CT scan revealed no abnormalities.Initial magnetic resonance imaging of the brain. A, Thickening and enlargement of both optic nerves (with greater intensity in the right eye than the left eye). B, Leptomeningeal thickening over the convexities of anterior frontal lobes was also evident.Clinically, she initially responded to corticosteroids. Over the ensuing 5 years, she had multiple similar presentations that also included facial pain and paresthesias. She also developed a chronic small-fiber peripheral neuropathy and was treated with mycophenolate mofetil, cyclophosphamide, and intravenous immunoglobulin at various points. She remained clinically stable for 4 years and returned with similar symptoms.Repeat the magnetic resonance imaging of the brainRepeat the testing for angiotensin-converting enzyme in serum and cerebrospinal fluid

what would you do next?

What would you do next?

Repeat the testing for angiotensin-converting enzyme in serum and cerebrospinal fluid

Administer high-dose corticosteroids

Repeat the magnetic resonance imaging of the brain

Repeat the whole-body positron emission tomography scan

d

female

51-60

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2755403

A 76-year-old white woman with a history of left corneal stem-cell deficiency and cataract presented for a second opinion of recurrent left upper eyelid blepharedema, ptosis, erythema, photophobia, mucopurulent discharge, and a feeling she described as a “knife in my left eye” over the past 4 years (Figure 1). Previous treatment included topical steroids, antibiotics, and serum tears, with temporary relief. However, she experienced recurrences of symptoms after therapy discontinuation. Additional treatment included weekly bandage contact lenses for many months, which made the left eye pain tolerable. A dacryocystogram of the left lacrimal system indicated partial dacryostenosis, but compression of the canaliculi and lacrimal sac did not exacerbate discharge. A prior computed tomography scan of the orbits and sinuses showed no abnormalities. Her visual acuity was 20/30 OD and 20/100 OS. Deep superior conjunctival fornices were noted in both eyes (Figure 1), and eversion of the left upper eyelid revealed a pseudomembrane of the tarsal conjunctiva. Cultures of the copious discharge demonstrated many gram-negative Serratia marcescens. She subsequently started treatment with topical prednisolone acetate, moxifloxacin, and systemic azithromycin.Patient presented with recurrent left eye ptosis, erythema, blepharedema, chronic discharge, and knifelike pain over the past 4 years (arrowhead).Two weeks after the initial consultation, the patient reported persistent but improved symptoms in the left eye. At this follow-up visit, her visual acuity was 20/30 OD and 20/200 OS. What Would You Do Next?

Start treatment with systemic steroids

Perform a dacryocystorhinostomy

Sweep the superior fornix

Perform a canaliculotomy

Giant fornix syndrome with several retained foreign bodies in the superior fornix

C

Sweep the superior fornix

This patient’s symptoms of ptosis and recurrent conjunctivitis refractory to topical antibiotics indicated a probable diagnosis of giant fornix syndrome (GFS). Starting systemic steroids (choice A) would not be the next preferred step for GFS because it would not address the underlying sequestration of bacteria. Performing a dacryocystorhinostomy (choice B) would not be the best next step because lacrimal duct obstruction was not identified. Performing a canaliculotomy (choice D) was not indicated since canaliculi compression did not exacerbate discharge, which excluded canaliculitis. Sweeping the superior fornix with a cotton-tipped applicator (choice C) was the appropriate next step to remove the reservoir of bacteria contributing to the chronic inflammation.In this case, the clinical symptoms indicated GFS; however, cultures of the mucopurulent discharge revealed gram-negative S marcescens. This result was suspicious for an atypical reservoir of bacteria. In addition to following the standard of care by sweeping the patient’s superior fornix of the conjunctiva, the cotton-tipped applicator used for the procedure was soaked in povidone-iodine.1 Multiple sweeps extracted substantial granular discharge, yellowish debris, and portions of approximately 6 old, pigmented contact lenses (Figure 2).Several sweeps of the superior fornix of the left conjunctiva extracted pieces of approximately 6 contact lenses (black arrowhead) and a yellowish coagulum of debris (white arrowhead).Giant fornix syndrome was first described in a series of 12 cases.2 The symptoms of GFS consist of severe, chronic, recurrent, purulent pseudomembranous conjunctivitis that are often refractory to topical antibiotics and dacryocystorhinostomy.2-5 Cultures typically demonstrate Staphylococcus aureus and possibly Pseudomonas aeruginosa.2 Eye examination often reveals punctate keratopathy and corneal changes with prolonged disease: vascularization, stromal scarring, and possibly corneal perforation.2 The causative mechanism appears to be an age-associated deepening of the fornices, primarily attributable to dehiscence of the levator palpebrae aponeurosis. Deep superior sulci form, predisposing inflammatory proteins to become sequestered and form a coagulum. Ultimately, a reservoir of colonized bacteria develops, which continuously reseeds the tear lake and causes severe persistent conjunctivitis.First-line therapy for GFS includes frequent topical antibiotics, oral antibiotics, and corticosteroid drops for up to 4 weeks.2-5 Continuous topical application of antibiotics to prevent recurrence may be warranted.2 Additionally, sweeping the fornices is indicated to remove the protein coagulum and reduce the bacterial reservoir in the ocular environment. Adding a cotton-tipped applicator soaked in povidone-iodine to perform the sweep has, in some cases, sufficiently eradicated the infection without the need for systemic antibiotics.1 Lastly, in individuals with chronically relapsing, medically intolerant cases of GFS, surgical reconstruction to reduce forniceal depth and minimize coagulum formation can successfully improve symptoms.6-8Giant fornix syndrome may be misdiagnosed or inappropriately managed, potentially leading to delayed treatment, risk of irreversible corneal changes, and possible loss of visual acuity. This Clinical Challenge exemplifies how GFS should be considered in some patients with chronic, relapsing conjunctivitis and potentially managed using medication, a fornix sweep, and surgical reconstruction if necessary.The patient returned 2 weeks after the sweeping procedure with substantially improved visual acuity and decreased pain. At the 3-month follow-up visit, all symptoms of pain, irritation, visual disturbances, and inflammation had resolved.

Ophthalmology

A 76-year-old white woman with a history of left corneal stem-cell deficiency and cataract presented for a second opinion of recurrent left upper eyelid blepharedema, ptosis, erythema, photophobia, mucopurulent discharge, and a feeling she described as a “knife in my left eye” over the past 4 years (Figure 1). Previous treatment included topical steroids, antibiotics, and serum tears, with temporary relief. However, she experienced recurrences of symptoms after therapy discontinuation. Additional treatment included weekly bandage contact lenses for many months, which made the left eye pain tolerable. A dacryocystogram of the left lacrimal system indicated partial dacryostenosis, but compression of the canaliculi and lacrimal sac did not exacerbate discharge. A prior computed tomography scan of the orbits and sinuses showed no abnormalities. Her visual acuity was 20/30 OD and 20/100 OS. Deep superior conjunctival fornices were noted in both eyes (Figure 1), and eversion of the left upper eyelid revealed a pseudomembrane of the tarsal conjunctiva. Cultures of the copious discharge demonstrated many gram-negative Serratia marcescens. She subsequently started treatment with topical prednisolone acetate, moxifloxacin, and systemic azithromycin.Patient presented with recurrent left eye ptosis, erythema, blepharedema, chronic discharge, and knifelike pain over the past 4 years (arrowhead).Two weeks after the initial consultation, the patient reported persistent but improved symptoms in the left eye. At this follow-up visit, her visual acuity was 20/30 OD and 20/200 OS.

what would you do next?

What would you do next?

Perform a canaliculotomy

Perform a dacryocystorhinostomy

Start treatment with systemic steroids

Sweep the superior fornix

d

female

71-80

White

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2755972

A 73-year-old African American woman was referred for the evaluation of a pigmented lesion on her left upper eyelid margin of 6 weeks’ duration. The patient first noted an erythematous, tender swelling with yellow discharge, which later evolved to the pigmented mass. Her ocular history was unremarkable. Her medical history revealed hypertension, type 2 diabetes mellitus, and hyperlipidemia.On examination, her visual acuity was 20/40 OD and 20/30 OS. There was a sausage-shaped, darkly pigmented (black), focally ulcerated nodule involving the medial upper eyelid margin and measuring 8 × 6 × 4 mm. Associated madarosis, eyelid margin notching, and telangiectasia were noted (Figure 1). The remainder of the anterior segment and a dilated fundus examination were unremarkable.A, The multilobular pigmented mass is noted along the superomedial upper eyelid margin. B, The lesion demonstrates notching of the eyelid margin, ulceration, and madarosis.Treat with hot compresses and an antibiotic-steroid ointmentPerform a full-thickness eyelid resection with intraoperative control of margins What Would You Do Next?

Treat with hot compresses and an antibiotic-steroid ointment

Perform an incision and drainage

Provide a corticosteroid injection

Perform a full-thickness eyelid resection with intraoperative control of margins

Pigmented basal cell carcinoma

D

Perform a full-thickness eyelid resection with intraoperative control of margins

The differential diagnosis of a pigmented eyelid lesion includes a broad spectrum of benign and malignant tumors.1,2 Diagnostic considerations include benign tumors, such as nevi, blue nevi, seborrheic keratosis, apocrine hidrocystomas, vascular malformations, and inflammatory processes (eg, a chalazion). Malignant considerations include melanoma, metastasis, pigmented squamous cell carcinoma, and pigmented basal cell carcinoma (BCC).The original symptoms of a tender, erythematous swelling with discharge raised initial concern for an inflammatory process, such as a chalazion; however, the large, firm, pretarsal nodule with a focal madarosis suggested a neoplastic process. Thus, hot compresses and an antibiotic-steroid ointment (choice A), an incision and drainage (choice B), and a corticosteroid injection (choice C), all of which treat inflammatory chalazia, would not be appropriate management options. Surgical excision is the mainstay of treatment for most primary eyelid malignant conditions. An anterior lamellar resection is a reasonable option for anteriorly situated tumors that do not involve the tarsus or posterior lamella of the eyelid. However, in this case, the tumor was associated with madarosis, which is indicative of tarsal involvement, leading to the decision to perform a full-thickness eyelid resection with intraoperative control of margins (choice D) and a subsequent reconstruction.1 At the time of surgery, the mass was found to be temporally invasive, and final margins were clear. Pathological testing confirmed pigmented BCC of the nodular and infiltrative types, involving the anterior and posterior lamellae of the eyelid (Figure 2).Histopathological staining demonstrates nests and bands of basal cell carcinoma with focal retraction artifacts from the desmoplastic stroma (yellow arrowheads) and peripheral palisading of the neoplastic nuclei (white arrowheads). Focal pigment is present, predominantly confined to melanophages and, to a lesser degree, neoplastic cells. The pigmentation is most conspicuous in the superficial aspect of the tumor (hematoxylin-eosin stain; original magnification ×100).Basal cell carcinoma is the most common malignant condition of the eyelid, typically appearing on the lower eyelid as a pearly, ulcerated mass.1 This tumor demonstrates a strong predilection for white individuals, with much lower incidence in Asian and black individuals.2-5 Several clinical and histopathological types of BCC have been recognized. The most common variant is nodular BCC, which classically presents as a firm, raised, pearly nodule with rolled borders associated with telangiectasia and central ulceration. Histopathologically, nodular BCC forms basophilic islands with peripheral palisading of tumor cells and retraction artifacts from the desmoplastic dermis.2 Infiltrative BCC, including morpheaform BCC, typically manifests as a firm, slightly thickened eyelid mass with indistinct margins and madarosis. Histopathologically, this locally aggressive variant of BCC is composed of slender infiltrating tendrils of basophilic cells within desmoplastic and fibrotic stroma.2Pigmented BCC is a rare BCC variant, manifesting clinically as a light or dark pigmented lesion ranging in color from brown to blue-gray to black, as in this case. The pigmentation can be speckled, multifocal, or diffuse.6,7 Clinically and histopathologically, pigmented BCC can demonstrate all growth patterns recognized in a conventional nonpigmented BCC, including nodular and morpheaform morphology. The defining histopathologic feature of pigmented BCC is an irregular foci of pigmentation confined to melanophages and tumor cells, with a predilection toward the superficial portion of the tumor. The intensity of microscopic pigmentation directly correlates with the degree of pigmentation observed clinically.8,9Clinically pigmented BCC demonstrates racial/ethnic dependency. Pigmented BCC among black individuals has been noted to be as high as 68% (21 of 31 patients)3 or 100% (14 of 14 patients)4 of all BCC cases. Pigmented BCC has been shown to make up 66%, 75%, and 80% of all BCC in Hispanic,10 Japanese,5 and Singaporean9 populations, respectively. Conversely, pigmented BCC is uncommon among white populations, representing only 2% to 11% of all BCC found in this group.8,10The patient underwent a successful and uncomplicated resection of her eyelid tumor followed by a reconstruction. In the postoperative period, the patient was monitored for wound security, cornea integrity, and tumor recurrence. She will be followed up on a 6-month basis.

Ophthalmology

A 73-year-old African American woman was referred for the evaluation of a pigmented lesion on her left upper eyelid margin of 6 weeks’ duration. The patient first noted an erythematous, tender swelling with yellow discharge, which later evolved to the pigmented mass. Her ocular history was unremarkable. Her medical history revealed hypertension, type 2 diabetes mellitus, and hyperlipidemia.On examination, her visual acuity was 20/40 OD and 20/30 OS. There was a sausage-shaped, darkly pigmented (black), focally ulcerated nodule involving the medial upper eyelid margin and measuring 8 × 6 × 4 mm. Associated madarosis, eyelid margin notching, and telangiectasia were noted (Figure 1). The remainder of the anterior segment and a dilated fundus examination were unremarkable.A, The multilobular pigmented mass is noted along the superomedial upper eyelid margin. B, The lesion demonstrates notching of the eyelid margin, ulceration, and madarosis.Treat with hot compresses and an antibiotic-steroid ointmentPerform a full-thickness eyelid resection with intraoperative control of margins

what would you do next?

What would you do next?

Perform a full-thickness eyelid resection with intraoperative control of margins

Provide a corticosteroid injection

Treat with hot compresses and an antibiotic-steroid ointment

Perform an incision and drainage

a

female

71-80

African American

original

https://jamanetwork.com/journals/jama/fullarticle/2757314

A 61-year-old man with a history of hypertension, psychosis, and recurrent venous thromboembolism was admitted to the emergency department with fatigue, weakness, and arthralgias after an unexplained fall. At presentation, he was experiencing psychosis and being treated in an inpatient psychiatric ward. He was nonadherent with medications and denied drug and alcohol abuse.On examination, he appeared comfortable. His blood pressure was 150/67 mm Hg; heart rate, 77/min; temperature, 36.7°C (98.1°F); respiratory rate, 16/min; and oxygen saturation, 99% on room air. On both lower extremities, there was peripheral edema with widespread hematomas, scattered ecchymosis, petechiae, and diffuse perifollicular purpura (Figure). The remainder of the examination was unremarkable. Laboratory test results showed a normocytic anemia (hemoglobin level, 5.2 g/dL [reference, 13.5-17.5 g/dL]; mean corpuscular volume, 85 fL [reference, 80-100 fL]); normal platelet count (thrombocytes, 285 ×109/L [reference, 150-400 ×109/L]); and a mild leukopenia (leukocytes, 3.9 ×109 [reference, 4.3-10 ×109/L]). Folic acid level was low (3 nmol/L [reference, ≥5 nmol/L]) and vitamin B12 level was normal (478 pg/mL [reference, 193-982 pg/mL]). Results for iron panel, reticulocyte count, prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio, liver function tests, and levels of indirect bilirubin, haptoglobin, fibrinogen, and creatine kinase were all within reference range. Chest radiographs and computed tomography of the head were negative for any acute pathology. A 12-lead electrocardiogram revealed no abnormalities. Ultrasound of both lower legs showed no thromboembolism.Order additional coagulation tests (thrombin time, platelet function assay) What Would You Do Next?

Order a bone marrow biopsy

Administer prothrombin complex concentrate

Initiate vitamin C supplementation

Order additional coagulation tests (thrombin time, platelet function assay)

Vitamin C deficiency (scurvy)

C

Initiate vitamin C supplementation

The key to the correct diagnosis is the history of psychiatric illness, which is a risk factor for nutritional deficiencies, together with multiple hemorrhages in the setting of normal coagulation test results, which raises concern for scurvy. This diagnosis was confirmed with a low vitamin C level of 2 μmol/L (reference, 23-100 μmol/L). Performing a bone marrow biopsy (option A) would be premature. Given the normal coagulation test results, administering prothrombin complex concentrate would be unnecessary (option B), and additional coagulation tests (option D) would not help establish the diagnosis.Vitamin C deficiency (scurvy) is a nutritional disease presumed to be archaic. As early as 1753, Sir James Lind found that citrus fruits could prevent and treat scurvy affecting sailors on long sea voyages. The antiscorbutic factor in citrus fruits and potatoes was identified in the 20th century and was called vitamin C.1 Vitamin C, also known as ascorbic acid, cannot be synthesized or stored endogenously; therefore, regular and adequate dietary consumption is essential. The absorption of vitamin C takes place in the ileum. Blood concentrations of vitamin C are regulated by renal excretion.2Vitamin C has several functions. First, vitamin C has antioxidant capabilities providing electrons needed for reducing molecular oxygen.2 More precisely, vitamin C acts as a cofactor by reducing transition of metal ions in the active sites of specific biosynthetic and regulatory metalloenzymes. Second, the antioxidant capabilities of vitamin C stabilize vitamin E, folic acid, and iron. Therefore, scurvy can predispose to concomitant deficiency states. Third, vitamin C is a cofactor in collagen synthesis.3 Failure of this process leads to structural instability of collagen, resulting in blood vessel fragility with bleeding tendencies and impaired wound healing due to disordered connective tissue. Low levels of vitamin C within red blood cells may also cause a low-grade chronic hemolysis.4 Fourth, vitamin C is a required cofactor in neurotransmitter synthesis. In this patient, anemia was caused by blood loss due to the widespread hemorrhages together with altered iron absorption and concomitant folate deficiency.Several patient groups are at risk for developing vitamin C deficiency,5 including patients with gastrointestinal disease (eg, colitis), patients with cancer receiving chemotherapy, patients with alcohol use disorder, and, as in this instance, patients with psychiatric disorders.Scurvy is characterized by cutaneous abnormalities. The most specific cutaneous symptoms are follicular hyperkeratosis and perifollicular hemorrhage (including petechiae), especially on the lower extremities.6 These findings may resemble vasculitis. Other symptoms include arthralgia, ecchymosis, bleeding gums with gingivitis, impaired wound healing, fatigue, and edema. Fatigue, noted in about one-third of patients, is thought to be related to both impaired catecholamine synthesis3 as well as anemia. For these symptoms to occur, vitamin C must be completely absent from the diet for 60 to 90 days.7 Interestingly, vitamin C deficiency can also be a contributing factor to developing psychiatric illness. Although psychosis was part of this patient’s medical history, the vitamin C deficiency may have exacerbated his current psychotic episode.A serum vitamin C level of 11 μmol/L or lower is suggestive of scurvy, but it remains a clinical diagnosis.3 A leukocyte ascorbate level is the most accurate for determining tissue stores of vitamin C; however, this test is not readily available in all hospitals.8,9 The diagnosis of scurvy is often delayed because patients often undergo testing for rare coagulation factor deficiencies before scurvy is considered. This delay could lead to potentially severe complications such as cardiovascular collapse or multiorgan dysfunction resulting in death.1 Secondary infections (eg, pneumonia) also occur.Scurvy is an easily curable disease. Both oral and parenteral supplementation can be given. There are no studies to date addressing the optimal treatment regimen.9The patient was also treated with ascorbic acid (500 mg/d) and folic acid (0.5 mg/d) orally. Dietary modification targeting vitamin intake was started. He received blood transfusions for symptomatic anemia and was concurrently treated for psychosis. His muscle weakness and anemia improved dramatically within 2 days and 3 weeks, respectively. At 3-month follow up, his widespread hemorrhages were completely resolved.

General

A 61-year-old man with a history of hypertension, psychosis, and recurrent venous thromboembolism was admitted to the emergency department with fatigue, weakness, and arthralgias after an unexplained fall. At presentation, he was experiencing psychosis and being treated in an inpatient psychiatric ward. He was nonadherent with medications and denied drug and alcohol abuse.On examination, he appeared comfortable. His blood pressure was 150/67 mm Hg; heart rate, 77/min; temperature, 36.7°C (98.1°F); respiratory rate, 16/min; and oxygen saturation, 99% on room air. On both lower extremities, there was peripheral edema with widespread hematomas, scattered ecchymosis, petechiae, and diffuse perifollicular purpura (Figure). The remainder of the examination was unremarkable. Laboratory test results showed a normocytic anemia (hemoglobin level, 5.2 g/dL [reference, 13.5-17.5 g/dL]; mean corpuscular volume, 85 fL [reference, 80-100 fL]); normal platelet count (thrombocytes, 285 ×109/L [reference, 150-400 ×109/L]); and a mild leukopenia (leukocytes, 3.9 ×109 [reference, 4.3-10 ×109/L]). Folic acid level was low (3 nmol/L [reference, ≥5 nmol/L]) and vitamin B12 level was normal (478 pg/mL [reference, 193-982 pg/mL]). Results for iron panel, reticulocyte count, prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio, liver function tests, and levels of indirect bilirubin, haptoglobin, fibrinogen, and creatine kinase were all within reference range. Chest radiographs and computed tomography of the head were negative for any acute pathology. A 12-lead electrocardiogram revealed no abnormalities. Ultrasound of both lower legs showed no thromboembolism.Order additional coagulation tests (thrombin time, platelet function assay)

what would you do next?

What would you do next?

Order a bone marrow biopsy

Initiate vitamin C supplementation

Administer prothrombin complex concentrate

Order additional coagulation tests (thrombin time, platelet function assay)

b

male

61-70

original

https://jamanetwork.com/journals/jama/fullarticle/2753224

A 59-year-old man who had been taking warfarin for 16 years for recurrent deep vein thrombosis and a left ventricular thrombosis presented to the anticoagulation management service for a follow-up visit. His warfarin had been managed via point-of-care (POC) testing for the past 4 years with a goal international normalized ratio (INR) of 2.0 to 3.0. On presentation, his POC INR was 3.7. He reported no extra warfarin doses, medication changes, dietary nonadherence, or bleeding. His warfarin dosage was 36 mg/wk (3 mg every Wednesday and Saturday and 6 mg all other days) for the past year. The Table shows the patient’s laboratory test results.Continue current warfarin dosing and perform a point-of-care (POC) international normalized ratio (INR) test in 1 week.Skip 2 doses of warfarin then resume current dosage and perform a POC INR test in 2 weeks.Skip 2 doses of warfarin, reduce weekly dosage by 10%, and perform a POC INR in 2 weeks.Perform a plasma INR test to confirm POC INR test results. What Would You Do Next?

Continue current warfarin dosing and perform a point-of-care (POC) international normalized ratio (INR) test in 1 week.

Skip 2 doses of warfarin then resume current dosage and perform a POC INR test in 2 weeks.

Skip 2 doses of warfarin, reduce weekly dosage by 10%, and perform a POC INR in 2 weeks.

Perform a plasma INR test to confirm POC INR test results.

D

Perform a plasma INR test to confirm POC INR test results.

Prothrombin time (PT) is a screening coagulation assay in which thromboplastin (tissue factor and phospholipid) and calcium are added to citrated platelet-poor plasma and clotting time is measured. PT, the primary method for monitoring vitamin K antagonists (VKAs), is sensitive to factor II, VII, and X deficiencies. INR standardizes PT by normalizing for thromboplastin reagent strength and mean PT of the local population.POC INR testing devices are approved by the US Food and Drug Administration for VKA monitoring and have been shown to reduce thromboembolic events and all-cause mortality compared with standard outpatient monitoring.1 Clinics use POC INR tests to provide immediate results, thereby improving testing efficiency. POC INR testing devices use fingerstick capillary whole blood applied to a test strip, which is inserted into a device in which thromboplastin initiates clotting.An extreme hematocrit (<25% or >55%) or an abnormal platelet count can alter POC INR assays and reduce test accuracy. Additional causes of inaccurate results, compared with plasma INR testing, include (1) systematic overestimation of plasma INR by POC INR testing, especially at INR values greater than 3.5 and (2) reduced precision reflected by an increased coefficient of variation (CV). The CV represents the precision of repeated measurements and quantifies the variability compared with the mean. The CV for plasma INR is less than 3% and ranges from 1.4% to 8.4% for POC INR.2POC INR results correlate with plasma INR results when the POC INR is less than or equal to 3.5, with differences generally less than 0.5.3,4 Clinically important differences between POC and plasma INR results may occur with POC INR values greater than 3.5.4,5 Medicare reimbursement for INR assays is $4.37, according to the 2019 Medicare fee schedule.6Because a POC INR value greater than 3.5 is imprecise, a confirmatory plasma INR test should be performed. This patient’s POC INR and plasma INR results 1 and 2 months before presentation differed meaningfully (Table). Guidelines recommend against warfarin dose adjustments for isolated plasma INR values less than or equal to 0.5 units away from the target range.7 Therefore, before the current presentation, the patient was treated with 36 mg/wk of warfarin and returned monthly.INR testing (POC or plasma) is the preferred method for warfarin monitoring. Certain patients, such as those with congenital factor deficiency, lupus anticoagulant, or chronic liver disease, may have elevated baseline INRs prior to VKA initiation, precluding accurate warfarin monitoring using the INR. In these patients, a seemingly therapeutic INR does not accurately reflect the VKA effect.8Chromogenic factor II or X levels can assess warfarin anticoagulation effect in patients with prolonged baseline PT or warfarin failure. Warfarin failure consists of acute thrombosis with a therapeutic INR. Chromogenic factor II and X assays are nonclotting-based VKA monitoring tests that quantify vitamin K–dependent factor levels, allowing a surrogate measurement of warfarin effect.8,9 Chromogenic factor X assays measure factor X enzymatic activity as a percentage of normal and are less susceptible to interference from clotting inhibitors and factor deficiencies, other than factor X, than INR. As VKA effect increases, hepatic synthesis of vitamin K–dependent factor X decreases. Therapeutic warfarin is associated with factor X activity of 20% to 40%.8 In one study, chromogenic factor X levels of less than or equal to 45% had 63.2% sensitivity, 80% specificity, 93.5% positive predictive value, and 32.3% negative predictive value for INRs greater than 2.0.9On presentation, the patient’s plasma INR value was 3.7. When the POC INR value is greater than 3.5 with a plasma INR at or near therapeutic levels for 3 visits, some protocols require transition to plasma-only INR testing. Significant INR discrepancies compromise patient safety. The plasma INR value remained at therapeutic levels (2.0 to 3.0) for 2 months, after which, because of 3 elevated readings, his warfarin dosage was decreased to 33 mg/wk. He continued this warfarin dosage for 1 year before increasing back to 36 mg/wk, which he has maintained for 20 months.POC INR testing devices are most accurate for INR values of 3.5 or less.Plasma INR testing should be performed when POC INR values are greater than 3.5 or when results are inconsistent with expected values.Lupus anticoagulant and chronic liver disease are associated with misleading elevations of PT or POC INR results. Patients with these conditions should be monitored with alternative methods, such as chromogenic factor X.

Diagnostic

A 59-year-old man who had been taking warfarin for 16 years for recurrent deep vein thrombosis and a left ventricular thrombosis presented to the anticoagulation management service for a follow-up visit. His warfarin had been managed via point-of-care (POC) testing for the past 4 years with a goal international normalized ratio (INR) of 2.0 to 3.0. On presentation, his POC INR was 3.7. He reported no extra warfarin doses, medication changes, dietary nonadherence, or bleeding. His warfarin dosage was 36 mg/wk (3 mg every Wednesday and Saturday and 6 mg all other days) for the past year. The Table shows the patient’s laboratory test results.Continue current warfarin dosing and perform a point-of-care (POC) international normalized ratio (INR) test in 1 week.Skip 2 doses of warfarin then resume current dosage and perform a POC INR test in 2 weeks.Skip 2 doses of warfarin, reduce weekly dosage by 10%, and perform a POC INR in 2 weeks.Perform a plasma INR test to confirm POC INR test results.

what would you do next?

What would you do next?

Continue current warfarin dosing and perform a point-of-care (POC) international normalized ratio (INR) test in 1 week.

Perform a plasma INR test to confirm POC INR test results.

Skip 2 doses of warfarin then resume current dosage and perform a POC INR test in 2 weeks.

Skip 2 doses of warfarin, reduce weekly dosage by 10%, and perform a POC INR in 2 weeks.

b

male

51-60

original

https://jamanetwork.com/journals/jama/fullarticle/2753853

A 30-year-old man presented to the emergency department with palpitations and tachycardia. He had been experiencing sore throat, fevers, and myalgias for the past day. He became alarmed when he awoke from sleep with strong palpitations and a heart rate greater than 200/min documented on his smartwatch. He had similar symptoms 1 year ago and was diagnosed with and treated for supraventricular tachycardia (SVT). A subsequent outpatient echocardiogram revealed a structurally normal heart; results of a follow-up electrocardiogram (ECG) were also normal (Figure 1, top).Patient’s baseline 12-lead electrocardiogram (top) and on presentation (bottom).On presentation to the emergency department, the patient’s temperature was 38.2°C; blood pressure, 125/67 mm Hg; and pulse, 241/min. Physical examination was notable for an erythematous oropharynx, tonsillar exudates, a tachycardic, regular heart rhythm, and clear lungs. An ECG was obtained (Figure 1, bottom). A modified Valsalva maneuver1 failed to convert the rhythm. He was subsequently given a series of doses of intravenous adenosine (6 mg, 12 mg, 12 mg), followed by direct current cardioversion at 200 J, which converted the rhythm to sinus for approximately 3 minutes. Intravenous metoprolol and intravenous diltiazem bolus and drip were then administered, which slowed the heart rate but did not terminate the arrhythmia. A rapid strep test result was positive, and he was given ampicillin.Repeat synchronized direct current cardioversion at 200 J What Would You Do Next?

Stop diltiazem drip and administer intravenous amiodarone

Repeat synchronized direct current cardioversion at 200 J

Switch to intravenous esmolol drip

Stop diltiazem drip and administer intravenous verapamil

Idiopathic fascicular left ventricular tachycardia (IFLVT) arising from the left anterior fascicle

D

Stop diltiazem drip and administer intravenous verapamil

The differential diagnosis for this patient’s narrow-complex tachycardia includes SVT, SVT with aberrancy, and IFLVT. The key to the correct diagnosis is to differentiate IFLVT from SVT with or without aberrancy by recognizing 3 factors—change in axis from sinus rhythm; QRS morphology typical of IFLVT arising from the left anterior fascicle; and atrioventricular (AV) dissociation.Figure 1 (top) shows the patient’s baseline ECG, which has a normal QRS axis and duration of 82 ms. This changes in the next ECG, which shows a wider QRS with an incomplete right bundle-branch block–like morphology and a right inferior axis. This QRS morphology and axis is typical of an IFLVT arising from the left anterior fascicle. Unlike most ventricular tachycardias, the QRS duration in IFLVTs is often only slightly prolonged (around 120 ms), and those arising from the left anterior and upper septal fascicles can even be narrow-complex with QRS durations less than 110 ms, which adds to the diagnostic difficulty.In SVT without aberrancy, QRS morphology is not changed from that during sinus rhythm. In contrast, both SVT with aberrancy and IFLVT will have abrupt changes in QRS morphology. One can also differentiate IFLVT from SVT with aberrancy by looking for AV dissociation, which suggests a ventricular origin of arrhythmia. In AV dissociation, atrial and ventricular activation are independent from each other, and the ventricular rate is faster than the atrial rate. This is more notable when the ventricular rate has slowed and the nonconducted P waves can be clearly seen (Figure 2).Patient’s 12-lead electrocardiogram after receipt of adenosine, metoprolol, and diltiazem. The ventricular rate has slowed from initial presentation (Figure 1, bottom). Arrowheads indicate nonconducted P waves.IFLVTs are typically verapamil sensitive; therefore, administration of intravenous verapamil would be the next best step in this patient with a structurally normal heart. Both amiodarone and intravenous esmolol may slow the heart rate but are generally ineffective at terminating the arrhythmia. Repeat cardioversion would work only temporarily, as the infection driving the IFLVT is still ongoing.Idiopathic ventricular tachycardia (IVT) is a classification given to ventricular tachycardias that occur in the absence of structural heart disease and account for 10% of all ventricular tachycardias.2,3 IFLVT accounts for 10% to 15% of IVT cases.4 IFLVTs can originate from the left posterior (≈90%), left anterior (5%-10%), or upper septal (rare) fascicles and behave as reentrant tachycardias.5 IFLVTs typically occur in adults aged 15 to 40 years (usually male [60%-80%]) and are often triggered by external stressors.6,7 In this patient, an upper respiratory tract infection was likely the stressor. IFLVT is often misdiagnosed as SVT with or without aberrancy because of the young age of presentation and frequent lack of hemodynamic compromise.8IFLVTs, unlike the majority of IVTs, are classically sensitive to verapamil because of its effect on the slow inward calcium channel, which is thought to be critical to the propagation of the arrhythmia.5,9 Intravenous adenosine, electrical cardioversion, and β-blockers are largely ineffective at terminating IFLVT because of lack of effect on the slow inward calcium channel. Diltiazem can sometimes be effective in suppressing IFLVT, as it also effects this calcium channel, although it has different binding sites than verapamil.10 There have been no studies examining the 2 drugs head-to-head. Anecdotally, verapamil seems to be more effective in terminating IFLVT acutely and is considered first-line treatment.4 Importantly, intravenous nondihydropyridines should only be used in patients with structurally normal hearts, as they can lead to hemodynamic instability due to negative inotropy. Over the long term, oral verapamil (usually 240-480 mg once daily) may fail to adequately suppress the arrhythmia; catheter ablation is then recommended. Because syncope and sudden death are rare in these patients, routine placement of an implantable cardiac defibrillator is not necessary.5The patient received intravenous verapamil with resolution of his arrhythmia. He has received maintenance oral verapamil, with no recurrences over 6 months.

General

A 30-year-old man presented to the emergency department with palpitations and tachycardia. He had been experiencing sore throat, fevers, and myalgias for the past day. He became alarmed when he awoke from sleep with strong palpitations and a heart rate greater than 200/min documented on his smartwatch. He had similar symptoms 1 year ago and was diagnosed with and treated for supraventricular tachycardia (SVT). A subsequent outpatient echocardiogram revealed a structurally normal heart; results of a follow-up electrocardiogram (ECG) were also normal (Figure 1, top).Patient’s baseline 12-lead electrocardiogram (top) and on presentation (bottom).On presentation to the emergency department, the patient’s temperature was 38.2°C; blood pressure, 125/67 mm Hg; and pulse, 241/min. Physical examination was notable for an erythematous oropharynx, tonsillar exudates, a tachycardic, regular heart rhythm, and clear lungs. An ECG was obtained (Figure 1, bottom). A modified Valsalva maneuver1 failed to convert the rhythm. He was subsequently given a series of doses of intravenous adenosine (6 mg, 12 mg, 12 mg), followed by direct current cardioversion at 200 J, which converted the rhythm to sinus for approximately 3 minutes. Intravenous metoprolol and intravenous diltiazem bolus and drip were then administered, which slowed the heart rate but did not terminate the arrhythmia. A rapid strep test result was positive, and he was given ampicillin.Repeat synchronized direct current cardioversion at 200 J

what would you do next?

What would you do next?

Switch to intravenous esmolol drip

Stop diltiazem drip and administer intravenous amiodarone

Repeat synchronized direct current cardioversion at 200 J

Stop diltiazem drip and administer intravenous verapamil

d

male

21-30

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2753263

A woman in her 50s presented with a 4- to 5-year medical history of mildly pruritic coalescent yellowish papules around the umbilicus (Figure 1A). She was obese and multiparous. Examination of the rest of the integument, systemic examination, and investigations including fundoscopy, electrocardiogram, and stool examination for occult blood revealed no significant abnormalities. Dermoscopic examination was performed (polarized mode, Dinolite) as shown in Figure 1B. We obtained a 4-mm punch biopsy from one of the papules for diagnostic clarification (Figure 1C).A, Coalescent yellowish periumbilical papules. B, Polarized dermoscopic image (Dinolite) showing curvilinear brown pigment lines (black arrowhead) with accentuation of normal pigmentary network (green box) without follicular plugging (red circle) or linear vessels (original magnification ×200). C, Lesional specimen (original magnification ×100) showing clumped eosinophilic elastic fibers (asterisk) in the middermis (inset, original magnification ×40). What Is Your Diagnosis?

Periumbilical pseudoxanthoma elasticum

Periumbilical pseudoxanthoma elasticum–like papillary dermal elastolysis

Elastosis perforans serpiginosa

Late-onset focal dermal elastosis

A. Periumbilical pseudoxanthoma elasticum

A

Periumbilical pseudoxanthoma elasticum

Dermoscopic findings (polarized mode, Dinolite) (Figure 1B) revealed curvilinear brownish pigment lines with accentuation of normal pigmentary network without follicular plugging or linear vessels. Histopathologic analysis was most helpful in reaching the diagnosis—it revealed predominantly middermal, clumped eosinophilic elastic fibers (Figure 1C). Verhoeff Van Gieson staining (Figure 2) showed the altered “ravelled wool” configuration of these elastic fibers. Von Kossa staining (Figure 2, inset) confirmed calcification. Even histopathologically, we were unable to find any evidence of transepidermal elimination. All these findings were suggestive of periumbilical pseudoxanthoma elasticum.Verhoeff Van Gieson stain of a lesional specimen showed the altered ravelled wool configuration of these elastic fibers (green circle compared with normal elastic fibers on the top) (original magnification ×400). Von Kossa staining (inset) showing black deposits confirming calcification (original magnification ×400).Periumbilical pseudoxanthoma elasticum is a rare, localized acquired variant of pseudoxanthoma elasticum1 purportedly owing to abdominal stretching as found in obese and multiparous women.2 When there is transepidermal elimination of calcified fragmented elastic fibers, it is also called perforating calcific elastosis, especially when limited to skin.3,4 On perforation, it presents with pruritic papules with a central dell superimposed on a yellowish plaque around the umbilicus. Systemic comorbidities (especially vascular diseases such as angina or hypertension) are reported in varied proportions of patients.5 Angioid streaks are noted in 22% of cases.5Histopathologic features are acanthosis, pseudoepitheliomatous hyperplasia, and irregularly fragmented elastic fibers at varying levels in the upper reticular and midreticular dermis,6 which are extruded. These elastic fibers assume a ravelled wool appearance—they are clumped, crinkly, and eosinophilic2 with calcium deposits.Two cases are reported wherein no perforation was noted despite a duration of 2 to 3 years (as in this case).2,7 Such cases may evolve into perforating calcific elastosis eventually.7Dermoscopic features recently described6 include curvilinear brown-yellow lines (as observed in this case) with follicular plugging and a few linear vessels (both not noted in this case).Pseudoxanthoma elasticum, like papillary dermal elastolysis, is a rare disorder that may present similarly on the abdomen.7,8 However, histopathologically, there is complete loss of papillary dermal elastic fibers, unlike findings in pseudoxanthoma elasticum, and it may be an accentuated form of skin aging.7In elastosis perforans serpiginosa, there are serpiginous or circinate skin-colored, pigmented or erythematous papules and/or nodules with keratotic plugs/crusts grouped mainly on the neck, upper trunk, or axillae.9 The individual papules may enlarge, appearing crateriform. Transepidermal elimination of fragmented elastic fibers is noted. The elastic fibers assume a lumpy/bumpy configuration, which is owing to the altered cross links.9 However, unlike findings in periumbilical pseudoxanthoma elasticum, there is no calcification of the altered elastic fibers.In late-onset focal dermal elastosis the patient, during the seventh to ninth decades, develops small yellow-white papules on the neck and flexures resembling pseudoxanthoma elasticum. Histopathologically, unlike in pseudoxanthoma elasticum, there are foci of increased amounts of normal-looking elastic tissue in the reticular dermis,10 and there is no systemic involvement related to this disease.The diagnosis of periumbilical pseudoxanthoma elasticum rests on clinical and histopathologic features to differentiate it from other entities described herein. Dermoscopic features have been recently described that may be helpful pointers toward the correct diagnosis. However, all dermoscopic features may not be noted, underlining the importance of histopathologic analysis. We planned to prescribe the patient topical Tretinoin cream, 0.025%, along with dietary calcium restriction. However, the patient refused any treatment.

Dermatology

A woman in her 50s presented with a 4- to 5-year medical history of mildly pruritic coalescent yellowish papules around the umbilicus (Figure 1A). She was obese and multiparous. Examination of the rest of the integument, systemic examination, and investigations including fundoscopy, electrocardiogram, and stool examination for occult blood revealed no significant abnormalities. Dermoscopic examination was performed (polarized mode, Dinolite) as shown in Figure 1B. We obtained a 4-mm punch biopsy from one of the papules for diagnostic clarification (Figure 1C).A, Coalescent yellowish periumbilical papules. B, Polarized dermoscopic image (Dinolite) showing curvilinear brown pigment lines (black arrowhead) with accentuation of normal pigmentary network (green box) without follicular plugging (red circle) or linear vessels (original magnification ×200). C, Lesional specimen (original magnification ×100) showing clumped eosinophilic elastic fibers (asterisk) in the middermis (inset, original magnification ×40).

what is your diagnosis?

What is your diagnosis?

Periumbilical pseudoxanthoma elasticum

Elastosis perforans serpiginosa

Periumbilical pseudoxanthoma elasticum–like papillary dermal elastolysis

Late-onset focal dermal elastosis

a

female

0-10

Black

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2753670

A woman in her early 80s presented with a 6-month history of an asymptomatic, enlarging, partly infiltrated erythematous cutaneous patch localized to the periareolar area of her left breast (Figure, A). She had no history of cancer or chronic diseases. No cutaneous nodules were present. Physical examination did not show adenopathies, hepatosplenomegaly, or other remarkable findings. Peripheral blood test results were within normal limits. Tests for tumor markers including cancer antigen (CA) 15-3, carcinoembryonic antigen, CA 19-9, and CA 125 were unremarkable. No palpable breast masses were identifiable. Breast ultrasonography and mammography did not reveal parenchymal nodules. A local steroid therapy was administered, with no benefit. A biopsy of the skin lesion was performed (Figure, B and C).A, Clinical image of the cutaneous breast lesion shows a large, erythematous, and slightly infiltrated patch in the periareolar region. B and C, Hematoxylin-eosin–stained lesional specimens show a dense dermal infiltrate of cells with focal epidermis involvement (B) and large atypical cells with scanty cytoplasm (C). What Is Your Diagnosis?

Langerhans cell histiocytosis

Primary cutaneous large B-cell lymphoma, leg type

Merkel cell carcinoma

Cutaneous angiosarcoma

B. Primary cutaneous large B-cell lymphoma, leg type

B

Primary cutaneous large B-cell lymphoma, leg type

Histologic analysis showed a densely cellular infiltrate filling the dermis (Figure, B), with occasional epidermal involvement. The cells were large, with a high nucleus to cytoplasm ratio (Figure, C); they were B lymphoid in nature with an activated phenotype, being diffusely positive for CD20, MUM1/IRF4, FOXP1, IgM, OCT2, and Bcl-2 and focally positive for BCL6. Assay results for CD10, CD30, CD138, and CD3 were all negative. The proliferative index was elevated. In situ hybridization findings for Epstein-Barr virus were negative. The patient underwent staging evaluation with positron emission tomography and bone marrow biopsy, and no other sites of disease were identified. Primary cutaneous large B-cell lymphoma, leg type (CLBCL-LT) was diagnosed. The patient refused therapy.Five months later, the patient presented with anorexia, weight loss, and diffuse bone pain. Positron emission tomography confirmed systemic disease involving bones, stomach, and multiple lymph nodes. Despite multiagent chemotherapy, with R-COMP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-BAC regimens (rituximab, bendamustine, and cytarabine), the patient died about 24 months after diagnosis.Primary CLBCL-LT generally affects elderly patients, mostly women, typically involving one or both legs.1 Cutaneous sites other than the legs are affected in a minority of cases (15%-20%).2 Primary CLBCL-LT diagnosis can be made if staging evaluation confirms skin as the unique site involved at disease onset.1 Dissemination to extracutaneous organs often occurs during the disease course.1,2 The classic clinical presentation is with single or multiple ulcerated nodules.1 In the fourth edition of Skin Lymphoma: The Illustrated Guide,3 an unusual presentation is described, characterized in the early phase by patches or thin plaques, often clinically misinterpreted as inflammatory diseases. The classic dense infiltrate filling the dermis and subcutis was lacking; only a sparse, subtle perivascular infiltrate was identified.3 The present case shows more typical histologic characteristics with a dense infiltrate replacing dermis. However, we believe that this case presented a diagnostic challenge because the classic cutaneous nodules were absent, and the primary CLBCL-LT presented with a large erythematous patch affecting a body site other than the legs.The differential diagnoses in this case included Langerhans cell histiocytosis, Merkel cell carcinoma, and cutaneous angiosarcoma. Langerhans cell histiocytosis is more common in childhood, ranging from localized, self-healing lesions to disseminated life-threatening forms.1,4 Skin involvement can present as eruptions or nodules, plaques, and ulcers.5 The key histological feature of dermal infiltrate is the Langerhans cell, a bland-looking cell with a “coffee bean” grooved nucleus and moderately abundant cytoplasm.4,5 Mitoses can be frequent.4,5 The background contains eosinophils, neutrophils, and small lymphocytes.4,5 Detection of Langerhans cell immunohistochemical markers (CD1a, S100, clusterin, and langerin CD207) is mandatory to confirm Langerhans cell histiocytosis.4,5Merkel cell carcinoma, or primary cutaneous neuroendocrine carcinoma, is an aggressive neoplasm affecting primarily elderly people and presenting as solitary violaceous nodule, commonly on head, neck, or extremities.6 Histologic analysis shows sheets of monotonous small to medium-sized cells with scanty cytoplasm, effacing the dermis, and extending to the subcutis.6 Mitotic figures are numerous.6 Merkel cell carcinoma expresses neuroendocrine markers (chromogranin, synaptophysin), with a characteristic paranuclear dotlike staining for cytokeratin 20.6Cutaneous angiosarcoma, an aggressive neoplasm originating from the endothelium lining of vascular channels, presents as a hematomalike lesion on the head and neck of elderly individuals.7 It is often radiation-induced.7 Histopathologic findings are variable, ranging from well-differentiated cutaneous angiosarcoma consisting of anastomosing vascular channels with inconspicuous endothelium and dissecting dermis to poorly differentiated disease with sheets of pleomorphic cells replacing the dermis.7 Useful immunohistochemical markers include CD31, CD34, and ERG.7 Cases of cutaneous angiosarcoma rich in lymphocytic infiltrate, strongly simulating cutaneous lymphoma, have been described.8The present case of primary CLBCL-LT, presenting as erythematous patch in the breast, highlights the need to biopsy erythematous lesions, especially those not responding to local treatment.

Dermatology

A woman in her early 80s presented with a 6-month history of an asymptomatic, enlarging, partly infiltrated erythematous cutaneous patch localized to the periareolar area of her left breast (Figure, A). She had no history of cancer or chronic diseases. No cutaneous nodules were present. Physical examination did not show adenopathies, hepatosplenomegaly, or other remarkable findings. Peripheral blood test results were within normal limits. Tests for tumor markers including cancer antigen (CA) 15-3, carcinoembryonic antigen, CA 19-9, and CA 125 were unremarkable. No palpable breast masses were identifiable. Breast ultrasonography and mammography did not reveal parenchymal nodules. A local steroid therapy was administered, with no benefit. A biopsy of the skin lesion was performed (Figure, B and C).A, Clinical image of the cutaneous breast lesion shows a large, erythematous, and slightly infiltrated patch in the periareolar region. B and C, Hematoxylin-eosin–stained lesional specimens show a dense dermal infiltrate of cells with focal epidermis involvement (B) and large atypical cells with scanty cytoplasm (C).

what is your diagnosis?

What is your diagnosis?

Merkel cell carcinoma

Langerhans cell histiocytosis

Cutaneous angiosarcoma

Primary cutaneous large B-cell lymphoma, leg type

d

female

81-90

original

https://jamanetwork.com/journals/jamaneurology/fullarticle/2751254

A 30-year-old man had involuntary orofaciolingual movements for 7 years and unsteady gait for 2 months. At age 23 years, he began experiencing involuntary orofaciolingual movements and vocalizations. At age 27 years, he developed dysphagia, dysarthria, and involuntary tongue- and lip-biting. This oral dyskinesias worsened while eating. However, a handkerchief in the mouth markedly reduced involuntary tongue-biting and mouth movements. No neuropsychiatric symptoms or seizures were exhibited.Neurological examination results revealed mild cognitive decline, with a Montreal Cognitive Assessment score of 18/30. Orofacial dyskinesia (Video 1), involuntary vocalizations, and mild dysarthria were exhibited. His muscle strength and tone were normal, but his deep reflexes were diminished or absent. The patient’s sensory and coordination examination results were unremarkable, and bilateral Babinski signs were negative. The patient’s gait was mildly wide based (Video 2). Fundus examination results were normal. Laboratory examination results, including blood electrolytes and lactate, liver, kidney, and thyroid function, antinuclear antibodies, ceruloplasmin levels, and vitamin A and E levels were normal. Routine and biochemical examination results, oligonucleotide band, antibodies against antiaquaporin 4, and autoimmune encephalitis-related antibodies (ie, N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic, γ-aminobutyric acid-B, leucine-rick glioma inactivated 1, contactin-associated protein 2, and IgLON5) of cerebrospinal fluid were normal. Creatine kinase (CK) levels were significantly elevated at 2304 U/L (to convert to microkatals per liter, multiply by 0.0167; normal range, 25-200 U/L). Low-density lipoprotein and apolipoprotein B levels were slightly decreased at 61 mg/dL (to convert to micromoles per liter, multiply by 0.0357; normal range, 80-119 mg/dL) and 58 mg/dL (to convert to grams per liter, multiply by 0.01; normal range, 66-133 mg/dL), respectively. Acanthocytes were found in the blood smear via Wright staining (Figure, A). Electrophysiological examination results revealed reduced compound muscle action potential and sensory nerve action potential of bilateral median and ulnar nerves. Electromyogram results showed neurogenic damage in lower limb muscles. Cerebral magnetic resonance imaging results revealed a marked bilateral caudate head atrophy (Figure, B).A, Acanthocytes in the peripheral blood smear shown via Wright staining (original magnification, ×1000). B, Axial T2-weighted magnetic resonance image of the patient’s brain. What Is Your Diagnosis?

Pantothenate kinase–associated neurodegeneration

Hypobetalipoproteinemia

Chorea-acanthocytosis

Huntington disease–like 2

C. Chorea-acanthocytosis

C

Chorea-acanthocytosis

The patient’s most prominent clinical manifestation was orofacial dyskinesia; therefore, hereditary and secondary dystonia was considered. Wilson disease was excluded because his ceruloplasmin levels were normal. There was no evidence of other metabolic or autoimmune diseases.Acanthocytes in peripheral blood were a significant feature. This led to the consideration of neuroacanthocytosis and inherited disorders of lipoprotein metabolism (eg, abetalipoproteinemia and hypobetalipoproteinemia); the latter leads to vitamin E malabsorption.1 The prominence of caudate head atrophy indicated several extrapyramidal diseases, including Huntington disease, Huntington disease–like 2 (HDL-2), chorea-acanthocytosis (ChAc), and McLeod syndrome.1-3 Although his low-density lipoprotein and apolipoprotein B levels decreased, his vitamin E levels were normal; thus, hypobetalipoproteinemia was unlikely. Acanthocytes are not present in Huntington disease, therefore it was excluded.Neuroacanthocytosis describes a group of heterogeneous neurological disorders in which the basal ganglia are affected, leading to various movement disorders. Neuroacanthocytosis includes pantothenate kinase–associated neurodegeneration (PKAN), HDL-2, ChAc, and McLeod syndrome.1,4 Orofacial, lingual, and limb dystonia, dysarthria, choreoathetosis, and spasticity are the initial manifestations of PKAN. Patients usually develop pigmentary retinopathy. Cognitive impairment is also a prominent feature in many PKAN cases. In some patients, iron accumulation in the basal ganglia results in the typical “eye-of-the-tiger” magnetic resonance imaging sign.5 The patient’s fundus examination results were normal, so PKAN was unlikely. Huntington disease–like 2 is autosomal dominant inherited because of an expanded trinucleotide repeat of the junctophilin-3 gene and it presents with chorea, parkinsonism, and dystonia. Deep reflexes are usually brisk, and there is no peripheral nerve or muscle involvement.6 Diminished/absent deep reflexes combined with markedly elevated CK levels and reduced sensory nerve action potentials ruled out HDL-2.Chorea-acanthocytosis is a progressive autosomal recessive neurodegenerative disorder. It is characterized by chorea and orofaciolingual dystonia resulting in orofacial dyskinesias, dysarthria, involuntary vocalizations, and involuntary tongue- and lip-biting. Neuromuscular involvement is another important ChAc feature, including variable muscle weakness and atrophy, areflexia, and mild axonal neuropathy. Creatine kinase elevation (up to 3000 U/L) occurs in most patients with ChAc; however, electromyogram results usually demonstrate neuropathic changes.1,4The patient showed obvious orofacial dyskinesias, combined with substantial CK elevation, axonal peripheral neuropathy, muscle neurogenic damage, and typical caudate head atrophy. This suggested ChAc, although trunk and limb chorea had not yet been revealed. We performed whole-exome sequencing to verify the diagnosis and exclude other rare causes. Sequencing results revealed a compound heterozygous mutation in the VPS13A gene: a point mutation c.2964 + 5(IVS28)G>A in one allele and c.5881(exon45)C>T in the other. The patient’s parents were carriers of a mutation but were themselves unaffected. Thus, the patient received a diagnosis of ChAc. Haloperidol, 2 mg twice daily, was administered to ameliorate hyperkinetic movement.Chorea-acanthocytosis is caused by mutations of the VPS13A gene, which codes for chorein. Chorein is implicated in intracellular protein sorting and transport; however, to our knowledge, the exact mechanisms are unknown. Chorein is widely expressed in various organs and tissues, including the brain and erythrocytes. In ChAc, chorein is markedly reduced or absent.1,4 Treatment is symptomatic as no curative treatments exist. The disorder progresses gradually, with patients eventually experiencing fatal aspiration pneumonia or other systemic infections.

Neurology

A 30-year-old man had involuntary orofaciolingual movements for 7 years and unsteady gait for 2 months. At age 23 years, he began experiencing involuntary orofaciolingual movements and vocalizations. At age 27 years, he developed dysphagia, dysarthria, and involuntary tongue- and lip-biting. This oral dyskinesias worsened while eating. However, a handkerchief in the mouth markedly reduced involuntary tongue-biting and mouth movements. No neuropsychiatric symptoms or seizures were exhibited.Neurological examination results revealed mild cognitive decline, with a Montreal Cognitive Assessment score of 18/30. Orofacial dyskinesia (Video 1), involuntary vocalizations, and mild dysarthria were exhibited. His muscle strength and tone were normal, but his deep reflexes were diminished or absent. The patient’s sensory and coordination examination results were unremarkable, and bilateral Babinski signs were negative. The patient’s gait was mildly wide based (Video 2). Fundus examination results were normal. Laboratory examination results, including blood electrolytes and lactate, liver, kidney, and thyroid function, antinuclear antibodies, ceruloplasmin levels, and vitamin A and E levels were normal. Routine and biochemical examination results, oligonucleotide band, antibodies against antiaquaporin 4, and autoimmune encephalitis-related antibodies (ie, N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic, γ-aminobutyric acid-B, leucine-rick glioma inactivated 1, contactin-associated protein 2, and IgLON5) of cerebrospinal fluid were normal. Creatine kinase (CK) levels were significantly elevated at 2304 U/L (to convert to microkatals per liter, multiply by 0.0167; normal range, 25-200 U/L). Low-density lipoprotein and apolipoprotein B levels were slightly decreased at 61 mg/dL (to convert to micromoles per liter, multiply by 0.0357; normal range, 80-119 mg/dL) and 58 mg/dL (to convert to grams per liter, multiply by 0.01; normal range, 66-133 mg/dL), respectively. Acanthocytes were found in the blood smear via Wright staining (Figure, A). Electrophysiological examination results revealed reduced compound muscle action potential and sensory nerve action potential of bilateral median and ulnar nerves. Electromyogram results showed neurogenic damage in lower limb muscles. Cerebral magnetic resonance imaging results revealed a marked bilateral caudate head atrophy (Figure, B).A, Acanthocytes in the peripheral blood smear shown via Wright staining (original magnification, ×1000). B, Axial T2-weighted magnetic resonance image of the patient’s brain.

what is your diagnosis?

What is your diagnosis?

Pantothenate kinase–associated neurodegeneration

Chorea-acanthocytosis

Hypobetalipoproteinemia

Huntington disease–like 2

b

male

21-30

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2753758

A 65-year-old man presented with an acute onset of aphasia for which he received intravenous thrombolysis with substantial improvement. This was the second stroke he had in 6 months. The patient’s other medical problems included well-controlled hypertension and diabetes. Seven months before this admission, a dual-chamber pacemaker was implanted at an outside institution for sick sinus syndrome. Device interrogation revealed no atrial fibrillation and normal lead parameters. Electrocardiogram results showed atrial pacing with capture and intrinsic ventricular conduction. Magnetic resonance angiography results of carotid, vertebral, and cerebral arteries were normal. Chest radiography was taken (Figure 1).Chest radiography. A, In the posterior-anterior projection, the ventricular lead curves more superiorly than usual and lacks the expected indentation as it traverses the tricuspid valve. B, Lateral projection demonstrates a posterior orientation of the lead that is suspicious for left ventricular placement. What Would You Do Next?

Transthoracic echocardiogram

Screen for thrombophilia

Prolonged Holter monitoring

Take serial blood cultures

Mispositioned lead in the left ventricle through an atrial septal defect

A

Transthoracic echocardiogram

On the posterior-anterior projection (Figure 1A), the ventricular lead curves more superiorly than usual and lacks the expected indentation as it traverses the tricuspid valve. The lateral projection (Figure 1B) demonstrates a posterior orientation of the lead that is suspicious of left ventricular placement. A correctly placed right ventricular lead courses more laterally in the right atrium, is closer to the inferior border of the cardiac silhouette, and points anteriorly on the lateral radiograph. Dynamic tenting of the lead by the tricuspid annulus in systole can be visualized on fluoroscopy. A right-bundle branch block pattern of depolarization is another indicator of lead malposition but was not present in this patient because of intrinsic conduction.Inadvertent placement of the pacemaker lead in the left ventricle is a rare complication. Risk factors include chest wall deformity, congenital heart disease, and inexperienced operators.1 Mitral valve injury may result,2 predisposing patients to develop infective endocarditis.3 When exposed to the systemic circulation, thrombus may form on the lead and embolize. Case series describe a substantial risk of thromboembolism, although the number of cases is limited.1 Clinical trials of trans-septal endocardial left ventricular lead placement for the purpose of cardiac resynchronization offer insight into the thromboembolic risk.4 Despite adequate anticoagulation, thromboembolism occurs more frequently than patients without left ventricular leads.5Management depends on the time of diagnosis, risk of lifelong anticoagulation, and concurrent indication for cardiac surgery. If recognized perioperatively, lead extraction and revision can be performed. For long-term implanted leads, it is technically challenging and carries embolic risk,1 although young patients may benefit from an extraction that would obviate the need for long-term warfarin use. If cardiac surgery is planned for another indication, the lead may be extracted in the same occasion.Transthoracic echocardiogram results found a pacing lead traversing the interatrial septum inserting into the posterolateral wall of the left ventricle (Video 1). A review of cardiac computed tomography images, which were taken before pacemaker implant, confirmed the presence of an intermediate-sized atrial septal defect (Figure 2) with a left-to-right shunt (Video 2). The patient underwent anticoagulation with warfarin to an international normalized ratio range of 2.5 to 3.5 with no further embolic events.

Cardiology

A 65-year-old man presented with an acute onset of aphasia for which he received intravenous thrombolysis with substantial improvement. This was the second stroke he had in 6 months. The patient’s other medical problems included well-controlled hypertension and diabetes. Seven months before this admission, a dual-chamber pacemaker was implanted at an outside institution for sick sinus syndrome. Device interrogation revealed no atrial fibrillation and normal lead parameters. Electrocardiogram results showed atrial pacing with capture and intrinsic ventricular conduction. Magnetic resonance angiography results of carotid, vertebral, and cerebral arteries were normal. Chest radiography was taken (Figure 1).Chest radiography. A, In the posterior-anterior projection, the ventricular lead curves more superiorly than usual and lacks the expected indentation as it traverses the tricuspid valve. B, Lateral projection demonstrates a posterior orientation of the lead that is suspicious for left ventricular placement.

what would you do next?

What would you do next?

Screen for thrombophilia

Take serial blood cultures

Transthoracic echocardiogram

Prolonged Holter monitoring

c

male

61-70

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2752882

A Chinese woman had painless, gradually declined vision for 2 years without redness. She had a medical history of vomiting and emaciation in her early 40s. Pars plana vitrectomy (PPV) had been done for her left eye owing to vitreous opacity half a year prior. She claimed that her younger brother died of liver cancer and her mother had lost vision because of vitreous hemorrhage and glaucoma. She denied any history of systemic disorders.On initial examination, best-corrected visual acuity was measured at 0.1 (20/200) OU. Intraocular pressure was 14 mm Hg OD and 16 mm Hg OS. Her anterior segment examination results were within normal limits. Dilated fundus examination demonstrated bilateral vitreous opacity without cells (Figure). The peripheral residual vitreous cortex in the left eye was as cloudy as the cortex in the right eye. Fundus was not visible in the right eye and was normal in the left eye. A bilateral ocular ultrasonography showed normal results except for vitreous opacity. The patient weighed 37.0 kg and was 155 cm tall. Her blood pressure was 113/70 mm Hg. Mild anemia (hemoglobin level 10.5 g/dL vs a normal range of 11.0-15.0 g/dL [to convert to grams per liter, multiply by 10]) was found in routine blood test results. Liver and renal functions were normal according to serum test results. The results of an electronic cardiogram were negative.Mosaic 9-field 50° fundus photography showed a uniform, glassy, woollike appearance of the vitreous in the right eye (A) and peripheral vitreous opacity in the left after pars plana virectomy (B).Aqueous humor biopsy for cytometry and biochemical test What Would You Do Next?

Aqueous humor biopsy for cytometry and biochemical test

PPV plus pathological examination plus genetic test

Abdominal ultrasonography

Follow-up

Vitreous amyloidosis owing to familial amyloid polyneuropathy

B

PPV plus pathological examination plus genetic test

The differential diagnosis of vitreous opacity includes inflammatory, infectious, hemorrhagic, and degenerative diseases. Vitreous cells usually indicate intraocular inflammation, with the opacity often severe in the inferior part of the vitreous. However, the vitreous of this patient was a uniform glassy, woollike appearance. The patient had no signs of inflammation. Additionally, the dehemoglobinized vitreous hemorrhage is similarly white. However, red blood cell ghosts could be seen in the vitreous, usually accompanied by sudden vision loss. Furthermore, primary intraocular lymphoma should be differentiated because primary intraocular lymphoma could also lead to vitreous opacity. However, primary intraocular lymphoma typical leopard spot–like subretinal lesion and vitreous cells were not seen in this case. Therefore, option A is inappropriate.The patient presented with emaciation; therefore, cachexia should be considered. Cachexia is associated with chronic malignancies such as AIDS and cancer. A preoperative HIV test result was negative, but cancer could not be excluded because of the patient’s family’s medical history. Cancer-associated retinopathy (CAR) represents retinal disorders mediated by the autoimmune mechanism and is associated with serum antiretinal autoantibodies. Cancer-associated retinopathy usually damages photoreceptors and causes acute/subacute vision loss and visual field defects but seldom vitreous opacity.1 This excludes option C.Asteroid hyalosis is a common cause of degenerative vitreous opacity. It usually presents in patients older than 55 years. However, it rarely causes visual disturbances.2 Asteroid hyalosis granules, starry sky–like calcium or lipids, were not found in the patient’s vitreous; therefore, option D was excluded. Other degenerative vitreous opacities are usually accompanied by high myopia and signs such as frontal dysplasia in Stickler syndrome and loose joints or stretchy skin in Ehlers-Danlos syndrome. The patient had no such symptoms.The patient’s signs and family’s medical history could hint at a systemic, hereditary disorder. Amyloidosis should be considered because it can be inherited and usually involves the liver. The vitreous cortex is commonly where amyloidosis occurs; therefore, PPV and pathological examination (option B) could aid the diagnosis. The vitreous showed positive staining with Congo red, indicating vitreous amyloidosis. Gene sequencing showed a missense mutation of transthyretin (TTR) exon2 (c.199G>C). Transthyretin is a protein transport thyroxine and retinol-binding protein, a mutant form of a normal serum protein that is deposited in the genetically determined familial amyloid polyneuropath.3 Transthyretin is mainly formed in the liver. In the central nervous system, TTR is secreted by the choroid plexus, while in the eye, TTR is secreted by the choroid and retinal pigment epithelium.4Amyloidosis could affect multiple organs. The transthyretin type, 1 of the major 3 types of amyloidosis, causes familial amyloid polyneuropathy, usually affects the vitreous, and subsequently leads to glaucoma and neurotrophic keratitis.4 Amyloidosis could cause peripheral neuropathy and autonomic nervous system dysfunction and presents with nonspecific gastrointestinal tract symptoms such as constipation, nausea, or early satiety.5 Liver transplant is an effective approach for familial amyloidosis owing to TTR (Val30Met) mutation. Because the choroid and retinal pigment epithelium could secrete TTR in the eye, amyloidosis could recur even after liver transplantation.6 Long-term follow-up for the patient is needed.A month after genetic diagnosis and right eye surgery, the left eye underwent PPV to remove residual vitreous. The BCVA was 0.6 (20/32) OU 3 months later. Six months later, there was no recurrence. The patient was transferred to the internal medicine service for further treatment.

Ophthalmology

A Chinese woman had painless, gradually declined vision for 2 years without redness. She had a medical history of vomiting and emaciation in her early 40s. Pars plana vitrectomy (PPV) had been done for her left eye owing to vitreous opacity half a year prior. She claimed that her younger brother died of liver cancer and her mother had lost vision because of vitreous hemorrhage and glaucoma. She denied any history of systemic disorders.On initial examination, best-corrected visual acuity was measured at 0.1 (20/200) OU. Intraocular pressure was 14 mm Hg OD and 16 mm Hg OS. Her anterior segment examination results were within normal limits. Dilated fundus examination demonstrated bilateral vitreous opacity without cells (Figure). The peripheral residual vitreous cortex in the left eye was as cloudy as the cortex in the right eye. Fundus was not visible in the right eye and was normal in the left eye. A bilateral ocular ultrasonography showed normal results except for vitreous opacity. The patient weighed 37.0 kg and was 155 cm tall. Her blood pressure was 113/70 mm Hg. Mild anemia (hemoglobin level 10.5 g/dL vs a normal range of 11.0-15.0 g/dL [to convert to grams per liter, multiply by 10]) was found in routine blood test results. Liver and renal functions were normal according to serum test results. The results of an electronic cardiogram were negative.Mosaic 9-field 50° fundus photography showed a uniform, glassy, woollike appearance of the vitreous in the right eye (A) and peripheral vitreous opacity in the left after pars plana virectomy (B).Aqueous humor biopsy for cytometry and biochemical test

what would you do next?

What would you do next?

Aqueous humor biopsy for cytometry and biochemical test

Abdominal ultrasonography

PPV plus pathological examination plus genetic test

Follow-up

c

female

41-50

Chinese

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2753568

A man in his 80s with pseudophakia presented for routine follow-up of an elevated choroidal nevus in his right eye. His medical history was notable for stage III non-Hodgkin follicular lymphoma in the hilar and axillary nodes, which was asymptomatic and actively monitored by oncology, prostate cancer treated surgically that was in remission, and atrial fibrillation managed with medication (digoxin and warfarin). The choroidal nevus had been observed for the past 2 years; ultrasonography from 2 years prior revealed dimensions of 1.9 (height) × 9.3 (base) mm with medium internal reflectivity. There were no other concerning features noted, such as orange pigment or associated subretinal fluid.At presentation, the patient was asymptomatic with no diplopia, pain, constitutional symptoms, or blurred vision. His best-corrected visual acuity was 20/30 OU. Pupils were reactive without a relative afferent pupillary defect, extraocular motility was full, and intraocular pressures were normal. His slitlamp and fundus examination results were unremarkable aside from the choroidal nevus in his right eye, which appeared similar to previous examinations (Figure 1A). Proptosis, resistance to retropulsion, conjunctival injection, and strabismus were notably absent. However, a new retro-orbital hypoechoic cavity causing right globe deformation was noted on B-scan ultrasonography (Figure 1B).A, Color fundus photography of the right eye illustrates a hyperpigmented choroidal nevus (arrowhead) in the macula. B, B-scan ultrasonography demonstrates a large hypoechoic cavity posterior to the globe (arrowhead) causing deformity of the globe wall.Monitor the patient with follow-up in 6 months What Would You Do Next?

Perform fluorescein angiography

Obtain orbital imaging

Recommend a liver biopsy

Monitor the patient with follow-up in 6 months

Mantle cell orbital lymphoma

B

Obtain orbital imaging

The differential diagnosis includes lymphoproliferative lesions, granulomatosis with polyangiitis, IgG4-related disease, idiopathic orbital inflammation, solitary fibrous tumor, metastatic lesions, pleomorphic adenoma, and adenoid cystic carcinoma. While fluorescein angiography (choice A) can characterize the vasculature of choroidal lesions, including double circulation associated with choroidal melanomas, the lesion of concern here is located in the extraocular space. Choroidal melanomas are acoustically hollow, like the mass seen here, and they most commonly metastasize to the liver, but obtaining an invasive biopsy (choice C) without further orbital imaging is inappropriate. Close monitoring alone (choice D) in the setting of a new mass is inappropriate. Orbital computed tomography was obtained (choice B).The patient presented to oculoplastics 3 weeks later with new proptosis of his right eye and restriction of upgaze motility. Imaging revealed a homogenously enhancing lesion measuring 2.5 × 3.3 × 1.9 cm displacing the superior and lateral rectus muscles (Figure 2). The mass was located proximal to the lacrimal gland in the superotemporal quadrant of the right orbit without associated bony erosion or hyperostosis. The most likely diagnoses were narrowed to lymphoma, pleomorphic adenoma, or solitary fibrous tumor.Orbital computed tomography shows a homogenously enhancing orbital mass (arrowhead) measuring 2.5 × 3.3 × 1.9 cm in the right superotemporal orbit without bony erosion or hyperostosis. There is regional mass effect on the right lateral rectus muscle.This patient required a biopsy even in the setting of a previously diagnosed lymphoma, as this lesion could represent transformation to a higher grade or a new type of lymphoma. Additionally, there have been rare reports of extraocular extension of small choroidal melanomas presumed to be choroidal nevi.1 Pathology revealed mantle cell lymphoma with κ light chain restriction, overexpression of tumor protein p53, and low mitotic count. Results of tests for tumor markers for melanoma, including S100 and human melanoma black-45 levels, were negative. The patient was referred to oncology with a plan for systemic chemotherapy with bendamustine and rituximab.Orbital lymphoma is the most common orbital neoplasm in adults.2 Most cases of orbital lymphoma are unilateral and derive from B lymphocyte origins or mucosa-associated lymphoid tissue origins.3-5 Mantle cell lymphoma is relatively rare, representing only 2% to 7% of all orbital lymphoma cases.6 It may present as a secondary lymphoma of the orbit or eyelid, most often in older men.7 A 2015 review of 226 consecutive cases of conjunctival and ocular adnexal lymphoma8 showed that mantle cell lymphoma presents as a secondary manifestation of lymphoma in 61% of cases. Only a minority of patients experience classic B symptoms, including fever, lymphadenopathy, or night sweats.9 Mantle cell lymphoma can mimic myasthenia gravis with positive anti–muscle-specific tyrosine kinase antibodies.10 Biopsy is needed to establish a definitive diagnosis.Mantle cell lymphoma management was previously limited to palliative chemotherapy; newer strategies of systemic chemotherapy combining multiple agents (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) have improved response rates.6,9 In patients who are CD20 positive, rituximab improves 5-year survival.6,9 In spite of this, many patients with mantle cell lymphoma present during advanced stages of disease, resulting in multiple relapses with poor prognosis.9 In an international multicenter review of 55 patients with a median follow-up of 33 months,6 overall survival was 65% at 3 years, and disease-specific survival was 34% at 5 years.After extensive discussion with his oncologist, the patient decided not to pursue any further treatment. He remains stable at the time of publication.

Ophthalmology

A man in his 80s with pseudophakia presented for routine follow-up of an elevated choroidal nevus in his right eye. His medical history was notable for stage III non-Hodgkin follicular lymphoma in the hilar and axillary nodes, which was asymptomatic and actively monitored by oncology, prostate cancer treated surgically that was in remission, and atrial fibrillation managed with medication (digoxin and warfarin). The choroidal nevus had been observed for the past 2 years; ultrasonography from 2 years prior revealed dimensions of 1.9 (height) × 9.3 (base) mm with medium internal reflectivity. There were no other concerning features noted, such as orange pigment or associated subretinal fluid.At presentation, the patient was asymptomatic with no diplopia, pain, constitutional symptoms, or blurred vision. His best-corrected visual acuity was 20/30 OU. Pupils were reactive without a relative afferent pupillary defect, extraocular motility was full, and intraocular pressures were normal. His slitlamp and fundus examination results were unremarkable aside from the choroidal nevus in his right eye, which appeared similar to previous examinations (Figure 1A). Proptosis, resistance to retropulsion, conjunctival injection, and strabismus were notably absent. However, a new retro-orbital hypoechoic cavity causing right globe deformation was noted on B-scan ultrasonography (Figure 1B).A, Color fundus photography of the right eye illustrates a hyperpigmented choroidal nevus (arrowhead) in the macula. B, B-scan ultrasonography demonstrates a large hypoechoic cavity posterior to the globe (arrowhead) causing deformity of the globe wall.Monitor the patient with follow-up in 6 months

what would you do next?

What would you do next?

Perform fluorescein angiography

Recommend a liver biopsy

Monitor the patient with follow-up in 6 months

Obtain orbital imaging

d

male

81-90

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2753768

A 57-year-old woman with a history of hypertension presented to the emergency department with blurry vision in her right eye for a duration of 2 weeks. Her visual acuity with correction was 20/40 OD and 20/25 OS. Her intraocular pressures were 14 mm Hg OD and 15 mm Hg OS. A dilated fundus examination of the right eye was notable for an amelanotic choroidal mass with overlying subretinal fluid (Figure 1A). Results of a dilated fundus examination of the left eye were unremarkable. Results of fluorescein angiographic imaging of the right eye showed late leakage corresponding to the choroidal mass; the left eye was unremarkable. Optical coherence tomography demonstrated a choroidal mass with an irregular surface contour and a mild overlying vitreous cell. On B-scan ultrasonography of the right eye, a superotemporal choroidal mass with an irregular surface contour and medium internal reflectivity was observed (Figure 1B). On further questioning, the patient reported a 9 pack-year smoking history. She had no known history of malignant conditions. She denied recent fevers, chills, weight loss, night sweats, and travel to foreign countries, and she was otherwise feeling well.A, Color fundus photograph of the right eye demonstrates a large, solitary amelanotic choroidal mass (arrowheads) with overlying subretinal fluid. B, B-scan ultrasonographic image of the right eye shows an irregularly contoured choroidal mass (white arrowhead) and fluid in the Tenon space (open arrowhead).Investigate for sarcoidosis and tuberculosis; if negative, start treatment with steroidsRefer the patient to a primary care physician for a metastatic workup What Would You Do Next?

Investigate for sarcoidosis and tuberculosis; if negative, start treatment with steroids

Treat the mass with radiotherapy

Refer the patient to a primary care physician for a metastatic workup

Proceed with pars plana vitrectomy and biopsy

Giant nodular posterior scleritis

A

Investigate for sarcoidosis and tuberculosis; if negative, start treatment with steroids

The patient was diagnosed with giant nodular posterior scleritis. Test results for tuberculosis, sarcoidosis, and syphilis were negative. She started receiving oral prednisone at a dosage of 60 mg daily. Giant nodular posterior scleritis is uncommon, and diagnosis can be challenging, because there is a broad differential diagnosis for an amelanotic choroidal mass, including choroidal metastasis, amelanotic choroidal melanoma, choroidal lymphoma, circumscribed choroidal hemangioma, and choroidal granuloma (most commonly seen in association with sarcoidosis and tuberculosis). When present, typical features, such as eye pain, headache, and loss of visual acuity, are helpful; however, up to 25% of cases of posterior scleritis are painless.1,2 Most studies show a female predominance. Systemic associations are found in 29% of cases; most commonly, these are rheumatoid arthritis, systemic vasculitis, and granulomatosis with polyangiitis.1,2 Coexisting anterior scleritis is seen in 36% of cases.2 Posterior manifestations include serous retinal detachment (21% of cases), optic disc edema (18%), and (rarely) an amelanotic choroidal mass (13%). Fluid in the Tenon space (the classic T sign) can be observed on ultrasonography (Figure 1B) and is supportive of the diagnosis; however, in a review of 11 patients with nodular posterior scleritis, only 4 (36%) had this feature.2 Most patients respond well to treatment with nonsteroidal anti-inflammatory drugs or oral steroids. Patients with recurrent disease may require steroid-sparing immunosuppressive therapy.Treating the mass with radiotherapy (choice B) is an appropriate next step for treatment of choroidal melanoma. Choroidal melanoma is the most common primary intraocular malignant condition in adults and is usually dome shaped or mushroom shaped on ultrasonography, with low to medium internal reflectivity. Referring the patient to a primary care physician (choice C) is indicated for suspected choroidal metastasis. Up to one-third of patients with choroidal metastasis do not have a known primary malignant condition at the time of ocular presentation.3 Ultrasonography results usually reveal a choroidal mass with an irregular contour and medium to high internal reflectivity. Proceeding with pars plana vitrectomy and biopsy (choice D) could be undertaken for suspected choroidal lymphoma. Distinguishing features in this case are intraocular inflammation and fluid in the Tenon space on ultrasonography. Other diagnoses to consider include choroidal granuloma attributable to sarcoidosis or tuberculosis—thus the importance of obtaining a complete workup to exclude these possibilities.Laboratory studies to rule out underlying systemic conditions, such as rheumatoid arthritis, systemic lupus erythematosus, and antineutrophil cytoplasmic antibody–associated vasculitis, had unremarkable results. The patient responded well to 3 weeks of oral prednisone at a dosage of 60 mg daily, followed by a slow taper. She had almost immediate improvement in pain. The intraocular inflammation gradually subsided, and the choroidal mass regressed. At a follow-up visit 5 months after initial presentation, her visual acuity with correction was 20/20 OD and the mass was no longer visible on a dilated examination (Figure 2).Color fundus photograph of the right eye demonstrating complete regression of the choroidal mass. The previous area of the mass is outlined by arrowheads.

Ophthalmology

A 57-year-old woman with a history of hypertension presented to the emergency department with blurry vision in her right eye for a duration of 2 weeks. Her visual acuity with correction was 20/40 OD and 20/25 OS. Her intraocular pressures were 14 mm Hg OD and 15 mm Hg OS. A dilated fundus examination of the right eye was notable for an amelanotic choroidal mass with overlying subretinal fluid (Figure 1A). Results of a dilated fundus examination of the left eye were unremarkable. Results of fluorescein angiographic imaging of the right eye showed late leakage corresponding to the choroidal mass; the left eye was unremarkable. Optical coherence tomography demonstrated a choroidal mass with an irregular surface contour and a mild overlying vitreous cell. On B-scan ultrasonography of the right eye, a superotemporal choroidal mass with an irregular surface contour and medium internal reflectivity was observed (Figure 1B). On further questioning, the patient reported a 9 pack-year smoking history. She had no known history of malignant conditions. She denied recent fevers, chills, weight loss, night sweats, and travel to foreign countries, and she was otherwise feeling well.A, Color fundus photograph of the right eye demonstrates a large, solitary amelanotic choroidal mass (arrowheads) with overlying subretinal fluid. B, B-scan ultrasonographic image of the right eye shows an irregularly contoured choroidal mass (white arrowhead) and fluid in the Tenon space (open arrowhead).Investigate for sarcoidosis and tuberculosis; if negative, start treatment with steroidsRefer the patient to a primary care physician for a metastatic workup

what would you do next?

What would you do next?

Refer the patient to a primary care physician for a metastatic workup

Treat the mass with radiotherapy

Proceed with pars plana vitrectomy and biopsy

Investigate for sarcoidosis and tuberculosis; if negative, start treatment with steroids

d

female

51-60

White

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2753552

A 54-year-old woman presented with a 7-year history of a painful subungual mass of the right thumb. The lesion was initially believed to be an infection; however, results of both mycological and bacteriologic examinations were unremarkable. The patient had no notable medical history, including dyskeratosis congenita, trauma, sun exposure, radiation exposure, chemical exposure to tar or arsenic or exposure to minerals, chronic immunosuppression, or chronic infection. Physical examination revealed a subungual nodule with some exudation and crusts. The distal nail plate had been destroyed and showed onycholysis with obvious separation from the nail bed (Figure, A). Pertinent laboratory results (complete blood cell count, liver panel, kidney panel) were within normal limits. Lesional biopsy was also performed (Figure, B and C).A, Clinical photograph shows a subungual nodule with exudation and crusts as well as destruction of the distal nail plate with onycholysis. B, Lesional biopsy results show proliferation of atypical squamous cells invading the dermis. C, Large atypical squamous cells with hyperchromatic, pleomorphic, and atypical mitosis (B and C, hematoxylin-eosin). What Is Your Diagnosis?

Onychomycosis

Subungual squamous cell carcinoma

Subungual verruca vulgaris

Subungual exostosis

B. Subungual squamous cell carcinoma

B

Subungual squamous cell carcinoma

Malignant subungual tumors are rare and are associated with subungual squamous cell carcinoma (SCC), Bowen disease, melanoma, basal cell carcinoma, and subungual keratoacanthoma among others. Of these malignant neoplasms, subungual SCC is the most frequent.1-4 Subungual SCC has been considered a low-grade malignant neoplasm with a good prognosis compared with SCC arising elsewhere.2-4 About 20% of patients with subungual SCC have bony invasion, and metastasis and lymph node involvement is uncommon.1-4 Usually, the patients tend to be men aged 50 to 79 years, and typically, a single digit, especially the thumb or hallux, is likely to be involved.1-3The origin of subungual SCC has not been well described. However, some causative factors have been proposed, including trauma, dyskeratosis congenita, sun exposure, radiation exposure, chemical exposure (ie, tar, arsenic, or exposure to minerals), immunosuppression, chronic infection, and human papillomavirus (HPV) infection, especially HPV 16 infection.1-3,5,6The indolent natural history and the variable clinical manifestations of subungual SCC often lead to misdiagnosis or delayed diagnosis and, subsequently, poor prognosis. Therefore, the differential diagnosis is very important and should include subungual keratoacanthoma, verruca vulgaris, exostosis, onychomycosis, and chronic paronychia. Subungual keratoacanthoma, is a benign tumor that usually presents as a painful, locally aggressive, and rapidly growing mass with a well-defined osteolytic destruction of the underlying bone.7,8 Although the histologic appearance and clinical presentation of subungual keratoacanthoma is sometimes indistinguishable from subungual SCC, the diagnosis in the present case was definitive given the patient’s 7-year medical history and the histologic results, which supported the diagnosis of subungual SCC. Verruca vulgaris, especially a subungual wart, can be confused with subungual SCC because of the similar appearance; however, the histopathologic findings revealed the appearance of subungual SCC, and HPV was not detected in the neoplastic squamous cells. Another important differential diagnosis is subungual exostosis, a benign osteocartilaginous tumor that appears as a wartlike nodule under the nail with onycholysis and nail plate destruction. However, subungual exostosis often occurs in children and young adults, with a radiograph revealing a calcifying projection on the distal phalanx, and the pathologic results showing mature trabecular bone.9 Chronic paronychia and onychomycosis also should be ruled out. However, chronic paronychia often affects the proximal and lateral nail folds, presenting as a red, tender, and swelling lesion with the absence of cuticle and onychodystrophy, which is not consistent with the clinical appearance in the present case. Furthermore, complete blood cell count results and mycological and bacteriologic examinations were unremarkable in the present case. Distal subungual onychomycosis, defined as a fungal infection, usually manifests as dystrophic, thick nails with onycholysis, hyperkeratosis, and discoloration; although there are some similarities in the clinical appearances of onychomycosis and SCC, the unremarkable mycological examination was the most convincing evidence to exclude onychomycosis.A tissue biopsy should be performed for a definitive diagnosis and requires a high degree of suspicion. In the present case, hematoxylin-eosin staining of the initial biopsy specimen showed proliferation of atypical squamous cells invading the dermis on low power (magnification ×60) (Figure, B). Higher-power images (magnification ×100) showed large atypical neoplastic squamous cells with hyperchromatic, pleomorphic, and atypical mitosis (Figure, C). These findings were consistent with a diagnosis of subungual SCC. Immunohistochemical analysis showed that the specimen was negative for HPV 16/18.Once subungual SCC is diagnosed, a lesion without bony involvement can be microscopically excised using Mohs micrographic surgery; otherwise, an amputation of the distal phalanx is recommended.1-3 The patient was referred for imaging and analytical studies to rule out bony involvement, lymph node involvement, and metastasis. Surgical excision was not performed, and the patient was lost to follow-up.

Oncology

A 54-year-old woman presented with a 7-year history of a painful subungual mass of the right thumb. The lesion was initially believed to be an infection; however, results of both mycological and bacteriologic examinations were unremarkable. The patient had no notable medical history, including dyskeratosis congenita, trauma, sun exposure, radiation exposure, chemical exposure to tar or arsenic or exposure to minerals, chronic immunosuppression, or chronic infection. Physical examination revealed a subungual nodule with some exudation and crusts. The distal nail plate had been destroyed and showed onycholysis with obvious separation from the nail bed (Figure, A). Pertinent laboratory results (complete blood cell count, liver panel, kidney panel) were within normal limits. Lesional biopsy was also performed (Figure, B and C).A, Clinical photograph shows a subungual nodule with exudation and crusts as well as destruction of the distal nail plate with onycholysis. B, Lesional biopsy results show proliferation of atypical squamous cells invading the dermis. C, Large atypical squamous cells with hyperchromatic, pleomorphic, and atypical mitosis (B and C, hematoxylin-eosin).

what is your diagnosis?

What is your diagnosis?

Subungual squamous cell carcinoma

Subungual verruca vulgaris

Subungual exostosis

Onychomycosis

a

female

51-60

original

https://jamanetwork.com/journals/jama/fullarticle/2753204

A 62-year-old woman with extranodal marginal zone lymphoma noticed small, asymptomatic, purpuric patches on her right buttock and bilateral lower extremities. This was accompanied by fever, night sweats, and fatigue. She was found to have clinical and radiologic progression of her lymphoma and began receiving R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride + vincristine [Oncovin] + prednisone) chemotherapy. Her purpuric patches improved initially after the first cycle of chemotherapy; however, in the weeks before the second cycle, they recurred more extensively, involving her right cheek and bilateral ears, arms, and legs. This time she also experienced pain in those areas as well as lower extremity edema.On presentation to the outpatient infusion suite, she appeared well, and her temperature was 37°C (98.6°F); heart rate, 91/min; blood pressure, 114/58 mm Hg; respiratory rate, 18/min; and blood oxygen saturation, 98%. Diffuse, symmetric patches and soft, thin plaques of retiform purpura with minimally erythematous borders covered her extremities and acral surfaces, some with overlying bullae (Figure 1). A complete blood cell count showed an elevated white blood cell count (18 860/μL with 13% neutrophils, 43% lymphocytes, 9% monocytes, 33% others); hemoglobin, 7.2 g/dL; hematocrit, 21.8%; and platelet count, 142 ×103/μL. Results of a comprehensive metabolic panel were unremarkable. Fibrinogen level, prothrombin level, and partial thromboplastin time were within normal limits. Blood was sent for cultures.Skin findings on examination of patient’s lower extremities. What Would You Do Next?

Administer empirical intravenous antibiotics

Administer protein C concentrate

Calculate a calcium-phosphate product

Test for serum cryoglobulin level

Lymphoma-associated cryoglobulinemia

D

Test for serum cryoglobulin level

The key to the correct diagnosis is recognizing the subacute presentation of acral-predominant retiform purpura in a well-appearing patient with underlying lymphoma.Retiform purpura can also present in ecthyma gangrenosum, a cutaneous syndrome that occurs when bacterial pathogens (commonly Pseudomonas aeruginosa) invade dermal vessels and cause neutrophilic cutaneous vasculitis.1 However, patients with ecthyma gangrenosum are usually septic and toxic-appearing, which is not the case in this patient. Patients with acute disseminated intravascular coagulation and cutaneous purpura are also generally ill-appearing and hemodynamically unstable. Some of them, especially those with the widespread purpura of purpura fulminans, can benefit from administration of protein C concentrate.2 However, disseminated intravascular coagulation is unlikely in this patient, given that she was otherwise well and her fibrinogen level and results of a coagulation panel were within normal limits. The calcium-phosphate product can be elevated in uremic calciphylaxis. However, extensive calciphylaxis typically involves fatty areas of the trunk and proximal extremities; involvement of the face and ears is atypical.Cryoglobulinemia is defined by the presence of serum cryoglobulins, immunoglobulin proteins that precipitate at temperatures below 37°C and dissolve when rewarmed.3 There are 3 types of cryoglobulinemia, and classification depends on the nature of the immunoglobulins involved. Type I cryoglobulinemia comprises a single population of monoclonal immunoglobulin. Type II cryoglobulinemia contains both monoclonal and polyclonal immunoglobulins, commonly monoclonal IgM and polyclonal IgG. Type III consists of only polyclonal immunoglobulins. Type I cryoglobulins, usually monoclonal IgM, cause direct intravascular occlusion in the dermal vessels and lead to skin necrosis and purpura, often on the cooler, acral surfaces.4 In types II and III cryoglobulinemia, IgM proteins with rheumatoid factor activity can bind to IgGs to form immune complexes.5 These immune complexes deposit in dermal vessel walls and activate the complement system to cause vascular inflammation.5 Both direct intravascular occlusion and vasculitis result in infarct and necrosis that follow cutaneous vascular territories, giving rise to purpura with angulated borders described as retiform, or net-like.6Type I cryoglobulinemia is strongly associated with B-cell lymphoproliferative disorders such as Waldenström macroglobulinemia and non-Hodgkin lymphoma.3 Types II and III cryoglobulinemia are seen in chronic viral infections, autoimmune diseases, as well as lymphoproliferative disorders.3 Skin biopsy can aid in differentiating between the types of cryoglobulinemia. On histology, type I cryoglobulinemia shows widespread vascular congestion with intravascular thrombi containing glassy hyaline deposits and minimal perivascular inflammatory infiltrate (Figure 2). Types II and III cryoglobulinemia may show evidence of vasculitis. Immunochemical characterization of the cryoprecipitate and direct immunofluorescence of the tissue biopsy sample may confirm the presence of a single species of immunoglobulin in type I cryoglobulinemia.3,4 Furthermore, results of testing for rheumatoid factor are negative in type I cryoglobulinemia.3,4Histopathological features of biopsy of the purpura plaque from left thigh showing vascular congestion with hyaline intravascular deposit and minimal perivascular inflammation (hematoxylin-eosin, original magnification ×100).Treatment of cryoglobulinemia focuses on the underlying cause—ie, cancer, infection, or autoimmune disease.3 In severe cases, patients may require plasmapheresis or administration of rituximab or systemic corticosteroids.3,5This patient had cryoglobulinemia with 20% cryocrit. No rheumatoid factor was identified. Evaluation of the skin biopsy sample by direct immunofluorescence showed intravascular aggregates with strong immunoreactivity for IgM and light chains, supporting a diagnosis of type I cryoglobulinemia. Infectious workup was negative. R-CHOP for her lymphoma was administered and was supplemented with therapeutic anticoagulation, plasmapheresis, and a prolonged taper of the prednisone dose. Over the course of the admission, her purpura stabilized and gradually evolved into necrotic plaques, bullae, and retiform ulcers. Long-term follow-up was characterized by the development of new lesions as steroid dose was tapered but resolved with increase in steroid dose followed by a slower taper; she has been clear of new lesions for more than 1 year. She underwent peripheral blood stem cell transplant 1 year after the presentation described here, with complete response. She will receive enoxaparin indefinitely.

General

A 62-year-old woman with extranodal marginal zone lymphoma noticed small, asymptomatic, purpuric patches on her right buttock and bilateral lower extremities. This was accompanied by fever, night sweats, and fatigue. She was found to have clinical and radiologic progression of her lymphoma and began receiving R-CHOP (rituximab + cyclophosphamide + doxorubicin hydrochloride + vincristine [Oncovin] + prednisone) chemotherapy. Her purpuric patches improved initially after the first cycle of chemotherapy; however, in the weeks before the second cycle, they recurred more extensively, involving her right cheek and bilateral ears, arms, and legs. This time she also experienced pain in those areas as well as lower extremity edema.On presentation to the outpatient infusion suite, she appeared well, and her temperature was 37°C (98.6°F); heart rate, 91/min; blood pressure, 114/58 mm Hg; respiratory rate, 18/min; and blood oxygen saturation, 98%. Diffuse, symmetric patches and soft, thin plaques of retiform purpura with minimally erythematous borders covered her extremities and acral surfaces, some with overlying bullae (Figure 1). A complete blood cell count showed an elevated white blood cell count (18 860/μL with 13% neutrophils, 43% lymphocytes, 9% monocytes, 33% others); hemoglobin, 7.2 g/dL; hematocrit, 21.8%; and platelet count, 142 ×103/μL. Results of a comprehensive metabolic panel were unremarkable. Fibrinogen level, prothrombin level, and partial thromboplastin time were within normal limits. Blood was sent for cultures.Skin findings on examination of patient’s lower extremities.

what would you do next?

What would you do next?

Test for serum cryoglobulin level

Administer empirical intravenous antibiotics

Calculate a calcium-phosphate product

Administer protein C concentrate

a

female

61-70

White

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2751511

A man in his 50s was referred to the dermatology clinic with a diagnosis of granuloma annulare made on the basis of prior skin biopsy results. He had been treated by a rheumatologist for polyarticular inflammatory arthritis involving the wrists, metacarpophalangeal joints, and proximal interphalangeal joints, as well as fatigue and dyspnea on exertion. Examination revealed numerous, pink-purple dermal papules on the trunk and extremities, with preference for the extensor surfaces of the arms (Figure, A) and legs. No lymphadenopathy was noted. The patient reported a 5- to 7-kg weight loss without fever or sweats. His pulmonary and joint symptoms were relieved by daily oral prednisone and flared with taper below 10 mg. Other medications prescribed included hydroxychloroquine, 400 mg, daily for 18 months and weekly adalimumab injections for 7 months, without improvement.A, Pink-purple papules on the extensor surface of the arms. B, Biopsy results show a nodular to diffuse lymphohistiocytic infiltrate (hematoxylin-eosin). C, Admixed atypical, irregularly contoured lymphocytes with numerous histiocytes are present. D, Biopsy results show low CD4 signal and robust CD8 signal (magnification ×20).Pulmonary function testing revealed mild restrictive disease with decreased forced vital capacity and total lung capacity. Results of a complete blood cell count and metabolic panel; hemoglobin A1c; viral and rheumatologic panels, including HIV blood tests; chest radiograph; high-resolution chest computed tomographic scan; echocardiography; endoscopic studies; hand radiographs; and serum and urine protein electrophoresis were normal or otherwise unremarkable. The results of lesional skin biopsies obtained from multiple involved sites initially revealed nonspecific granulomatous dermatitis before a diagnostic biopsy was performed (Figure, B, C, and D). What Is Your Diagnosis?

Cutaneous T-cell lymphoma

Granuloma annulare

Small-vessel vasculitis

Sarcoidosis

A. Cutaneous T-cell lymphoma

A

Cutaneous T-cell lymphoma

On further histopathological evaluation, lymphocytes present in skin biopsy specimens stained positive for CD3, with an inverted CD8 to CD4 ratio, and were predominantly α/β positive. Many CD8-positive cells displayed hyperchromicity, irregular nuclear contours, and focal perinuclear halos. Most T cells were α/β positive, and few γ/δ-positive cells were present. Staining with CD30 highlighted rare scattered cells, and CD56 results were negative. Flow cytometric analysis of bone-marrow aspirate revealed lymphocytes with an atypical CD3-negative, CD4-negative, CD5-positive, CD8-positive phenotype representing 2% of total cells. Quantitative immunoglobulins testing and Epstein-Barr encoding region in situ hybridization of tissue and bone marrow were performed, and the results were negative. Matching clonal rearrangements were identified through T-cell receptor polymerase chain reaction on 3 skin biopsy specimens and a bone marrow sample. Based on the histopathologic findings, the patient was diagnosed with CD8-positive granulomatous cutaneous T-cell lymphoma (CTCL).Cutaneous T-cell lymphoma encompasses a diverse group of cutaneous neoplasms characterized by clonal T-cell proliferation with heterogenous histological and clinical features.1 In most cases, the implicated clone is a skin-homing CD4-positive memory T cell; however, rare cases of CD8-positive CTCL have been reported, with variable prognosis ranging from indolent to aggressive.1-3Clinical subtypes in CD8-positive CTCL overlap with those seen in CD4-positive CTCL and include granulomatous variants.1,2 Granulomas are a well-known feature of nodal lymphomas; however, granulomatous CTCL (GCTCL) is itself a rare entity noted in only 2% of all CTCL cases.2,4,5 Given its rarity, GCTCL is not yet fully understood or recognized in the World Health Organization classification of cutaneous lymphomas. However, it is considered a separate entity from mycosis fungoides, granulomatous slack skin, and granulomatous mycosis fungoides. Whether granuloma formation represents a specific disease variant or is due to nonspecific reactive inflammation is unclear.5 Granulomatous CTCL is commonly misdiagnosed as granulomatous dermatitis or similar conditions if lymphocytic atypia is not readily detectable on biopsy results.3,4,6 In 1 report, a patient with CD8-positive CTCL was initially misdiagnosed with granuloma annulare; it is likely that the present patient was similarly misdiagnosed.3 The clinical course of GCTCL has not been established. Early reports of improved prognosis have been followed by later reports documenting prognosis similar to that of other CTCL variants.2,4,6Given the rarity of both CD8-positive CTCL and GCTCL, only 9 other cases of CD8-positive GCTCL have been documented in the literature. Most patients were noted to have erythematous papules and nodules on the extremities and occasionally on the trunk. The histopathological findings establishing the diagnosis in these patients centered on the presence of atypical CD3-positive/CD8-positive lymphocytic infiltration, as noted here.2,4-6 Studies in which T-cell receptor polymerase chain reaction was performed similarly documented clonal proliferation.5,6 Of note, many patients with reported CD8-positive GCTCL had underlying immunodeficiency, including common variable immunodeficiency, acquired immunodeficiency syndrome, and X-linked agammaglobulinemia; this association is postulated to stem from a predisposition to granuloma formation in these disease states.5,6 No immunodeficiency preceding the onset of symptoms was identified in this patient after extensive evaluation.A case series of CD8-positive GCTCL identified lung granulomas in all 4 cases reported.5 One patient also developed bilateral metacarpophalangeal joint destructive arthritis, demonstrating the potential systemic manifestations of GCTCL.5 However, it is unclear whether the present patient’s pulmonary symptoms and arthritis are related to GCTCL.Psoralen plus UV-A therapy has been successful in multiple patients with GCTCL and in 2 patients with CD8-positive GCTCL.2-4 Other options may include methotrexate, bexarotene, and total skin electron beam therapy.

Dermatology

A man in his 50s was referred to the dermatology clinic with a diagnosis of granuloma annulare made on the basis of prior skin biopsy results. He had been treated by a rheumatologist for polyarticular inflammatory arthritis involving the wrists, metacarpophalangeal joints, and proximal interphalangeal joints, as well as fatigue and dyspnea on exertion. Examination revealed numerous, pink-purple dermal papules on the trunk and extremities, with preference for the extensor surfaces of the arms (Figure, A) and legs. No lymphadenopathy was noted. The patient reported a 5- to 7-kg weight loss without fever or sweats. His pulmonary and joint symptoms were relieved by daily oral prednisone and flared with taper below 10 mg. Other medications prescribed included hydroxychloroquine, 400 mg, daily for 18 months and weekly adalimumab injections for 7 months, without improvement.A, Pink-purple papules on the extensor surface of the arms. B, Biopsy results show a nodular to diffuse lymphohistiocytic infiltrate (hematoxylin-eosin). C, Admixed atypical, irregularly contoured lymphocytes with numerous histiocytes are present. D, Biopsy results show low CD4 signal and robust CD8 signal (magnification ×20).Pulmonary function testing revealed mild restrictive disease with decreased forced vital capacity and total lung capacity. Results of a complete blood cell count and metabolic panel; hemoglobin A1c; viral and rheumatologic panels, including HIV blood tests; chest radiograph; high-resolution chest computed tomographic scan; echocardiography; endoscopic studies; hand radiographs; and serum and urine protein electrophoresis were normal or otherwise unremarkable. The results of lesional skin biopsies obtained from multiple involved sites initially revealed nonspecific granulomatous dermatitis before a diagnostic biopsy was performed (Figure, B, C, and D).

what is your diagnosis?

What is your diagnosis?

Sarcoidosis

Small-vessel vasculitis

Cutaneous T-cell lymphoma

Granuloma annulare

c

male

51-60

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2751866

A girl in her teens presented for evaluation of asymptomatic, punctate, keratotic papules localized to the right palm and right third proximal finger that had been present since age 2 years. Prior treatments included cryotherapy, pulsed dye laser, and 40% salicylic acid, with partial improvement reported but never complete clearance. Medical history and family history were unremarkable. Physical examination revealed grouped and circumscribed, firm, skin-colored, 1- to 3-mm papules with a central punctate dark core (Figure, A and B). A 4-mm punch biopsy from a papule on the palm was performed (Figure, C and D).A and B, Grouped, dome-shaped, skin-colored, punctate papules with central keratotic plugging localized to the right palm and finger. C and D, Dilated follicular infundibulum with keratinous core and absent hair shaft (hematoxylin-eosin). What Is Your Diagnosis?

Porokeratotic eccrine ostial and dermal duct nevus

Punctate palmoplantar keratoderma

Familial comedonal Darier disease

Nevus comedonicus

D. Nevus comedonicus

D

Nevus comedonicus

Punch biopsy results revealed dilated cystic spaces with mild squamous hyperplasia and central laminated keratin resembling a dilated terminal hair follicle infundibulum (Figure, C and D). The clinical and pathologic findings were considered diagnostic of a nevus comedonicus.Nevus comedonicus is a hamartomatous proliferation resulting from improper keratinization of the pilosebaceous unit, and it presents as punctate papules with a central keratotic core. Individual lesions may be present at birth or develop during childhood, but they are generally fully established by age 10 years.1 Linear or blaschkoid presentations involving the face, neck, upper extremities, and trunk are most common, with a prevalence of 1 in 45 000 to 1 in 100 000 persons.2 However, palmar-plantar presentations have been described despite these areas being devoid of pilosebaceous units.3,4 Nevus comedonicus development is postulated to reflect abnormal filaggrin expression or overstimulation of fibroblast growth factor receptor 2, with high expression of interleukin 1 leading to improper pilosebaceous unit development.2 However, there is still debate as to whether development of nevus comedonicus, particularly on the palms and soles where pilosebaceous units are absent, may be caused by abnormal epidermal invagination. Histopathology is characterized by keratin-filled, dilated, cystic spaces with infundibular differentiation in the absence of hair shafts, arrector pili muscle, or sebaceous glands with variable acanthosis.2Nevus comedonicus most often occurs in isolation, but familial clustering and association with skeletal, ocular, and central nervous system involvement can occur in nevus comedonicus syndrome.5 These syndromic presentations are variably associated with other cutaneous tumors such as trichoepithelioma, pilar sheath acanthoma, or syringocystadenoma papilliferum.2Clinical history and histopathologic examination may be required to differentiate nevus comedonicus from other punctate palmar-plantar disorders. Porokeratotic eccrine ostial and dermal duct nevus and nevus comedonicus both present early in life and tend to be unilateral, but porokeratotic eccrine ostial and dermal duct nevus is characterized by a cornoid lamella overlying a dilated acrosyringium with loss of granular layer and focal dyskeratosis.6 Punctate palmoplantar keratoderma generally has a later age of onset (teens to 20s), bilateral distribution, and mild epidermal invagination with central overlying orthohyperkeratosis on histopathologic analysis.1 Familial comedonal Darier disease has comedonelike lesions but shows focal acantholytic dyskeratosis on histologic analysis and typically presents with a generalized seborrheic distribution rather than a linear or circumscribed distribution.7 Lastly, nevus comedonicus can be confused with verruca vulgaris, but verruca vulgaris classically has interrupted skin lines and pinpoint hemorrhage on dermoscopy, bleeds on paring, and reveals papillomatosis with orthokeratosis and parakeratosis in addition to hypergranulosis and koilocytosis on histologic analysis.Treatment is challenging. Destructive approaches using fractional carbon dioxide laser,8 cryotherapy, surgical excision, and comedone extraction have been reported as well as medical approaches using topical or oral retinoids, topical antibiotics, calcipotriene, and keratolytics, with highly variable results described.9 Because most cases are asymptomatic, patients can be reassured that treatment is not necessary aside from cosmetic concerns.

Dermatology

A girl in her teens presented for evaluation of asymptomatic, punctate, keratotic papules localized to the right palm and right third proximal finger that had been present since age 2 years. Prior treatments included cryotherapy, pulsed dye laser, and 40% salicylic acid, with partial improvement reported but never complete clearance. Medical history and family history were unremarkable. Physical examination revealed grouped and circumscribed, firm, skin-colored, 1- to 3-mm papules with a central punctate dark core (Figure, A and B). A 4-mm punch biopsy from a papule on the palm was performed (Figure, C and D).A and B, Grouped, dome-shaped, skin-colored, punctate papules with central keratotic plugging localized to the right palm and finger. C and D, Dilated follicular infundibulum with keratinous core and absent hair shaft (hematoxylin-eosin).

what is your diagnosis?

What is your diagnosis?

Punctate palmoplantar keratoderma

Porokeratotic eccrine ostial and dermal duct nevus

Nevus comedonicus

Familial comedonal Darier disease

c

female

11-20

original

https://jamanetwork.com/journals/jamaneurology/fullarticle/2751250

A 53-year-old man developed patchy numbness in his right arm. The numbness progressed over 10 months to involve his entire right arm, patches of his left arm, and his distal lower extremities. He also developed right-hand incoordination and imbalance. A magnetic resonance image (MRI) of the brain is shown in Figure 1A. A complete blood cell count with a differential; liver function testing; tests for HIV, rapid plasma reagin, serum aquaporin-4 antibody, and antinuclear antibodies; and levels of sodium, calcium, creatinine, glucose, thyroxine, and vitamin B12 were unremarkable. Examinations of the cerebrospinal fluid had normal results twice, including for white blood cell count with a differential, glucose level, total protein level, IgG index, oligoclonal bands, cultures, and cytology testing.A, A brain coronal T1 postgadolinium magnetic resonance image (MRI), showing a lobulated heterogeneously enhancing mass in the brainstem and dural enhancement. B, A brain coronal T1 postgadolinium MRI from 10 months later with persistent yet evolving enhancement and mild size increase in brainstem lesion and ongoing dural enhancement.He sought neurological reconsultation 9 months later, reporting progressive blurred vision bilaterally, dysphagia, dysarthria, and urinary and bowel urgency. His gait had worsened, requiring a cane and, for 6 months, a walker. A physical examination was otherwise unremarkable, except for mild lower-extremity edema. A neurologic examination revealed decreased visual acuity (20/50 OU) with normal pupillary responses and discs; cerebellar dysarthria, dysmetria, and dysdiadochokinesia; and decreased proprioception in the toes with positive Romberg testing. He could not tandem walk. A follow-up brain MRI (Figure 1B) showed persistent enhancement plus bilateral optic nerve enhancement (not shown). Computed tomography of the chest, abdomen, and pelvis revealed infiltrative soft tissue in the pericardium and intra-atrial septum and throughout the retroperitoneum.Acute disseminated encephalomyelitis associated with myelin oligodendrocyte glycoprotein antibody What Is Your Diagnosis?

Sarcoidosis

Erdheim-Chester disease

Diffuse large B-cell lymphoma

Acute disseminated encephalomyelitis associated with myelin oligodendrocyte glycoprotein antibody

B. Erdheim-Chester disease

B

Erdheim-Chester disease

A skeletal survey radiographic series revealed sclerosis of the bilateral proximal tibias. A tibial bone biopsy by interventional radiology showed replacement of the marrow with fibrous stroma and bland, fibroblast-like spindle cells. Further biopsy testing included hematoxylin-eosin staining with foamy histiocytes and testing for cluster of differentiation 68 protein to confirm histiocyte presence. Tests for S100 and cluster of differentiation 1a proteins had negative results. Together, these findings supported the diagnosis of Erdheim-Chester disease (ECD), a rare, non-Langerhans cell–associated histiocytic disorder.Neurosarcoidosis can also cause persistently enhancing parenchymal mass lesions, pachymeningitis, and optic neuritis, but these types of infiltrative soft-tissue and osteosclerotic lesions are atypical. Osteosclerotic lesions are also atypical for diffuse large B-cell lymphoma, and the relative MRI stability of the brain lesions over time is less consistent (particularly without exposure to glucocorticoids). Anti–myelin oligodendrocyte glycoprotein (MOG) antibody can cause an acute disseminated encephalomyelitis phenotype, but anti-MOG disease would not account for extranervous system pathology, and the pattern of persistent nodular enhancement and pachymeningeal involvement are not consistent. The pathology of ECD is also distinct; this case highlights the importance of clinical correlation, systemic evaluation, and pathological confirmation.Mean age at ECD presentation is in the fifth decade of life, and there is a slight male predominance.1,2 Clinical manifestations include bone pain (in 50% of patients), neurologic involvement (50%), diabetes insipidus (25%), and constitutional symptoms (20%).1,2 Neurologic manifestations of ECD almost always occur contemporaneously with systemic symptoms and are the presenting syndrome in about 20% of cases.1 Classic neurologic associations include retro-orbital masslike structures, resulting in proptosis; hypothalamic or pituitary involvement, resulting in endocrinopathic conditions, mainly central diabetes insipidus; multifocal mass–type and infiltrating-type lesions, with a predilection for the brainstem; neurodegeneration; myelopathy; peripheral neuropathy; and dural thickening, which may initially appear similar to a meningioma.2Imaging support for ECD diagnosis typically includes skeletal survey radiography focused on identifying the osteosclerotic lesions in proximal long bones that occur in more than 90% of patients.2,3 On body computed tomography, there are also commonly soft-tissue infiltrative findings in large vessels (60%), retroperitoneum (60%), heart (50%), and lungs (50%); the diagnosis may initially be suggested by a radiologist.2,3 Fludeoxyglucose positron emission tomography can show hypermetabolic activity in areas of extraosseous over osseous sclerotic lesions.2,4 Pathologic confirmation is most commonly secured by long-bone biopsy. Brain biopsies of ECD frequently show atypical or less specific pathological features than biopsies from other organ systems.5 Retroperitoneal biopsy was considered but deferred in this case after interventional radiology personnel cited concerns about procedural risk and the likelihood of success relative to a long-bone target.About 50% of ECD cases are associated with a BRAF V600E mutation, which activates the mitogen-activated protein kinase signaling pathway.2,4,5 Treatment is typically based on BRAF V600E mutation status; vemurafenib (a BRAF inhibitor) has been shown to stabilize or improve disease in patients with this mutation.4,6 In BRAF V600E–negative ECD, emerging data support benefit with cobimetinib, an oral inhibitor of the mitogen-activated protein 1 and 2 (MEK1 and MEK2) genes.6 In this patient, the BRAF V600E mutation was technically negative on decalcified long-bone biopsy, but there was concern about a false-negative result (because a nondecalcified specimen was not put aside for genetic analysis). The patient chose an empirical trial of vemurafenib, but empirical treatment with MEK1 and MEK2 inhibition would also have been reasonable, because empirical BRAF inhibition may worsen some cases of Ras-mutated BRAF-negative ECD. At 6 weeks of vemurafenib, his brain MRI exhibited marked improvement, with near resolution of abnormal findings (Figure 2) and gradual clinical improvement, supporting that his ECD was most likely BRAF V600E positive.A brain coronal T1 postgadolinium magnetic resonance image showing substantially improved enhancing mass in the brainstem.

Neurology

A 53-year-old man developed patchy numbness in his right arm. The numbness progressed over 10 months to involve his entire right arm, patches of his left arm, and his distal lower extremities. He also developed right-hand incoordination and imbalance. A magnetic resonance image (MRI) of the brain is shown in Figure 1A. A complete blood cell count with a differential; liver function testing; tests for HIV, rapid plasma reagin, serum aquaporin-4 antibody, and antinuclear antibodies; and levels of sodium, calcium, creatinine, glucose, thyroxine, and vitamin B12 were unremarkable. Examinations of the cerebrospinal fluid had normal results twice, including for white blood cell count with a differential, glucose level, total protein level, IgG index, oligoclonal bands, cultures, and cytology testing.A, A brain coronal T1 postgadolinium magnetic resonance image (MRI), showing a lobulated heterogeneously enhancing mass in the brainstem and dural enhancement. B, A brain coronal T1 postgadolinium MRI from 10 months later with persistent yet evolving enhancement and mild size increase in brainstem lesion and ongoing dural enhancement.He sought neurological reconsultation 9 months later, reporting progressive blurred vision bilaterally, dysphagia, dysarthria, and urinary and bowel urgency. His gait had worsened, requiring a cane and, for 6 months, a walker. A physical examination was otherwise unremarkable, except for mild lower-extremity edema. A neurologic examination revealed decreased visual acuity (20/50 OU) with normal pupillary responses and discs; cerebellar dysarthria, dysmetria, and dysdiadochokinesia; and decreased proprioception in the toes with positive Romberg testing. He could not tandem walk. A follow-up brain MRI (Figure 1B) showed persistent enhancement plus bilateral optic nerve enhancement (not shown). Computed tomography of the chest, abdomen, and pelvis revealed infiltrative soft tissue in the pericardium and intra-atrial septum and throughout the retroperitoneum.Acute disseminated encephalomyelitis associated with myelin oligodendrocyte glycoprotein antibody

what is your diagnosis?

What is your diagnosis?

Sarcoidosis

Diffuse large B-cell lymphoma

Erdheim-Chester disease

Acute disseminated encephalomyelitis associated with myelin oligodendrocyte glycoprotein antibody

c

male

51-60

White

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2751312

A man in his late 50s with a history of remote coronary artery bypass grafting presented with unstable angina and underwent percutaneous coronary intervention with a drug-eluting stent. He was discharged and prescribed ticagrelor, 90 mg twice daily, in addition to his home regimen of aspirin and metoprolol tartrate. Three months later, he experienced worsening exertional dyspnea and had multiple episodes of syncope. He had no history of syncopal episodes or arrhythmias. His baseline transthoracic echocardiogram results demonstrated normal systolic function and no significant valvular disease. Ambulatory electrocardiogram (ECG) monitoring results showed 31 episodes of high-grade atrioventricular (AV) block (AVB), with ventricular pauses ranging from 3.0 to 13.0 seconds occurring during the day and at night (Figure 1). Among them, 4 episodes were associated with presyncope.Discontinue metoprolol tartrate and repeat the ambulatory ECG What Would You Do Next?

Implant a permanent pacemaker

Discontinue metoprolol tartrate and repeat the ambulatory ECG

Administer oral theophylline

Switch ticagrelor to clopidogrel

Ticagrelor-induced bradyarrhythmia

D

Switch ticagrelor to clopidogrel

The key to the correct diagnosis is in the detailed analysis of the ECG rhythm strip, which elucidates a plausible mechanism of bradyarrhythmia in this case. The initial part of the rhythm demonstrates normal P and QRS wave morphologies with normal intervals, followed by a simultaneous prolongation of the P-P and P-R intervals manifesting as sinus bradycardia and AVB with a 10-second pause (Figure 2). The pause leads to junctional and ventricular escape beats followed by a resumption of a normal sinus rhythm and AV nodal (AVN) conduction. This pattern is a result of the transient suppression of sinus node (SN) activity and AVN conduction. Such a phenomenon usually suggests a sudden increase in parasympathetic activity or vagal tone because SN and AVN are innervated by vagal efferent fibers rather than structural abnormalities of SN and AVN.1,2On the labeled electrocardiogram monitor strip, the initial part of the rhythm demonstrates normal P and QRS wave morphologies with normal intervals, followed by a simultaneous prolongation of the P-P and the P-R interval manifesting as sinus bradycardia and atrioventricular block with a 10-second pause. The pause leads to junctional and ventricular escape beats that are followed by a resumption of a normal sinus rhythm and atrioventricular (AV) nodal conduction.Ticagrelor was the only new medication added to his metoprolol tartrate, which he had taken safely for several years. Therefore, metoprolol-induced conduction suppression was excluded and ticagrelor-induced bradyarrhythmia was strongly suspected. All symptoms resolved spontaneously after switching from ticagrelor to clopidogrel and a repeated ambulatory ECG monitoring was unremarkable and without further evidence for the persistent bradyarrhythmias. Ticagrelor is an oral, reversible direct-acting inhibitor of the adenosine diphosphate receptor that provides a more potent and consistent inhibition of platelet aggregation than clopidogrel. In patients with acute coronary syndrome, the Platelet Inhibition and Patient Outcomes (PLATO) trial demonstrated that ticagrelor was superior to clopidogrel in reducing mortality, myocardial infarction, and stroke.3 The PLATO trial also showed that treatment with ticagrelor compared with clopidogrel was more likely to cause ventricular pauses in the first 7 days but not at day 30.3,4 Such pauses were mostly asymptomatic and there was no difference in the incidence of syncope and the need for a permanent pacemaker between the 2 groups. Yurtdas et al5 summarized 9 case reports of ticagrelor-induced bradyarrhythmia, and these patients had preexisting first degree AVB or bundle branch block with concurrent use of AVN-blocking agents. Almost all cases of ticagrelor-induced bradyarrhythmia occurred within the first few days after administering ticagrelor except for 1 patient who presented with Mobitz type II AVB 6 months after taking ticagrelor.5 After switching to clopidogrel, the bradyarrhythmias spontaneously resolved, with the exception of 1 patient who required a permanent pacemaker.5The mechanism of ticagrelor-induced bradyarrhythmia is not well understood, but the most commonly accepted pathophysiologic mechanism is that ticagrelor increases plasma adenosine concentrations by inhibiting adenosine reuptake through the sodium-independent equilibrating nucleoside transporters on erythrocytes.4,6 The increased plasma adenosine concentration can suppress SN activity and AVN conduction, leading to sinus pause and/or AVB. Although ticagrelor is now widely used, ticagrelor-induced bradyarrhythmia is uncommon and not well recognized by cardiologists. Therefore, these patients might undergo unnecessary pacemaker implants. In establishing the diagnosis of ticagrelor-induced bradyarrhythmia, it is important to recognize clues in the ECG rhythm strip, such as simultaneous suppressions of SN activity and AVN conduction. Finally, the appropriate treatment of ticagrelor-induced bradyarrhythmia is switching to an alternative antiplatelet medication, not pacemaker implantation.At 2 years’ follow-up, the patient has been doing very well, with no further recurrence of the presyncope or syncope. In addition, he did not have hospitalizations due to heart failure an recurrent chest pain after switching to clopidogrel.

Cardiology

A man in his late 50s with a history of remote coronary artery bypass grafting presented with unstable angina and underwent percutaneous coronary intervention with a drug-eluting stent. He was discharged and prescribed ticagrelor, 90 mg twice daily, in addition to his home regimen of aspirin and metoprolol tartrate. Three months later, he experienced worsening exertional dyspnea and had multiple episodes of syncope. He had no history of syncopal episodes or arrhythmias. His baseline transthoracic echocardiogram results demonstrated normal systolic function and no significant valvular disease. Ambulatory electrocardiogram (ECG) monitoring results showed 31 episodes of high-grade atrioventricular (AV) block (AVB), with ventricular pauses ranging from 3.0 to 13.0 seconds occurring during the day and at night (Figure 1). Among them, 4 episodes were associated with presyncope.Discontinue metoprolol tartrate and repeat the ambulatory ECG

what would you do next?

What would you do next?

Discontinue metoprolol tartrate and repeat the ambulatory ECG

Switch ticagrelor to clopidogrel

Administer oral theophylline

Implant a permanent pacemaker

b

male

51-60

original

https://jamanetwork.com/journals/jamaotolaryngology/fullarticle/2751950

An 11-day-old boy with 22q11.2 deletion syndrome, tetralogy of Fallot, and unilateral renal agenesis presented with a right neck mass and intermittent inspiratory stridor present at birth. The patient did not require positive pressure or intubation, but he had intermittent stridor associated with desaturations. He had feeding difficulty and failure to thrive. On physical examination, the newborn had facial dysmorphism, including a broad and flat nasal dorsum and mild micrognathia. Flexible fiberoptic laryngoscopy revealed a cystic lesion consistent with a vallecular cyst. A modified barium swallow study demonstrated laryngeal penetration and aspiration of thin and nectar-thick liquids. A diffuse, soft, palpable mass was present along the right neck.Magnetic resonance imaging (MRI) demonstrated a multispatial mildly enhancing mass within the bilateral retropharyngeal, parapharyngeal, and carotid spaces, with a mildly hyperintense signal relative to muscle on T1-weighted and T2-weighted images and associated restricted diffusion. The mass was largest on the right side, with convex borders, mild superior displacement of the right parotid gland, and posterior displacement of the right sternocleidomastoid muscle (Figure, A, B). The T2-weighted MRI also demonstrated a hyperintense, nonenhancing lesion within the base of the tongue consistent with a vallecular cyst. The thyroid appeared normal and in its expected location, but no thymus was present in the mediastinum. The patient was taken to the operating room for excision of the vallecular cyst, and a fine-needle aspiration biopsy of the right neck mass was performed for cytopathological analysis (Figure, C, D).A, Axial magnetic resonance image (MRI) of the neck shows a mildly hyperintense mass (arrowheads) with posterior displacement of the right sternocleidomastoid muscle. B, Axial fat-saturated MRI shows the mass (arrowheads), with encasement of the left internal and external carotid arteries. C, Biopsy results reveal a polymorphic population of lymphocytes, fibroadipose tissue, and a concentric island of squamous cells with central keratinization (arrowhead). D, Reference specimen from a study set of the tissue shown in panel C demonstrates islands of squamous cells in a background of small mature lymphocytes (hematoxylin-eosin). What Is Your Diagnosis?

Lipoma

Branchial cleft cyst

Ectopic thymus

Rhabdomyosarcoma

C. Ectopic thymus

C

Ectopic thymus

The biopsy results of the mass in this newborn with 22q11.2 deletion syndrome were consistent with ectopic thymic tissue. Cytopathologic findings demonstrated features consistent with normal thymic tissue: a polymorphic population of lymphocytes, fibroadipose tissue, and Hassall corpuscles (eosinophilic concentric islands of squamous cells with central keratinization). A cervical ectopic thymus is typically located deep within the neck and is not palpable; these lesions are commonly incidental and asymptomatic. The infant’s palpable neck mass was therefore an unusual presentation of an ectopic thymus, although this presentation has been documented in case reports.1,2In an infant, ectopic thymus usually appears similar to normal thymus tissue in terms of imaging characteristics, with a mildly hyperintense signal relative to muscle on T1-weighted and T2-weighted images. When there is a mediastinal thymus, continuity can usually be demonstrated by MRI; the diagnosis is often made without the need for a biopsy. However, this patient had no mediastinal thymic tissue. Low apparent diffusion coefficient values have been described with ectopic thymus tissue,1,2 but the degree to which diffusion restriction can be seen with malignant processes and convex masslike features prompted us to perform a fine-needle aspiration of the neck mass during the vallecular cyst excision.The incidence of 22q11.2 deletion syndrome is approximately 1 in 4000 to 6000 newborns, and it is inherited in an autosomal dominant manner, although 93% of probands have a de novo deletion.3 Various phenotypes of 22q11.2 deletion syndrome include DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome. Classic features include T-cell deficiency secondary to thymic hypoplasia, conotruncal cardiac malformations, hypoparathyroidism, learning difficulties, and facial abnormalities.4,5The anomalies attributed to 22q11.2 deletion syndrome are the result of abnormal embryologic development of the third and fourth pharyngeal arches. These arches give rise to certain structures that are classically involved in 22q11.2 deletion syndrome: the great vessels of the heart, parathyroid glands, and thymus. During normal development, the paired thymic primordia descend from the angle of the mandible and fuse together at their final location in the superior mediastinum.6 Disruptions in migration can result in an ectopic thymus, most commonly located in the cervical region or mediastinum. However, ectopic tissue can occur anywhere along this path of descent and has even been discovered within the thyroid itself.7Complete absence of the thymus occurs in less than 1% of patients with 22q11.2 deletion syndrome.8 Complete athymia is fatal within the first year of life unless treated with immunologic reconstitution either through thymic or hematopoietic stem cell transplant. More commonly, there is deficiency of thymic tissue or ectopic location rather than the absence of thymic tissue. However, thymic size is not a reliable predictor of T-cell counts or immune function, and the immunological phenotype of these patients may range from partial immunodeficiency to completely normal immune function.4,5 In this patient, the immunologic workup revealed low CD4 T-cell counts and normal CD3, CD8, natural killer cell, and B-cell counts.Although this presentation of ectopic thymus was uncommon, the differential diagnosis of a neck mass in patients with 22q11.2 deletion syndrome should include ectopic thymus because these patients are more likely to have an aberrant location of the thymus than to be athymic.9,10 Most ectopic thymic masses are asymptomatic, thus obviating the need for surgical intervention. In this patient, it was initially unclear if the thymic mass or the vallecular cyst was contributing to his stridor and feeding difficulty. However, the patient’s dysphagia and airway obstruction improved after vallecular cyst excision and supraglottoplasty. Four weeks after the procedure, laryngoscopy demonstrated a well-healed upper airway, and no further intervention was required.

General

An 11-day-old boy with 22q11.2 deletion syndrome, tetralogy of Fallot, and unilateral renal agenesis presented with a right neck mass and intermittent inspiratory stridor present at birth. The patient did not require positive pressure or intubation, but he had intermittent stridor associated with desaturations. He had feeding difficulty and failure to thrive. On physical examination, the newborn had facial dysmorphism, including a broad and flat nasal dorsum and mild micrognathia. Flexible fiberoptic laryngoscopy revealed a cystic lesion consistent with a vallecular cyst. A modified barium swallow study demonstrated laryngeal penetration and aspiration of thin and nectar-thick liquids. A diffuse, soft, palpable mass was present along the right neck.Magnetic resonance imaging (MRI) demonstrated a multispatial mildly enhancing mass within the bilateral retropharyngeal, parapharyngeal, and carotid spaces, with a mildly hyperintense signal relative to muscle on T1-weighted and T2-weighted images and associated restricted diffusion. The mass was largest on the right side, with convex borders, mild superior displacement of the right parotid gland, and posterior displacement of the right sternocleidomastoid muscle (Figure, A, B). The T2-weighted MRI also demonstrated a hyperintense, nonenhancing lesion within the base of the tongue consistent with a vallecular cyst. The thyroid appeared normal and in its expected location, but no thymus was present in the mediastinum. The patient was taken to the operating room for excision of the vallecular cyst, and a fine-needle aspiration biopsy of the right neck mass was performed for cytopathological analysis (Figure, C, D).A, Axial magnetic resonance image (MRI) of the neck shows a mildly hyperintense mass (arrowheads) with posterior displacement of the right sternocleidomastoid muscle. B, Axial fat-saturated MRI shows the mass (arrowheads), with encasement of the left internal and external carotid arteries. C, Biopsy results reveal a polymorphic population of lymphocytes, fibroadipose tissue, and a concentric island of squamous cells with central keratinization (arrowhead). D, Reference specimen from a study set of the tissue shown in panel C demonstrates islands of squamous cells in a background of small mature lymphocytes (hematoxylin-eosin).

what is your diagnosis?

What is your diagnosis?

Rhabdomyosarcoma

Branchial cleft cyst

Lipoma

Ectopic thymus

d

male

0-10

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2749090

A 33-year-old otherwise healthy black woman presented to the emergency department for evaluation of blurry vision in both eyes. She had no relevant medical, family, or ocular history. There was no history of trauma or ocular surgery. One month prior to presentation, she had developed fevers, chills, and coughing. After several days, she had developed redness, pain, photophobia, and blurry vision in her left eye, and she had subsequently developed similar symptoms in her right eye. On presentation, her visual acuity was counting fingers OU. Intraocular pressures were 14 mm Hg OU. A slitlamp examination revealed mild conjunctival redness, 2+ anterior chamber cell, and flare in both eyes, as well as mild posterior synechiae. The cornea was clear without keratic precipitates, and there were no iris nodules. Pigment was present on the anterior lens capsule. A fundus examination demonstrated a moderate amount of vitreous cell, hyperemia and edema of the optic disc, and retinal detachments in both eyes (Figure). The detachments were inferior and shifted with the patient’s head position, suggesting serous detachments. Findings were similar bilaterally. A B-scan ultrasonographic test demonstrated bullous retinal detachments and diffusely thickened choroid.Fundus photograph of the left eye, demonstrating optic disc edema (arrowhead) and retinal detachment (asterisk).Quantiferon and rapid plasma reagin tests and chest radiographyA pars plana vitrectomy with a chorioretinal biopsy What Would You Do Next?

Intravitreal triamcinolone

Quantiferon and rapid plasma reagin tests and chest radiography

Human leukocyte antigen genotyping

A pars plana vitrectomy with a chorioretinal biopsy

Vogt-Koyanagi-Harada disease

B

Quantiferon and rapid plasma reagin tests and chest radiography

The patient underwent a systemic workup, including chest radiography and serum testing for quantiferon gold and rapid plasma reagin (choice B) as well as treponemal antibodies, which were all unremarkable. Given the negative results of the workup, the patient’s presentation was consistent with probable Vogt-Koyanagi-Harada (VKH) disease.Intravitreal triamcinolone injections (choice A) would not be the preferred next step because, while VKH disease is most likely, it is important to rule out infectious causes of panuveitis first, especially prior to local steroid treatments. Furthermore, systemic and not intravitreal steroids would be the preferred route.1Human leukocyte antigen genotyping (choice C) is not the best next step because diagnosis of VKH disease is clinical. Vogt-Koyanagi-Harada disease is associated with HLA-DR4 in Japanese patients2 and HLA-DR4 and HLA-DQ4 in Hispanic patients,3 but associations in black individuals have not been described, and the genotyping utility in this patient would therefore be unclear.Diagnostic pars plana vitrectomy with chorioretinal biopsy (choice D) would not be the best next step, because while intraocular lymphoma remains on the differential diagnosis, lymphoma is typically more insidious in onset, with suggestive retinal or vitreous lesions.4 An evaluation for lymphoma would begin with vitreous sampling and cytologic analysis. Chorioretinal biopsy may be indicated only after inconclusive testing results.Vogt-Koyanagi-Harada disease is rare and characterized by chronic bilateral panuveitis with characteristic systemic manifestations. The condition typically affects those of Asian, Hispanic, and Middle Eastern descent and is rare among white and black patients. In the prodromal stage of VKH disease, flulike symptoms predominate, followed by the acute uveitic stage, which involves a bilateral granulomatous panuveitis, including choroidal thickening, hyperemia and edema of the optic nerve, and serous retinal detachments. A convalescent phase characterized by progressive choroidal depigmentation follows over the ensuing weeks to months. The patient may experience periodic granulomatous choroiditis in the recurrent stage.A differential diagnosis may include lupus choroidopathy, posterior scleritis, intraocular lymphoma, and ocular Lyme disease, in addition to tuberculosis and syphilis. However, a diagnosis of VKH disease is clinical, guided by the revised diagnostic criteria for VKH disease.5 A probable case of VKH disease is suggested by examination (with findings of bilateral disease, diffuse choroiditis, and serous retinal detachments) with an absence of surgical or traumatic history. Integumentary and neurological findings would further support the diagnosis. The ocular and systemic findings are explained by the proposed mechanism, which involves a T-lymphocyte–mediated reaction against melanocyte-associated antigens.6,7In the acute stage, fluorescein angiography may show irregular focal or patchy hyperfluorescence of the choroidal circulation. Optical coherence tomography may show subretinal fluid with choroidal thickening. Ultrasonography can show diffuse choroidal thickening, serous retinal detachments, and vitreous opacities.Treatment during the acute phase is often with high-dose intravenous corticosteroids and subsequent oral corticosteroids. Azathioprine or cyclosporine is commonly used for maintenance therapy. Treatment for less than 6 months may be more likely to lead to recurrences than a treatment duration longer than 6 months (58.5% vs 11.1%, according to one study8). A favorable visual prognosis is associated with initial visual acuity, improvement of visual acuity at 1 month, younger age, and earlier treatment.9The patient started treatment with high-dose oral prednisone with a 6-month taper, as well as long-term methotrexate. The inflammation and subretinal fluid gradually resolved, and her visual acuity at the latest visit, 8 months after presentation, was 20/40 OD and 20/25 OS.

Ophthalmology

A 33-year-old otherwise healthy black woman presented to the emergency department for evaluation of blurry vision in both eyes. She had no relevant medical, family, or ocular history. There was no history of trauma or ocular surgery. One month prior to presentation, she had developed fevers, chills, and coughing. After several days, she had developed redness, pain, photophobia, and blurry vision in her left eye, and she had subsequently developed similar symptoms in her right eye. On presentation, her visual acuity was counting fingers OU. Intraocular pressures were 14 mm Hg OU. A slitlamp examination revealed mild conjunctival redness, 2+ anterior chamber cell, and flare in both eyes, as well as mild posterior synechiae. The cornea was clear without keratic precipitates, and there were no iris nodules. Pigment was present on the anterior lens capsule. A fundus examination demonstrated a moderate amount of vitreous cell, hyperemia and edema of the optic disc, and retinal detachments in both eyes (Figure). The detachments were inferior and shifted with the patient’s head position, suggesting serous detachments. Findings were similar bilaterally. A B-scan ultrasonographic test demonstrated bullous retinal detachments and diffusely thickened choroid.Fundus photograph of the left eye, demonstrating optic disc edema (arrowhead) and retinal detachment (asterisk).Quantiferon and rapid plasma reagin tests and chest radiographyA pars plana vitrectomy with a chorioretinal biopsy

what would you do next?

What would you do next?

Quantiferon and rapid plasma reagin tests and chest radiography

Intravitreal triamcinolone

Human leukocyte antigen genotyping

A pars plana vitrectomy with a chorioretinal biopsy

a

female

31-40

Black

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2749326

An adolescent boy presented to the hospital with bilateral eye redness, an erythematous chest rash, lip blistering, and worsening sore throat for 2 days while undergoing a 10-day outpatient treatment course of ciprofloxacin and trimethoprim-sulfamethoxazole for community-acquired pneumonia. He complained of a cough, sore throat, and ocular itching. He denied prior ocular history and reported no visual changes. He had no significant medical history aside from documented allergies to β-lactam, macrolide, and cephalosporin antibiotics resulting in rashes, angioedema, and hives.The patient was febrile on admission, and results from chest radiography were consistent with pneumonia. Bedside ophthalmic examination revealed bilateral limbus-sparing conjunctival hyperemia that blanched minimally with phenylephrine, bilateral nasal and temporal conjunctival epithelial ulcerations, and inferior forniceal pseudomembranes (Figure, A). There were no symblephara or eyelid margin defects. Examination of the face revealed erosions with hemorrhagic crusts on the lip mucosa (Figure, B) but no associated cutaneous lesions or desquamation. Findings from the remainder of the ophthalmologic examination, including visual acuity, intraocular pressure, and dilated fundus examination, were unremarkable. Mycoplasma pneumoniae IgG and IgM titers were obtained and found to be within normal limits.A, Peripheral conjunctival ulceration. Inset, peripheral conjunctival ulceration highlighted with fluorescein under cobalt blue light. B, Hemorrhagic crusting of lip mucosa.Initiate course of topical ophthalmic antibiotics and corticosteroidsDiscontinue antibiotics and avoid all medications associated with Stevens-Johnson syndrome What Would You Do Next?

Recommend systemic corticosteroids

Initiate course of topical ophthalmic antibiotics and corticosteroids

Perform amniotic membrane transplantation

Discontinue antibiotics and avoid all medications associated with Stevens-Johnson syndrome

Mycoplasma pneumoniae–induced rash and mucositis

B

Initiate course of topical ophthalmic antibiotics and corticosteroids

The leading diagnosis was pneumonia due to M pneumoniae, and the patient’s antibiotic regimen was switched to doxycycline and clindamycin. Given this patient’s presentation with mucosal erosions in the setting of pneumonia, his younger age, and evanescent mild skin involvement, a diagnosis of M pneumoniae–induced rash and mucositis (MIRM) was favored over M pneumoniae–induced Stevens-Johnson syndrome (SJS), which can have a similar presentation but is characterized by more severe mucocutaneous involvement.Because of the favorable prognosis of MIRM and its associated ocular manifestations,1 initiation of topical ophthalmic therapy consisting of antibiotic prophylaxis and mild corticosteroids (choice B) is the first recommended course. Systemic corticosteroids (choice A) are not recommended as the next step because the patient had a mild presentation and did not exhibit persistent conjunctivitis despite topical therapy. Amniotic membrane transplantation (choice C) is not recommended because it is an aggressive treatment reserved for cases of biopsy-proven or highly suspected SJS; this treatment carries substantial (albeit temporary) morbidity in conscious patients, given the reduction of vision due to amniotic membranes overlying the cornea and discomfort caused by symblepharon rings in the fornices.2 Antibiotic cessation (choice D) would not be the preferred answer because although drug-induced SJS or toxic epidermal necrolysis was on the differential diagnosis, given the patient’s medication allergies, the lack of characteristic skin sloughing argued against this diagnosis.2,3M pneumoniae immunoglobulin measurements were within normal limits on admission (IgM, <0.90 optical density; IgG, 513 U/mL), but repeated testing 3 weeks later confirmed the diagnosis (IgM, 3.09 optical density; IgG, 6525 U/mL), as occurs in 30% to 60% of children, given the delayed peak time of M pneumoniae IgG and IgM.4,5M pneumoniae is a common culprit among atypical pathogens causing pneumonia in children and adolescents, especially during the spring and autumn, and should be considered even with initially negative serologies.M pneumoniae–induced rash and mucositis was first described and distinguished from SJS in 2015.1 Both conditions may present with mucocutaneous eruptions following an infection with M pneumoniae, but MIRM remains predominantly mucosal with limited (if any) cutaneous involvement. Commonly involved sites are oral (94%), ocular (82%), and genital (63%) mucosa. Presentations characterized by eruptions isolated to the mucosa were previously termed incomplete SJS or Fuchs syndrome.1M pneumoniae–induced rash and mucositis most often presents in young boys and adolescents and has an excellent prognosis compared with SJS.1 Ocular findings include bilateral conjunctivitis and, less often, corneal ulceration, photophobia, and eyelid edema that typically resolve without sequelae.1,6-8 Conversely, SJS can have severe sequelae, including ocular surface sloughing and blindness.2To our knowledge, no evidence-based treatment guidelines for MIRM currently exist; however, topical antibiotic and steroid therapies combined with ocular surface lubrication are usually sufficient to allow for full resolution.1,6-9 In contrast to SJS or toxic epidermal necrolysis, amniotic membrane transplantation appears to be unnecessary.2This case illustrates recognizing MIRM as a distinct entity from M pneumoniae–induced SJS. Confidence in the diagnosis might avert measures such as amniotic membrane transplantation, which, although sight saving, might carry clinically relevant morbidity, especially in pediatric patients.The patient’s conjunctival ulcerations resolved 3 days after initiation of therapy; on discharge from hospital, antibiotic eyedrops were discontinued, and the corticosteroid ointment was gradually tapered. Oral mucosal and lung findings resolved over the following 2 weeks, and he was referred to the allergy and immunology clinic for follow-up.

Ophthalmology

An adolescent boy presented to the hospital with bilateral eye redness, an erythematous chest rash, lip blistering, and worsening sore throat for 2 days while undergoing a 10-day outpatient treatment course of ciprofloxacin and trimethoprim-sulfamethoxazole for community-acquired pneumonia. He complained of a cough, sore throat, and ocular itching. He denied prior ocular history and reported no visual changes. He had no significant medical history aside from documented allergies to β-lactam, macrolide, and cephalosporin antibiotics resulting in rashes, angioedema, and hives.The patient was febrile on admission, and results from chest radiography were consistent with pneumonia. Bedside ophthalmic examination revealed bilateral limbus-sparing conjunctival hyperemia that blanched minimally with phenylephrine, bilateral nasal and temporal conjunctival epithelial ulcerations, and inferior forniceal pseudomembranes (Figure, A). There were no symblephara or eyelid margin defects. Examination of the face revealed erosions with hemorrhagic crusts on the lip mucosa (Figure, B) but no associated cutaneous lesions or desquamation. Findings from the remainder of the ophthalmologic examination, including visual acuity, intraocular pressure, and dilated fundus examination, were unremarkable. Mycoplasma pneumoniae IgG and IgM titers were obtained and found to be within normal limits.A, Peripheral conjunctival ulceration. Inset, peripheral conjunctival ulceration highlighted with fluorescein under cobalt blue light. B, Hemorrhagic crusting of lip mucosa.Initiate course of topical ophthalmic antibiotics and corticosteroidsDiscontinue antibiotics and avoid all medications associated with Stevens-Johnson syndrome

what would you do next?

What would you do next?

Discontinue antibiotics and avoid all medications associated with Stevens-Johnson syndrome

Perform amniotic membrane transplantation

Initiate course of topical ophthalmic antibiotics and corticosteroids

Recommend systemic corticosteroids

c

male

11-20

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2751322

A 38-year-old man was referred to the medical retina service for evaluation of bilateral macular lesions noted by his general ophthalmologist. Medical history was otherwise unremarkable. On examination, his best-corrected visual acuity was 20/20 OU, although his vision was slightly eccentric. His pupils were round and reactive. The slitlamp examination of the anterior segment was unremarkable. Dilated fundus examination revealed subtle bilateral yellow foveal spots. Optical coherence tomography (OCT) displayed the presence of a bilateral foveal defect of the external limiting membrane and ellipsoid zone bands (Figure).Infrared (inset image) and spectral-domain optical coherence tomography (main image) of the right (A) and left eye (B) showing a focal interruption of the foveal photoreceptors.Prescribe laboratory testing to investigate causes of intraocular inflammationObtain an in-depth medical and personal history, including drug history What Would You Do Next?

Prescribe laboratory testing to investigate causes of intraocular inflammation

Perform dye angiography

Obtain an in-depth medical and personal history, including drug history

Treat patient with antiviral drugs

Poppers maculopathy

C

Obtain an in-depth medical and personal history, including drug history

Poppers is a term for the chemical class of alkyl nitrites, which are inhaled for recreational drug purposes, typically for the high or rush that the drug may produce. Poppers have also been historically used by men who have sex with men for their ability to relax the anal sphincter. Although poppers are illegal, they can be purchased in some countries as alternative products, which include room deodorizers or video head cleaners.1 The use of poppers is thought to be high and ranges between 5% to 6% in French teenagers2 and up to 10% of adults in the United Kingdom.1 However, their use may be higher in certain groups and is estimated to be about 60% in Australia’s gay community.3While the exact mechanism causing damage of the central photoreceptors is still uncertain, Brat el al4 suggested that alkyl nitrites may cause an increase in nitric oxide. Nitric oxide exposure is known to raise intracellular cyclic guanosine monophosphate levels, eventually causing photoreceptor apoptosis.A possible association between the use of poppers and maculopathy was first proposed in 2004.5 After this first description, several reports have characterized this clinical entity.2,4,6-8 In detail, ophthalmoscopy findings can be very subtle, with more striking changes seen on OCT, which may show either a hyperreflective or hyporeflective ellipsoid zone band. Although OCT changes associated with poppers maculopathy have been thus characterized, these alterations are not specific for this maculopathy. As an example, solar maculopathy may be characterized by similar changes at the fovea.9 Furthermore, similar foveal abnormalities may occur after blunt ocular trauma and whiplash injury.10 For these reasons, when a patient presents with a localized alteration of the foveal photoreceptors, a focused drug history of the patient is mandatory. Nonetheless, the diagnosis can be complicated by patient denial of popper use. Noteworthy, the use of poppers was suggested to produce a dose-related increase in photoreceptor damage, with individuals with long-term regular use showing most severe macular alterations.1The relatively easy availability of poppers has increased their popularity as recreational drugs. Lesions occurring in poppers maculopathy are frequently permanent and may be associated with a substantial effect on vision. This case highlights the importance of obtaining an in-depth medical and personal history of patients presenting with a focal damage of the foveal photoreceptors. In this case, the patient revealed his recreational use of different drugs, including poppers, cannabis, and cocaine, for approximately 15 years.Prescribing laboratory testing to investigate causes of intraocular inflammation (choice A) would not be preferred because a bilateral foveal photoreceptor loss is an uncommon presentation for uveitis, especially in a patient without other ocular signs of inflammation. A dye angiography (choice B) was not recommended as the next step because no other retinal and/or choroidal alterations were evident on spectral-domain OCT images. Treating the patient with antiviral drugs (choice D) would not be the next recommended step because of the absence of a viral infection.The patient was extensively informed about his condition and the prognosis. Moreover, he was screened for HIV, as many patients with poppers maculopathy were reported to be affected by this infection,1 and the result was negative. Importantly, he was advised to discontinue the use of poppers and to follow up with a medical retina specialist. His vision and foveal lesions remained stable throughout the 1-year follow-up.

Ophthalmology

A 38-year-old man was referred to the medical retina service for evaluation of bilateral macular lesions noted by his general ophthalmologist. Medical history was otherwise unremarkable. On examination, his best-corrected visual acuity was 20/20 OU, although his vision was slightly eccentric. His pupils were round and reactive. The slitlamp examination of the anterior segment was unremarkable. Dilated fundus examination revealed subtle bilateral yellow foveal spots. Optical coherence tomography (OCT) displayed the presence of a bilateral foveal defect of the external limiting membrane and ellipsoid zone bands (Figure).Infrared (inset image) and spectral-domain optical coherence tomography (main image) of the right (A) and left eye (B) showing a focal interruption of the foveal photoreceptors.Prescribe laboratory testing to investigate causes of intraocular inflammationObtain an in-depth medical and personal history, including drug history

what would you do next?

What would you do next?

Prescribe laboratory testing to investigate causes of intraocular inflammation

Treat patient with antiviral drugs

Obtain an in-depth medical and personal history, including drug history

Perform dye angiography

c

male

31-40

original

https://jamanetwork.com/journals/jamaophthalmology/fullarticle/2751373

An 18-month-old girl with an unremarkable medical history was referred to ocular oncology from pediatric ophthalmology for an intraocular mass near the optic nerve. Her parents noticed the left eye turning out for the past year. On examination, she fixed and followed with her right eye but not with the left, with 5.0-diopter exophoria at near in the left eye. Penlight examination results showed left leukocoria. Intraocular pressure and motility were normal bilaterally. On subsequent examination under anesthesia, the left optic nerve was obscured by a whitish mass. While the optic nerve itself was obscured, a pigmented crescent could be seen surrounding it (Figure, A). Ultrasonography results demonstrated an elevated retinal mass overlying an excavated optic nerve head. A small focus of hyperechogenicity was noted at the optic nerve head, consistent with calcium (Figure, B). Fluorescein angiography results demonstrated staining of the central whitish mass, which was obscuring the underlying retinal vessels. On fluorescein angiography results, no vessels were seen within the central whitish mass itself.A, Retinal fundus photograph of the left eye demonstrating a whitish mass obscuring the optic nerve with a surrounding pigmented crescent. B, Ultrasonography B-scan of the left eye demonstrating an excavated optic nerve underlying the intraocular mass (arrowheads).Orbital magnetic resonance imaging (MRI) to evaluate for optic nerve invasion and brain MRI to assess for a pineal gland tumor, followed by chemotherapy for the eyeObservation for the eye and MRI and magnetic resonance angiography of the headCareful examination of the skin and genetic testing of genes on chromosomes 9 and 16 What Would You Do Next?

Orbital magnetic resonance imaging (MRI) to evaluate for optic nerve invasion and brain MRI to assess for a pineal gland tumor, followed by chemotherapy for the eye

Observation for the eye and MRI and magnetic resonance angiography of the head

Careful examination of the skin and genetic testing of genes on chromosomes 9 and 16

Enucleation

Morning glory disc anomaly

B

Observation for the eye and MRI and magnetic resonance angiography of the head

The differential diagnosis of a white juxtapapillary mass in a young child includes retinoblastoma, retinal astrocytoma, and glial masses. Retinoblastoma presents as 1 or more retinal masses and is often associated with calcifications and subretinal or vitreous seeds.1 Large vessels generally dive into the tumor and fine intratumoral vessels can be seen. If retinal astrocytoma was suspected, a skin examination for other stigmata of tuberous sclerosis (eg, ash leaf spots and shagreen patches) should be performed. Genetic testing for the TSC1 gene (chromosome 9) and TSC2 gene (chromosome 16) can be informative. However, congenital and acquired astrocytomas present as whitish-gray masses within the retinal nerve fiber layer with fine intratumoral vessels.1 Diagnostic enucleation is indicated for medulloepithelioma, usually found in the ciliary body, for which a biopsy is contraindicated. Primary therapeutic enucleation may be indicated for retinoblastoma invading the optic nerve, for which orbital MRI can be helpful, along with brain MRI to assess for “trilateral” disease with pinealoblastoma. However, this case is most consistent with morning glory disc anomaly (MGDA).Morning glory disc anomaly is characterized by a funnel-shaped excavation in the optic disc with an overlying central glial tuft and surrounding chorioretinal pigmentation. In this case, the optic nerve head itself could not be well visualized because of the relatively large glial tuft that simulated a tumor, but ultrasonography results demonstrated the optic nerve excavation. Retinal vasculature emerging from the disc follows an abnormally straight, radial pattern and arteries and veins are often difficult to distinguish from one another.2 In this case, fluorescein angiography confirmed the absence of intratumoral vessels, as expected, with staining of the central glial tuft.Morning glory disc anomaly often presents with strabismus, leukocoria, or unilateral decreased vision. A visual prognosis of 20/200 to counting fingers is typical. Amblyopia treatment may improve visual acuity, with some patients reaching a visual acuity greater than 20/40.3 Ophthalmic care for patients with MGDA must also include patient education and close monitoring for retinal detachments, as one study found that over 10 years, one-third of patients with MGDA developed a retinal detachment.4Patients with MGDA should be evaluated for associated systemic anomalies. The most common is midline craniofacial defects, including a wide and flat nasal bridge and cleft lip and palate. Other central nervous system associations include basal encephalocele, agenesis of the corpus callosum, and Chiari 1 malformation.5,6 Morning glory disc anomaly is thought to be associated with these conditions through a primary mesenchymal defect, as MGDA is thought to arise from a failure in the development of the posterior sclera and lamina cribrosa.5 Importantly, MGDA is also associated with moyamoya disease, which is characterized by an abnormal narrowing of cerebral vasculature that greatly increases the risk of stroke. Routine monitoring with magnetic resonance angiography (MRA) or cerebral angiography is necessary, as this disease may be progressive.7 Furthermore, moyamoya disease increases the risk for anesthetic complications, so anesthesia should be minimized in these patients.8 For these reasons, the correct course of action for this patient includes MRI/MRA of the head.In summary, the central glial tuft of MGDA may obscure some of the more classic vascular features of the disease and simulate a white mass of the optic nerve head. Patients with MGDA need to be closely followed up by an ophthalmologist to optimize visual acuity and monitor for retinal detachments, and all patients should receive MRI/MRA of the head to evaluate for moyamoya disease or other brain or craniofacial defects.This patient underwent a brain MRI and MRA. The results revealed a Chiari 1 malformation but no moyamoya disease.

Ophthalmology

An 18-month-old girl with an unremarkable medical history was referred to ocular oncology from pediatric ophthalmology for an intraocular mass near the optic nerve. Her parents noticed the left eye turning out for the past year. On examination, she fixed and followed with her right eye but not with the left, with 5.0-diopter exophoria at near in the left eye. Penlight examination results showed left leukocoria. Intraocular pressure and motility were normal bilaterally. On subsequent examination under anesthesia, the left optic nerve was obscured by a whitish mass. While the optic nerve itself was obscured, a pigmented crescent could be seen surrounding it (Figure, A). Ultrasonography results demonstrated an elevated retinal mass overlying an excavated optic nerve head. A small focus of hyperechogenicity was noted at the optic nerve head, consistent with calcium (Figure, B). Fluorescein angiography results demonstrated staining of the central whitish mass, which was obscuring the underlying retinal vessels. On fluorescein angiography results, no vessels were seen within the central whitish mass itself.A, Retinal fundus photograph of the left eye demonstrating a whitish mass obscuring the optic nerve with a surrounding pigmented crescent. B, Ultrasonography B-scan of the left eye demonstrating an excavated optic nerve underlying the intraocular mass (arrowheads).Orbital magnetic resonance imaging (MRI) to evaluate for optic nerve invasion and brain MRI to assess for a pineal gland tumor, followed by chemotherapy for the eyeObservation for the eye and MRI and magnetic resonance angiography of the headCareful examination of the skin and genetic testing of genes on chromosomes 9 and 16

what would you do next?

What would you do next?

Orbital magnetic resonance imaging (MRI) to evaluate for optic nerve invasion and brain MRI to assess for a pineal gland tumor, followed by chemotherapy for the eye

Careful examination of the skin and genetic testing of genes on chromosomes 9 and 16

Enucleation

Observation for the eye and MRI and magnetic resonance angiography of the head

d

female

0-10

original

https://jamanetwork.com/journals/jamaoncology/fullarticle/2751872

A 58-year-old white woman with history of metastatic human papillomavirus–positive cervical adenocarcinoma presented with multiple joint deformities. Her initial symptoms started 1 month after the initiation of nivolumab, which was 1 year prior to the index visit. Treatment with nonsteroidal anti-inflammatory drugs failed, and the patient had a partial response to intra-articular steroids. She refused systemic therapies owing to concern about diminishing the effectiveness of nivolumab. Despite the joint symptoms, nivolumab treatment was continued for a year. Evaluation showed fixed swan neck deformities in multiple fingers (Figure, A). There was evidence of chronic synovial hypertrophy with no active synovitis on examination. The results of a comprehensive autoantibody blood panel, including antinuclear antibody, rheumatoid factor, and anti-citrullinated peptide antibody, were unremarkable. Plain radiographs of the hands demonstrated diffuse osteopenia, joint space narrowing, and multiple deformities. Magnetic resonance imaging of both hands revealed multifocal osseous erosions (Figure, B), synovitis, and tenosynovitis.Erosive deforming inflammatory arthritis. A, Fixed swan neck deformities in multiple fingers (arrowheads). B, Magnetic resonance images of both hands reveal multifocal osseous erosions (arrowheads). What Is Your Diagnosis?

Erosive osteoarthritis

Metastatic bone disease

Nivolumab-induced inflammatory arthritis

Seronegative rheumatoid arthritis

C. Nivolumab-induced inflammatory arthritis

C

Nivolumab-induced inflammatory arthritis

Nivolumab is a fully human monoclonal antibody that selectively binds to the programmed cell death 1 (PD-1) receptor on T cells and blocks the interaction with programed cell death ligand 1 (PD-L1) and PD-L2, resulting in T-cell activation and proliferation.1 The enhanced immune response associated with nivolumab improves antitumor immunity; however, it is also associated with various immune-related adverse events (irAEs). Based on pooled data from clinical trials of nivolumab, the most common irAE was skin related. Gastrointestinal, hepatic, and endocrine systems were among the other systems that were affected.1Inflammatory arthritis is a reported irAE associated with nivolumab, with a prevalence of approximately 2%.2 Most patients (65%) present with polyarticular inflammatory arthritis with involvement of small and/or large joints.2 Many of these patients do not develop autoantibodies like rheumatoid factor or anti-citrullinated peptide antibody and are thus seronegative. In a cohort of 9 patients who developed arthritis during nivolumab therapy, 5 patients progressed to polyarticular arthritis resembling rheumatoid arthritis, without any evidence of autoantibodies or notable bone erosions. These patients required a much higher dose of systemic steroids than those without polyarticular arthritis, and the arthritis persisted for several months after stopping nivolumab.3 In another case series, the authors described patients who developed seropositive rheumatoid arthritis shortly after receiving nivolumab, raising the concern that nivolumab may unmask underlying autoimmunity.4 In 1 report, a patient developed deforming arthritis during nivolumab therapy; however, imaging did not reveal erosions or joint damage.5The American Society of Clinical Oncology recommends a high index of suspicion for irAEs with any new symptoms after initiation of immune checkpoint inhibitors (ICIs).6 Timely referral to a rheumatologist is recommended. Immune checkpoint inhibitor therapy may be continued with close monitoring for grade 1 toxic effects except in the setting of some neurologic, hematologic, and cardiac toxic effects. However, ICIs should be withheld in patients with grade 2 or higher toxic effects, and systemic corticosteroid therapy should be added, with a slow taper as needed. In patients who are unable to taper prednisone, disease-modifying antirheumatic drugs may be offered, with methotrexate, leflunomide, or a tumor necrosis factor inhibitor as potential options.6There may be some concern about whether steroids affect the efficacy of ICIs;7 however, in a large cohort study in which steroids were used to treat irAEs, steroid use did not appear to affect progression-free survival.8 Conventional disease-modifying antirheumatic drugs (eg, methotrexate) and tumor necrosis factor inhibitors used for ICI-related irAEs also did not appear to affect the overall response rate or survival outcome.9,10 These studies are reassuring and suggest that early and appropriate management of arthritis may be possible without affecting the antitumor response of ICIs.Herein, we describe a patient with partially treated, seronegative inflammatory erosive arthritis that developed after the use of nivolumab. This is the first case, to our knowledge, of inflammatory arthritis associated with nivolumab that led to profound, irreversible joint damage. In this patient, nivolumab was continued for a year despite the ongoing inflammatory arthritis, which was partially treated.In the setting of inflammatory arthritis associated with ICIs, if the arthritis is not adequately treated, it could lead to erosive and deforming arthritis, underscoring the need for early recognition and appropriate management to prevent such deforming joint damage. Persistent subclinical inflammation was evident on magnetic resonance imaging even after discontinuation of nivolumab therapy. We recommend having a thorough discussion with patients about the potential risks vs benefits of various antirheumatic drugs for adequate treatment of arthritis to prevent significant joint damage, long-term morbidity, and implications for antitumor response.

Oncology

A 58-year-old white woman with history of metastatic human papillomavirus–positive cervical adenocarcinoma presented with multiple joint deformities. Her initial symptoms started 1 month after the initiation of nivolumab, which was 1 year prior to the index visit. Treatment with nonsteroidal anti-inflammatory drugs failed, and the patient had a partial response to intra-articular steroids. She refused systemic therapies owing to concern about diminishing the effectiveness of nivolumab. Despite the joint symptoms, nivolumab treatment was continued for a year. Evaluation showed fixed swan neck deformities in multiple fingers (Figure, A). There was evidence of chronic synovial hypertrophy with no active synovitis on examination. The results of a comprehensive autoantibody blood panel, including antinuclear antibody, rheumatoid factor, and anti-citrullinated peptide antibody, were unremarkable. Plain radiographs of the hands demonstrated diffuse osteopenia, joint space narrowing, and multiple deformities. Magnetic resonance imaging of both hands revealed multifocal osseous erosions (Figure, B), synovitis, and tenosynovitis.Erosive deforming inflammatory arthritis. A, Fixed swan neck deformities in multiple fingers (arrowheads). B, Magnetic resonance images of both hands reveal multifocal osseous erosions (arrowheads).

what is your diagnosis?

What is your diagnosis?

Erosive osteoarthritis

Seronegative rheumatoid arthritis

Nivolumab-induced inflammatory arthritis

Metastatic bone disease

c

female

51-60

White

original

https://jamanetwork.com/journals/jama/fullarticle/2749770

A 66-year-old man with a history of bilateral carpal tunnel syndrome was evaluated for chronic joint pain and stiffness involving the shoulders, hips, and knees over the past 6 years. He had no fever, skin rash, headaches, vision changes, or urinary symptoms. He reported occasional bruising around his eyes. His only medication was acetaminophen as needed for pain. His vital signs were normal. No joint tenderness, warmth, or fluid collections were present, and skin examination was normal. The presence of raised soft tissue masses around the sternoclavicular joints (Figure, left panel) and scapulae (Figure, right panel) were noted. Laboratory evaluation revealed normal results for complete blood cell count, erythrocyte sedimentation rate (ESR), and levels of electrolytes, creatinine, and C-reactive protein. A spot urinalysis showed a protein level of 220 mg/dL (reference range, <26 mg/dL), and a 24-hour urine collection revealed 1.8 g of albumin (reference range, <229 mg/24 h). Magnetic resonance imaging (MRI) of the shoulders and hips showed synovial and capsular thickening.Left, Soft tissue masses (arrowheads) around the sternoclavicular joints. Right, Soft tissue masses (arrowheads) around both scapulae.Order serum protein electrophoresis and serum free light chains assay What Would You Do Next?

Order bone scan

Order serum protein electrophoresis and serum free light chains assay

Start methotrexate

Perform temporal artery biopsy

Light-chain amyloidosis with joint and kidney involvement.

B

Order serum protein electrophoresis and serum free light chains assay

The key to the correct diagnosis is the presence of chronic joint pains associated with soft tissue masses, along with the history of bilateral carpal tunnel syndrome, periorbital purpura, and significant albuminuria, which should trigger consideration of light-chain amyloidosis. Inflammatory arthritis and vasculitis may present similarly; however, ESR, C-reactive protein level, or both are typically elevated.1-3 Giant cell (temporal) arteritis is less likely in this patient because of lack of headache or vision changes; thus, a temporal artery biopsy would not be diagnostic, although it may reveal amyloid deposits if the specimen was appropriately stained. Bone scan results would not be specific for a diagnosis in this case, and starting methotrexate is premature.Light-chain amyloidosis is the most common type of systemic amyloidosis and many different organs can be affected, including the heart, kidneys, liver, nerves, and soft tissues.4 Amyloid arthropathy occurs in 1% to 5% of patients with amyloidosis.5,6 Patients can have a rheumatoid arthritis–like presentation with symmetric bilateral polyarthritis with infiltration of the soft tissues that can limit movement.7 Many joints can be affected, including the shoulders, wrists, hips, and knees. Subcutaneous nodules can be present.6,8 Patients may also present with symptoms that mimic spinal stenosis due to amyloid infiltration in the muscles and ligaments surrounding the spine. Joint pain can be severe, and many patients require opioid medications for pain control. Physical examination may demonstrate the classic “shoulder pad” sign, as well as signs of amyloid infiltration in other joints, such as the sternoclavicular joints, as in this patient.When light-chain amyloidosis is suspected, evaluation should include serum and urine protein electrophoresis with immunofixation and assay for serum free light chains. ESR is usually normal but can also be elevated because of the monoclonal protein. Imaging using plain radiographs or MRI is not specific. A literature search for case reports or case series between 1931 and 2012 of amyloid arthropathy associated with light-chain amyloidosis identified 101 cases,9 including 5 patients (5%) with evidence of erosive articular changes and 5 patients (5%) with joint space widening on radiography. MRI showed articular and periarticular inflammation in 6 patients (6%). Synovial hypertrophy was noted in 2 patients (2%). Although rare, joint effusion was also reported.5 Synovial fluid analysis typically shows increased numbers of neutrophils but may also show amyloid deposits. A Congo red stain will not define the specific type of amyloidosis, and mass spectrometry is required for classification. A bone marrow aspirate and biopsy along with a fat pad aspirate are necessary for completing the evaluation.Renal involvement, presenting as hypoalbuminemia and albuminuria of variable degrees, occurs in approximately 58% of patients with light-chain amyloidosis.4 Patients can have foamy urine, edema, anasarca, and renal failure in advanced cases. When light-chain amyloidosis is suspected, evidence of renal, cardiac, gastrointestinal, and liver involvement needs to be assessed.Given that the presentation of amyloid arthropathy can mimic inflammatory arthritis,10 a major challenge in these patients is delayed diagnosis. In 1 report, time to diagnosis was anywhere between 1 to 84 months and in this patient was 6 years. Physicians should consider amyloid arthropathy in patients with a clinical course atypical for inflammatory arthritis. Patients with a persistently elevated ESR should have a screening serum protein electrophoresis performed.Treatment for amyloid arthropathy includes low-dose steroids, which are effective in improving pain symptoms and quality of life.5 Prednisone at a dose of 10 mg daily by mouth is generally well tolerated. Patients with light-chain amyloidosis also need therapy to eradicate the clonal plasma cells in the bone marrow and prevent the production of new abnormal light chains.4 This is achieved by using chemotherapy, autologous stem cell transplantation, or both. The most commonly used regimen is cyclophosphamide, bortezomib, and dexamethasone.Synovial biopsy of the shoulder showed amyloid deposition by Congo red staining. Mass spectroscopy identified light-chain λ amyloidosis, with lambda free light chain levels at 59.2 mg/dL (reference range, 0.57-2.63 mg/dL). Bone marrow aspirate and biopsy revealed 15% clonal plasma cells. The patient received chemotherapy with cyclophosphamide, bortezomib, and dexamethasone, which improved his joint pains dramatically.

General

A 66-year-old man with a history of bilateral carpal tunnel syndrome was evaluated for chronic joint pain and stiffness involving the shoulders, hips, and knees over the past 6 years. He had no fever, skin rash, headaches, vision changes, or urinary symptoms. He reported occasional bruising around his eyes. His only medication was acetaminophen as needed for pain. His vital signs were normal. No joint tenderness, warmth, or fluid collections were present, and skin examination was normal. The presence of raised soft tissue masses around the sternoclavicular joints (Figure, left panel) and scapulae (Figure, right panel) were noted. Laboratory evaluation revealed normal results for complete blood cell count, erythrocyte sedimentation rate (ESR), and levels of electrolytes, creatinine, and C-reactive protein. A spot urinalysis showed a protein level of 220 mg/dL (reference range, <26 mg/dL), and a 24-hour urine collection revealed 1.8 g of albumin (reference range, <229 mg/24 h). Magnetic resonance imaging (MRI) of the shoulders and hips showed synovial and capsular thickening.Left, Soft tissue masses (arrowheads) around the sternoclavicular joints. Right, Soft tissue masses (arrowheads) around both scapulae.Order serum protein electrophoresis and serum free light chains assay

what would you do next?

What would you do next?

Perform temporal artery biopsy

Order serum protein electrophoresis and serum free light chains assay

Order bone scan

Start methotrexate

b

male

61-70

original

https://jamanetwork.com/journals/jama/fullarticle/2751520

A 57-year-old white man with obesity and hypertension presents for a primary care visit, during which he expresses concern about having diabetes. He reports no symptoms of hyperglycemia, such as frequent urination, increased thirst, fatigue, or visual changes, and had no known family history of diabetes. A series of blood tests had recently been obtained (Table). His body mass index (BMI) is 33.9 and his blood pressure is 160/90 mm Hg. The patient wants to know if a test could be done in the office to determine if he has diabetes.Perform a laboratory-based glucose test to determine the patient’s glycemic status.Perform a point-of-care (POC) hemoglobin A1c (HbA1c) test via fingerstick to determine the patient’s glycemic status.Perform a laboratory-based HbA1c test to determine the patient’s glycemic status.Do not perform glycemic testing because it is not indicated for this patient. What Would You Do Next?

Perform a laboratory-based glucose test to determine the patient’s glycemic status.

Perform a point-of-care (POC) hemoglobin A1c (HbA1c) test via fingerstick to determine the patient’s glycemic status.

Perform a laboratory-based HbA1c test to determine the patient’s glycemic status.

Do not perform glycemic testing because it is not indicated for this patient.

C

Perform a laboratory-based HbA1c test to determine the patient’s glycemic status.

Hemoglobin A comprises approximately 97% of total hemoglobin and undergoes glycation with the nonenzymatic attachment of a sugar to its amino groups. Hemoglobin A1c (HbA1c) has glucose attached to the N terminus of β chains. The quantity of HbA1c is directly related to the glucose concentration that erythrocytes are exposed to over their life span, making HbA1c a clinically useful measure of mean glycemia during the preceding 3 months. Type 2 diabetes is defined by an HbA1c value of at least 6.5%, and prediabetes is defined by an HbA1c value of 5.7% to 6.4%. Individuals with prediabetes have an increased risk of developing type 2 diabetes, estimated at 5% to 10% annually and 70% in a lifetime.Point-of-care (POC) HbA1c testing may be performed during outpatient visits using a benchtop analyzer and capillary blood samples obtained by fingerstick. Expert groups have recommended using POC HbA1c testing in some clinical settings to guide outpatient treatment of patients with diabetes. This testing approach may enable more timely treatment changes by providing results when patients and their clinicians can immediately make therapeutic adjustments based on the results.1 Some clinicians also use POC HbA1c testing to diagnose diabetes, although this testing approach is not recommended. The utility of POC HbA1c testing to diagnose diabetes is limited by its analytic performance, namely its accuracy relative to a reference laboratory standard and precision (ie, the closeness of agreement between independent test results, as measured by the coefficient of variation).2 Inaccurate HbA1c values from POC testing may result in misdiagnosis of patients with true values close to the diagnostic threshold. Analytic performance is of less concern when treating patients with known diabetes, because inaccuracy of HbA1c values from POC testing is less likely to change therapy decisions.Some authors have proposed acceptable levels of accuracy (ie, within 0.2 percentage points of the true value) and precision (coefficient of variation <3%) for POC HbA1c testing devices.2,3 A 2017 meta-analysis of 13 commercially available POC instruments reported accuracy ranging from −0.9 to 0.7 percentage points from the laboratory value, with 9 devices exhibiting lower values and 4 devices demonstrating higher values.4 Individual studies of the same POC HbA1c device also report wide variability relative to the laboratory measure.4 Minimal evidence is available regarding the analytic performance of POC HbA1c test results obtained in clinical settings. A 2019 study reported that clinic-collected POC HbA1c test values were a mean of 0.2 percentage points lower than the laboratory test values.5 POC HbA1c testing should not be used to establish a diagnosis of diabetes unless the test is validated as accurate and is subject to regular monitoring of its accuracy in clinical settings.1,6 Medicare reimbursement for POC HbA1c testing was $11.99 in 2018.Because this patient has several risk factors for diabetes, including his age, BMI, and blood pressure, he should be screened for diabetes.7 Neither random glucose nor POC HbA1c tests are recommended for this purpose. A laboratory-based HbA1c test should be obtained to determine the patient’s glycemic status.Laboratory-based criteria for diagnosing diabetes include HbA1c (≥6.5%), fasting glucose (≥126 mg/dL), and 2-hour glucose following a 75 g oral glucose load (≥200 mg/dL). In the absence of hyperglycemic symptoms, 2 abnormal glycemic results are required to establish a diagnosis of diabetes.1 Importantly, the 3 glycemic tests recommended for diagnosing diabetes may not yield consistent conclusions regarding the presence of diabetes. Because there is not 1 widely accepted criterion standard test, the clinical performance (eg, sensitivity and specificity) of HbA1c is unknown. No large published studies have evaluated the clinical performance of POC HbA1c testing compared with laboratory-based HbA1c testing.Using laboratory-based HbA1c test results to diagnose diabetes has several advantages over glucose tests. It is more convenient because it does not require fasting, exhibits less intraindividual variation, and is not affected by acute fluctuations in blood glucose concentration.8 However, HbA1c may be affected by conditions with altered red blood cell turnover, iron deficiency anemia, or pregnancy. In addition, black patients may have slightly higher HbA1c values than white patients with the same glucose level. The reason for this difference is unknown.9At the presenting visit, the patient’s laboratory-based HbA1c value was 6.2% and he was referred to an intensive lifestyle program. When the patient returned for follow-up after participating in this program for 1 year, his BMI was 29.6 and laboratory-based HbA1c value was 5.8%.Laboratory-based HbA1c testing is recommended as 1 of 3 tests (including fasting glucose and 2-hour glucose after a 75 g oral glucose load) for diagnosing diabetes, monitoring glycemic status, and predicting the risk for microvascular complications in patients with known diabetes.There is wide variability in the performance of POC HbA1c testing devices among individual studies of the same device and across commercially available models, which limits its use for diabetes screening and diagnosis.POC HbA1c should not be used to establish a diagnosis of diabetes unless the test is regularly validated as accurate.According to clinical guidelines, POC HbA1c testing may be used to inform timely medical management of previously diagnosed diabetes.

Diagnostic

A 57-year-old white man with obesity and hypertension presents for a primary care visit, during which he expresses concern about having diabetes. He reports no symptoms of hyperglycemia, such as frequent urination, increased thirst, fatigue, or visual changes, and had no known family history of diabetes. A series of blood tests had recently been obtained (Table). His body mass index (BMI) is 33.9 and his blood pressure is 160/90 mm Hg. The patient wants to know if a test could be done in the office to determine if he has diabetes.Perform a laboratory-based glucose test to determine the patient’s glycemic status.Perform a point-of-care (POC) hemoglobin A1c (HbA1c) test via fingerstick to determine the patient’s glycemic status.Perform a laboratory-based HbA1c test to determine the patient’s glycemic status.Do not perform glycemic testing because it is not indicated for this patient.

what would you do next?

What would you do next?

Perform a laboratory-based HbA1c test to determine the patient’s glycemic status.

Perform a point-of-care (POC) hemoglobin A1c (HbA1c) test via fingerstick to determine the patient’s glycemic status.

Do not perform glycemic testing because it is not indicated for this patient.

Perform a laboratory-based glucose test to determine the patient’s glycemic status.

a

male

51-60

White

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2740804

A man in his 50s presented with a 12-year history of itchy eruptions over the whole body. Multiple nodules appeared on the upper back 1 year previously and gradually increased in number and size. The patient was otherwise healthy and denied a family history of inherited ichthyosis or atopy. Physical examination revealed extensive, dry scaly patches on the trunk, arms, and legs. Several 0.5- to 1-cm, dome-shaped, red papules and nodules were found on the upper back (Figure, A and B). Mildly enlarged lymph nodes were observed on the cervical, axillary, and inguinal regions. Results of routine blood tests, biochemistry analyses, and peripheral blood flow cytometry tests were within normal limits. No atypical cells were found in the peripheral blood. A biopsy specimen was obtained from the nodules on the patient’s back (Figure, C and D).Clinical images show multiple dome-shaped nodules on the back (A) and extensive, dry scaly patches on the leg (B). Lesional histopathologic images show small to medium-sized atypical cells, and focal areas of epidermotropism (C, hematoxylin-eosin) and CD4 on immunohistochemical analysis (D) (original magnification ×200). What Is Your Diagnosis?

Cutaneous pseudolymphoma

Ichthyosiform mycosis fungoides

Ichthyosis vulgaris with atopic dermatitis

Large plaque parapsoriasis

B. Ichthyosiform mycosis fungoides

B

Ichthyosiform mycosis fungoides

Histopathologic examination revealed an atrophy of the epidermis with focal orthokeratosis and an extensive, dense infiltrate of lymphocytes in the entire dermis. Small to medium-sized, atypical lymphocytes with focal areas of epidermotropism could be observed (Figure, C). Immunohistochemical staining results were consistent with a T-helper phenotype of the infiltrating lymphocytes, which were positive for CD2, CD3, CD4 (Figure, D), and CD45RO. A few small reactive CD8+ T cells and CD7+ T cells were observed in the dermis. DNA was extracted from paraffin sections, and polymerase chain reaction detected a clonal amplification product for the γ-chain of the T-cell receptor.The patient was treated with narrowband UV-B 3 times weekly, interferon α-2b, 3 million international units/m2, 3 times weekly and oral methotrexate, 10 mg once weekly. The patient had complete resolution of the skin lesions and enlarged lymph nodes at 6-month follow-up.Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, usually with an indolent clinical course.1,2 Many clinical variants of MF have been reported, such as hypopigmented and hyperpigmented, follicular, and hyperkeratotic-verrucous presentations.2 Ichthyosiform mycosis fungoides (IMF) was first described by Kütting et al3 in 1996. It is a rare variant of mycosis fungoides that is present in 1.8% to 3.5% of patients with mycosis fungoides (MF).4 Since the first report, very few cases have been reported in the literature.4Acquired ichthyosis usually begins in adult life and manifests as dry, scaly patches and plaques or as a generalized eruption resembling ichthyosis vulgaris.5 This disease can result from a wide range of underlying causes, such as neoplasms, malnutrition, infectious diseases, sarcoidosis, and inflammatory disorders.6 Acquired ichthyosis is recognized as a cutaneous manifestation associated with malignant diseases, including Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, and MF.2When acquired ichthyosis is related to MF, it can behave as a paraneoplastic syndrome or as a specific clinical variant of the lymphoma, that is, IMF.2,6 In the former condition, the ichthyosiform areas are usually completely separate from areas with conventional MF appearance, and a skin biopsy specimen of the ichthyotic lesions only shows epidermal hyperplasia. In IMF, the ichthyosiform eruptions are a specific manifestation of the lymphoma, and its histological presentation includes the typical findings of both MF and ichthyosis vulgaris.1,5Other differential diagnoses for IMF include ichthyosis vulgaris, large plaque parapsoriasis (LPP), and cutaneous pseudolymphoma. Ichthyosis vulgaris is an autosomal dominant disease that usually develops in patients between the ages of 3 months and 5 years with a positive family history.7 Large plaque parapsoriasis is a clinical condition characterized by erythematous scaly patches or, very rarely, patchy ichthyotic lesions.8 Approximately 10% to 35% of patients with LPP may progress to definite MF. Lesions of LPP show nonspecific spongiotic dermatitis or interface lymphocytic infiltrate. The typical histopathologic features of MF, such as epidermotropism and atypical lymphocytes, are absent in LPP.8 Cutaneous pseudolymphomas are benign lymphoproliferative processes that can clinically and histologically resemble MF.9 However, the absence of a mixed cellular infiltrate of CD8+ T cells, CD20+ B cells, and histiocytes helped us to rule out pseudolymphoma. And the presence of a clonal T-cell receptor γ gene rearrangement supported a diagnosis of MF in this case.In general, patients with IMF have a good prognosis and respond well to nonaggressive therapies, such as topical treatment, 8-methoxypsoralen plus UV-A or narrowband UV-B therapy, or combined treatment with interferon α and low-dose methotrexate.6,10

Dermatology

A man in his 50s presented with a 12-year history of itchy eruptions over the whole body. Multiple nodules appeared on the upper back 1 year previously and gradually increased in number and size. The patient was otherwise healthy and denied a family history of inherited ichthyosis or atopy. Physical examination revealed extensive, dry scaly patches on the trunk, arms, and legs. Several 0.5- to 1-cm, dome-shaped, red papules and nodules were found on the upper back (Figure, A and B). Mildly enlarged lymph nodes were observed on the cervical, axillary, and inguinal regions. Results of routine blood tests, biochemistry analyses, and peripheral blood flow cytometry tests were within normal limits. No atypical cells were found in the peripheral blood. A biopsy specimen was obtained from the nodules on the patient’s back (Figure, C and D).Clinical images show multiple dome-shaped nodules on the back (A) and extensive, dry scaly patches on the leg (B). Lesional histopathologic images show small to medium-sized atypical cells, and focal areas of epidermotropism (C, hematoxylin-eosin) and CD4 on immunohistochemical analysis (D) (original magnification ×200).

what is your diagnosis?

What is your diagnosis?

Ichthyosis vulgaris with atopic dermatitis

Large plaque parapsoriasis

Ichthyosiform mycosis fungoides

Cutaneous pseudolymphoma

c

male

11-20

original

https://jamanetwork.com/journals/jamadermatology/fullarticle/2747826

A white woman in her 50s without significant medical history underwent breast augmentation surgery with saline implants without postoperative complications. Five years later, she underwent a bilateral augmentation mammoplasty with removal and replacement of silicone gel implants and major mastopexy with capsulotomy. Although the patient’s surgical course was uncomplicated, several months postoperatively she noted persistent asymptomatic rough areas that she assumed were scars. Seven years after the second surgery, she was referred to dermatology for improvement of the areas for cosmetic reasons.On physical examination, the patient had well-healed, barely identifiable scars on the inframammary creases and lower breast areas. Separate from the scars and located on the inferior medial bilateral breasts were 1- to 2-cm slightly erythematous annular atrophic plaques with more involvement of the left breast than the right. The rims of the lesions were raised with slight white scale and the centers slightly depressed and wrinkled in appearance (Figure 1).Clinical images of the inferior medial bilateral breasts with 1- to 2-cm erythematous annular atrophic plaques with more involvement of the left breast (A) than the right (B). What Is Your Diagnosis?

Erythema annulare centrifugum

Annular atrophic lichen planus

Porokeratosis

Granuloma annulare

B. Annular atrophic lichen planus

B

Annular atrophic lichen planus

A skin biopsy taken from the rim of the left breast lesion showed focal epidermal atrophy, marked hypergranulosis with reactive keratinocytes, and an interface lichenoid reaction (Figure 2A). The upper dermis in the skin biopsy revealed a partial bandlike lymphoid infiltrate and numerous melanin-laden macrophages (Figure 2B). A periodic acid–Schiff with diastase (DPAS) test result was negative for fungi, and an elastic von Gieson stain showed preserved dermal elastic fibers. In view of the clinical presentation and atrophic lichenoid reaction, the skin biopsy specimens were classified as consistent with annular atrophic lichen planus (AALP).Hematoxylin-eosin staining of a biopsy taken at the advancing rim of the lesion demonstrated classic features of lichen planus, including squamatization of the basal layer with reactive keratinocytes, a dense bandlike lichenoid infiltrate with epidermal atrophy, hypergranulosis, and melanin-laden macrophages in the upper dermis.Annular atrophic lichen planus is a rare variant of lichen planus, first described by Friedman and Hashimoto1 in 1991. Diagnostically, AALP appears to be largely a clinicopathologic diagnosis based on histopathological characteristics and biopsy results. The histological morphology of AALP is characterized by features of annular lichen planus with an atrophic center. To our knowledge, all cases thus far have been described as brown to violaceous annular plaques with a raised outer rim and atrophic centers.1-9 The lesions occur most commonly on distal body regions vs proximal and can be pruritic or asymptomatic. On histopathological examination, the atrophic center of the lesion typically corresponds with a sparse lichenoid process, epidermal atrophy, and upper dermis anetoderma, while the rim of the lesion demonstrates classic features of lichen planus including hyperkeratosis, hypergranulosis, and a dense lichenoid infiltrate.1-9 In the present case the biopsy was taken from an area of the rim at the advancing border and demonstrated marked inflammation with clear squamatization of the basal cell layer, hypergranulosis, and reactive keratinocytes representing a lichenoid reaction.Entities on the differential diagnosis include erythema annulare centrifugum, porokeratosis, and granuloma annulare. Erythema annulare centrifugum is a gyrate erythema and is characterized by a dense perivascular lymphocytic infiltrate that is well demarcated and adjacent to vessels, which was not seen in this patient. A cornoid lamella was also not seen, thus ruling out a porokeratosis. Finally, dermal necrobiotic collagen, palisading histiocytes, vasculitis, and mucin deposition was not found, ruling out granuloma annulare.It is impossible to confirm whether the patient’s surgical history played a role in lesion induction, but we postulate that the patient’s lesions could be related to her recent breast surgery. The lichenoid infiltrate could represent a reaction to silicone or another foreign antigen. Cutaneous ulcerative lichen planus forming due to pathergy has been described previously in the literature.10We present this case of AALP in the setting of prior breast surgery to further characterize the clinical presentation and pathology of this rare entity; however, future reports are needed to better understand the condition’s pathogenesis, prevalence, and cause.

Dermatology

A white woman in her 50s without significant medical history underwent breast augmentation surgery with saline implants without postoperative complications. Five years later, she underwent a bilateral augmentation mammoplasty with removal and replacement of silicone gel implants and major mastopexy with capsulotomy. Although the patient’s surgical course was uncomplicated, several months postoperatively she noted persistent asymptomatic rough areas that she assumed were scars. Seven years after the second surgery, she was referred to dermatology for improvement of the areas for cosmetic reasons.On physical examination, the patient had well-healed, barely identifiable scars on the inframammary creases and lower breast areas. Separate from the scars and located on the inferior medial bilateral breasts were 1- to 2-cm slightly erythematous annular atrophic plaques with more involvement of the left breast than the right. The rims of the lesions were raised with slight white scale and the centers slightly depressed and wrinkled in appearance (Figure 1).Clinical images of the inferior medial bilateral breasts with 1- to 2-cm erythematous annular atrophic plaques with more involvement of the left breast (A) than the right (B).

what is your diagnosis?

What is your diagnosis?

Granuloma annulare

Annular atrophic lichen planus

Erythema annulare centrifugum

Porokeratosis

b

female

51-60

White

original

https://jamanetwork.com/journals/jamaneurology/fullarticle/2749164

A 48-year-old woman presented to the emergency department with a 2-month history of progressive lower extremity weakness, sensory loss, and sphincter dysfunction. In the weeks prior to onset, she traveled to Yosemite National Park but denied any particular infectious exposures or symptoms including rash. She reported no personal or family medical history. Although she did consume a variety of nutraceuticals, she denied medication and recreational drug use.On examination, mental status, cranial nerves, and upper extremities were normal. Lower extremities were significant for her right side having greater pyramidal weakness than the left, with brisk reflexes and right ankle clonus, as well as a sensory level to pinprick at T6. Magnetic resonance imaging (MRI) of the total spine with and without gadolinium is seen in Figure 1. Initial investigations were notable for normal complete blood cell count, electrolytes, kidney and liver function, B12, and thyrotropin as well as an unremarkable MRI of the brain. Three lumbar punctures were performed over the course of the patient’s hospitalization, each with a white blood cell count less than 5 /µL (to convert to ×109/L, multiply by 0.001), normal IgG index, absent oligoclonal bands, normal protein and glucose levels, and benign cytology. A comprehensive infectious and inflammatory workup including HIV, herpes simplex virus, varicella-zoster virus, Lyme disease, antinuclear antibodies, astrocyte aquaporin-4 autoantibody, myelin oligodendrocyte glycoprotein autoantibody, and serum and cerebrospinal fluid autoimmune panels were negative. Whole-body positron emission tomography demonstrated hypermetabolism of the midthoracic cord.A, Long-segment, expansile T2 hyperintense lesion spanning C5 through T12 and involving greater than two-thirds of the cord diameter. The spinal cord is mildly diffusely swollen without an appreciated focal mass. B, Associated extensive ill-defined enhancement of the spinal cord spanning T3 through T9. What Is Your Diagnosis?

Postinfectious myelopathy

Toxic myelopathy

Glioma

Spinal dural arteriovenous fistula

C. Glioma

C

Glioma

The clinical case and imaging were most suggestive of spinal cord tumor; subsequent spinal cord biopsy was consistent with H3-K27M mutant diffuse midline glioma. This case highlights an important early diagnostic consideration in the approach to myelopathy. Etiologies can be broadly categorized as inflammatory or noninflammatory, and cerebrospinal fluid is used to distinguish between them. Although the patient’s imaging demonstrated extensive enhancement, cerebrospinal fluid was repeatedly noninflammatory (absent pleocytosis and oligoclonal bands and normal IgG index). Infectious and postinfectious causes of myelopathy would typically be associated with these inflammatory markers as would immune-mediated causes of spinal cord dysfunction including neurosarcoidosis.Broadly speaking, causes of noninflammatory myelopathy include compressive, toxic, metabolic, vascular, and neoplastic etiologies. Extrinsic compression from degenerative cervical spine disease is the most common of these, but the patient’s MRI did not reveal any significant degenerative changes. Although she reported using a variety of nutraceutical products, an extensive literature review did not find any that were associated with central nervous system complications. More specifically, there was no evidence of excessive zinc ingestion, a well-recognized cause of hypocupremia-associated myelopathy. Furthermore, the patient denied a history of inadvertent pyridoxine (vitamin B6) excess. This can occur through overconsumption of energy drinks, body-building supplements, and energy bars and results in symptoms of a sensory-predominant myelopathy or ganglionopathy. Toxicology screen was negative and there was no reported history of nitrous oxide exposure, radiation, or heroin use—all known culprits of longitudinally extensive spinal cord lesions, some of which are enhancing.1 Screening for common metabolic causes including B12, copper, and vitamin E deficiency was unrevealing. Finally, although spinal dural arteriovenous fistulas are frequently associated with enhancement, MRI did not reveal tortuous flow voids or missing-piece sign2 and a spinal conventional angiogram was normal.The slowly progressive myelopathic symptoms and paraclinical data suggest the possibility of an underlying neoplasm. Given this suspicion, a thoracic (T5) spinal cord lesion biopsy was performed. Figure 2 shows representative photomicrographs of the biopsy. The histologic sections demonstrate slightly hypercellular tissue with scattered atypical cells and focal areas of necrosis, findings reminiscent of an infiltrating neoplasm. Immunohistochemical stain showed strong nuclear staining in the atypical cells for H3-K27M mutation specific antibody. H3-K27me3 was lost in the neoplastic cells, confirming the hypomethylation phenotype. These findings are diagnostic of a diffuse midline glioma, H3-K27M mutant, World Health Organization grade IV. This entity was added to the 2016 revised version of the World Health Organization classification of brain tumors.3 These high-grade gliomas are most commonly found in the pons but have been described at other midline sites including the thalamus, basal ganglia, and spinal cord.4 One series of adult patients with H3-K27M gliomas had evidence of abnormal enhancement on imaging in 21 of 26 cases.5 Regardless of location, they are universally associated with local infiltration and poor prognosis.6 Although the diagnosis remains ominous, a recent phase II study involving patients with recurrent glioblastoma and treatment with imipridone ONC201, a selective antagonist of the G protein-coupled receptor DRD2, resulted in a dramatic response in one patient with a H3-K27M mutation.7 A phase II open-label study is actively recruiting participants with this mutation and referral to this trial and others like it should be considered by physicians caring for these patients.Spinal cord biopsy of a lesion on T3 through T9. Representative photomicrograph (hematoxylin-eosin, original magnification ×200) demonstrating fragments of slightly hypercellular tissue with focal areas of necrosis. Rare thrombi are identified.The patient was treated with concurrent temozolamide and radiation therapy. Four months later, she remains clinically stable.

Neurology

A 48-year-old woman presented to the emergency department with a 2-month history of progressive lower extremity weakness, sensory loss, and sphincter dysfunction. In the weeks prior to onset, she traveled to Yosemite National Park but denied any particular infectious exposures or symptoms including rash. She reported no personal or family medical history. Although she did consume a variety of nutraceuticals, she denied medication and recreational drug use.On examination, mental status, cranial nerves, and upper extremities were normal. Lower extremities were significant for her right side having greater pyramidal weakness than the left, with brisk reflexes and right ankle clonus, as well as a sensory level to pinprick at T6. Magnetic resonance imaging (MRI) of the total spine with and without gadolinium is seen in Figure 1. Initial investigations were notable for normal complete blood cell count, electrolytes, kidney and liver function, B12, and thyrotropin as well as an unremarkable MRI of the brain. Three lumbar punctures were performed over the course of the patient’s hospitalization, each with a white blood cell count less than 5 /µL (to convert to ×109/L, multiply by 0.001), normal IgG index, absent oligoclonal bands, normal protein and glucose levels, and benign cytology. A comprehensive infectious and inflammatory workup including HIV, herpes simplex virus, varicella-zoster virus, Lyme disease, antinuclear antibodies, astrocyte aquaporin-4 autoantibody, myelin oligodendrocyte glycoprotein autoantibody, and serum and cerebrospinal fluid autoimmune panels were negative. Whole-body positron emission tomography demonstrated hypermetabolism of the midthoracic cord.A, Long-segment, expansile T2 hyperintense lesion spanning C5 through T12 and involving greater than two-thirds of the cord diameter. The spinal cord is mildly diffusely swollen without an appreciated focal mass. B, Associated extensive ill-defined enhancement of the spinal cord spanning T3 through T9.

what is your diagnosis?

What is your diagnosis?

Toxic myelopathy

Postinfectious myelopathy

Spinal dural arteriovenous fistula

Glioma

d

female

41-50

White

original

https://jamanetwork.com/journals/jamacardiology/fullarticle/2748987

A man in his mid-50s with no significant medical history was referred with 2 years of insidious exertional dyspnea and neck fullness. Examination of the jugular venous contour with the patient sitting upright at 90° is shown in Video 1. Auscultatory findings at the left lower sternal border showed normal S1 and S2 heart sounds with a diastolic sound and no murmurs (Figure 1; Video 2). Abdominal examination revealed an enlarged, pulsatile liver with smooth edges palpable 4 cm below the costal margin. Electrocardiography showed resting abnormalities (rightward axis and inferolateral T-wave inversions). Posteroanterior chest radiography showed normal heart size and clear lungs (Figure 1). Transthoracic echocardiography was performed, which showed normal left ventricular size and function without valvular abnormalities.A, Phonocardiography from the left sternal border. Asterisks indicate diastolic sound. B, Upright chest radiography with posteroanterior projection. What Would You Do Next?

Transesophageal echocardiography

Right and left heart catheterization

Magnetic resonance imaging with gadolinium enhancement