Case 1: Catastrophic antiphospholipid syndrome
By Gurbaj Singh, MD, ACP Member; Kiranveer Kaur, MD, ACP Member; Radhika Kalaria, MD; and Li-Teh Wu, MD
A 50-year-old man without known significant medical history was found unresponsive. His family said that he had returned from Europe one week prior to presentation and reported pain and swelling in his legs. He was intubated for airway protection in the field and transported to our facility.
Vital signs on arrival were unremarkable except for a mild elevation of blood pressure to 169/79 mm Hg. Physical examination demonstrated a global impairment of mental status, but no focal neurologic deficits were detected. There was no asymmetry, edema, or rash on his extremities. Laboratory tests showed leukocytosis, mild elevation of aminotransferase levels, and a troponin I level of 3.05 ng/mL (reference range, <0.045 ng/mL). Initial CT scan of the head showed multi-territorial infarcts involving right frontal, parietal, and occipital lobes (Figure 1).
He was started on a heparin drip for suspicion of an embolic stroke. Further workup revealed bilateral lower-extremity deep venous thrombosis, in addition to hepatic, splenic, and renal infarcts. Coagulation profile revealed an international normalized ratio of 1.3, a prothrombin time of 14.1 s (reference range, 9.8 to 12.7 s), and a normal partial thromboplastin time of 30.7 s (reference range, 27.5 to 37.4 s). Hypercoagulability testing, including anticardiolipin antibody, antithrombin III, and protein C and S levels, was normal except for positive lupus anticoagulant. High-dose IV dexamethasone was initiated, but despite treatment, the patient developed worsening cerebral edema and died on day 10 of hospitalization.
The patient was diagnosed with catastrophic antiphospholipid syndrome (CAPS), a life-threatening presentation of antiphospholipid syndrome (APS) that occurs in fewer than 1% of patients with APS. CAPS typically manifests as severe dysfunction and/or failure of multiple organ systems precipitated by rapid, diffuse small-vessel ischemia and thrombosis. Precipitating factors are infection, tissue ischemia and necrosis, medications (e.g., oral contraceptives), trauma (including surgical procedures), malignancy, and rheumatologic conditions. Diagnosis is based on an algorithm, and for a definite diagnosis of CAPS all four of the following criteria must be met: 1) evidence of involvement of three or more organ systems, 2) manifestations developed simultaneously or within a week, 3) confirmation of small-vessel occlusion in at least one organ/tissue, and 4) known APS or laboratory confirmation of presence of antiphospholipid antibodies (lupus anticoagulant and/or anti-cardiolipin and/or anti-β2GPI antibodies). If some but not all four criteria are met, the diagnosis is probable CAPS.
Mortality due to CAPS is estimated at approximately 50%, and thus prompt recognition and treatment are essential. A combination of systemic anticoagulation with heparin, high-dose corticosteroids, urgent plasma exchange, and/or intravenous immune globulin (IVIG) is recommended and is preferred over any single-agent therapy. Other treatment options include cyclophosphamide, prostacyclin, fibrinolytics, and defibrinogenating agents. Treatment of the underlying precipitant is also important. In survivors of CAPS, lifelong anticoagulation is recommended to prevent future thromboembolic events.
- CAPS is a rare but fatal complication of APS; early diagnosis and prompt treatment are essential due to its fulminant course and high mortality.
- Treatment of CAPS includes systemic corticosteroids and anticoagulation, as well as treatment of any underlying precipitant.
The authors are or were affiliated with Northwell Health Long Island Jewish Forest Hills Hospital in Forest Hills, N.Y.
Case 2: Diabetic muscle infarction
By Amy Cohen, DO, ACP Resident/Fellow Member; Thomas Oliver, DO, ACP Member; and David Fried, MD, ACP Member
A 39-year-old man with a history of type 1 diabetes complicated by retinopathy and end-stage renal disease developed right leg pain and swelling and sought acute care. He was given cephalexin for suspected cellulitis after an ultrasound was negative for thrombosis. The patient presented seven days later with worsening symptoms. On re-presentation, his temperature was 100.6 °F; other vital signs were normal. On physical examination, his right thigh was significantly swollen compared to the left and was warm to the touch but without erythema.
Laboratory tests showed a normal white blood cell count but marked elevations in creatine kinase level to 793 IU/L (reference range, 22 to 198 IU/L), C-reactive protein level to 234 mg/L (reference range, 0 to 10 mg/L), and erythrocyte sedimentation rate to above 119 mm/h (reference range, 0 to 22 mm/h). Empiric antibiotics were given, and surgical and infectious disease consultations were obtained due to concern for a deep-tissue infection and evolving compartment syndrome.
A CT scan of his right leg revealed diffuse subcutaneous edema without a drainable collection. The differential diagnosis was broadened to include inflammatory myositis, given the lack of obvious signs of infection, and a subsequent MRI revealed markedly increased T2 signal and edema in the vastus lateralis and intermedius, consistent with myositis and myonecrosis (Figure 2). The patient's symptoms improved upon initiation of aspirin and analgesics and withdrawal of antibiotics.
The patient was diagnosed with diabetic muscle infarction (DMI), a rare complication of diabetes. It is defined by ischemic muscle necrosis of unclear pathogenesis and typically presents with acute onset of atraumatic painful muscle swelling. It tends to occur in patients with long-standing insulin dependence who also have microvascular complications such as diabetic nephropathy and retinopathy. DMI is also considered a poor prognostic sign, as it occurs in patients with uncontrolled systemic disease who are at risk for future macrovascular events. Diagnosis is often delayed due to its rarity and clinical similarity to other conditions, such as soft-tissue infection, myositis, or calciphylaxis.
The vasti of the quadriceps are the most commonly affected muscle group, leading to patient reports of painful leg swelling and difficulty with ambulation. Laboratory tests often show elevations in inflammatory markers and creatine kinase levels. MRI is the most sensitive diagnostic imaging study, demonstrating diffuse edema and swelling of affected muscle groups. The disease is classically diagnosed via biopsy; however, a typical presentation with the aforementioned imaging findings often obviates the need for invasive testing.
Aspirin is the mainstay of therapy due to its anti-inflammatory analgesic properties. Additional treatment includes relaxation of the affected muscles, often requiring bed rest. Symptoms should spontaneously resolve within weeks to months, but the recurrence rate is about 45% on the contralateral side. For chronic secondary prevention, glycemic control and aspirin are considered the standards of care.
- DMI is a rare complication that tends to occur in patients with long-standing insulin dependence who also have microvascular complications and mimics conditions such as myositis and cellulitis; prompt diagnosis is challenging without a high index of suspicion.
- DMI is considered a poor prognostic sign, as it occurs in patients with uncontrolled systemic disease who are at risk for future macrovascular events.
The authors are affiliated with Lankenau Medical Center in Wynnewood, Pa.
Case 3: Neuroinvasive West Nile virus infection
By Helen H. Lin, MD; Thomas Iden, MD; and Oveimar De La Cruz, MD
A homeless 59-year-old man with alcohol use disorder presented via ambulance reporting difficulty walking and tremors. On arrival, he was febrile to 102.6 °F, tachycardic to 107 beats/min, tachypneic to 23 breaths/min, and hypertensive to 173/101 mm Hg. Due to progressively altered mentation, he was endotracheally intubated for airway protection.
Despite improvements in mentation in the ICU, he continued to have ongoing bilateral upper- and lower-extremity weakness with normal reflexes and sensation. MRI of the brain and spine showed T11-T12 leptomeningeal enhancement with lumbar nerve root involvement. Cerebrospinal fluid (CSF) was positive for Epstein-Barr virus (EBV) by polymerase chain reaction with normal cell differential, protein, and glucose. Due to ongoing weakness, additional CSF was obtained and revealed West Nile virus IgG and IgM. Flow cytometry showed no signs of malignancy. Peripheral EBV serologies were consistent with a prior infection: positive for EBV capsid and nuclear IgG but not IgM. Electromyography demonstrated motor neuropathy of the anterior horn cells.
Due to ongoing weakness, he received a tracheostomy and was discharged to a skilled nursing facility for physical rehabilitation. He has since been lost to follow-up.
This patient's diagnosis is West Nile virus (WNV). It is the most common cause of neuroinvasive arboviral encephalitis in the United States. Mosquitos are the primary vector, and the main period of infectivity is the summer, with extension into the autumn in warmer areas. Most patients who contract WNV are asymptomatic. Symptom onset is usually acute and nonspecific: headaches, fevers, chills, rash, and myalgias. About 1% of those infected will develop neuroinvasive disease, characterized by flaccid paralysis with or without meningoencephalitis. Involvement of the spinal cord produces flaccid paralysis. Involvement of the intercostal muscles and the diaphragm can result in respiratory failure. As IgM cannot cross the blood-brain barrier, the presence of WNV IgM antibodies in the CSF indicates true infection of the central nervous system (CNS). Antibodies to WNV are detectable in the serum three to eight days after illness onset. Treatment of WNV and related neuroinvasive disease is supportive. Approximately a third of patients will recover, a third will have mild long-term neurologic impairment, and a third will have little to no recovery from paralysis.
Due to his acute WNV infection, this patient developed peripheral EBV reactivation with likely subsequent CNS infection. Initial CNS studies suggested EBV encephalitis alone. However, the unexpected disease course prompted additional workup, which found the WNV. EBV has been documented as a dual pathogen in the CNS with viruses such as cytomegalovirus, herpes simplex virus, varicella zoster virus, and bacteria such as Streptococcus pneumoniae. Because EBV can exist as a dual pathogen, further investigation for a second pathogen is warranted if patients do not improve with appropriate treatment. Although the clinical significance of dual-pathogen EBV infection is not well understood, its presence is not benign. EBV's association with malignancy suggests immunomodulatory effects. Patients with EBV viral co-infections have increased CNS viral loads and increased CNS white blood cell counts compared to patients with EBV encephalitis alone, suggesting increased local inflammation. While the clinical significance of EBV co-infection in neuroinvasive diseases is unknown, it may have contributed to this patient's limited recovery.
- WNV is the most common cause of neuroinvasive arboviral disease in the U.S., and it may present with flaccid paralysis with or without altered mentation.
- EBV may be present as a dual pathogen in the CNS; its presence does not rule out other potential causes of meningoencephalitis.
The authors are or were affiliated with Virginia Commonwealth University Health System in Richmond, Va.
Case 4: Pheochromocytoma
By Dipesh Ludhwani, MD, ACP Resident/Fellow Member, and Sally Jreisat, MD
A 46-year-old man with a history of intermittent anxiety presented with reports of episodic headache, blurred vision, and elevated blood pressure (BP) of 239/139 mm Hg. Before presentation, the patient had taken three tablets of low-dose alprazolam for a possible anxiety attack. Apart from elevated blood pressure, the patient was afebrile with a heart rate of 88 beats/min and a normal respiratory rate. The remainder of the physical examination, including cardiovascular auscultation, was normal.
Laboratory studies most notably revealed a serum creatinine level of 2.3 mg/dL (reference range, 0.6 to 1.2 mg/dL). CT and MRI of the brain showed no acute intracranial abnormality. After early BP treatment with IV hydralazine, the patient was switched to oral carvedilol. Due to persistently elevated BP, the carvedilol dose was maximized and oral hydralazine was added. Renal ultrasound showed bilateral renal cysts without renal artery stenosis.
An evaluation for secondary hypertension revealed 24-hour urine normetanephrine and metanephrine levels of 1,319 μg/24 h (reference range, 125 to 510 μg/24 h) and 478 μg/24 h (reference range, 62 to 207 μg/24 h), respectively. Morning serum cortisol level, plasma aldosterone concentration, and plasma renin activity were within normal limits. A subsequent CT of the abdomen confirmed multiple simple renal cysts and showed a 4-cm right adrenal mass (Figure 3).
The patient was started on amlodipine, and BP was maintained between 130/80 and 150/90 mm Hg. Phenoxybenzamine was also initiated. The patient subsequently underwent adrenalectomy. Surgical pathologic evaluation was consistent with a catecholamine-secreting tumor. The patient ultimately required antihypertensives for long-term BP control.
This patient presented with resistant hypertension due to pheochromocytoma, a rare catecholamine-secreting tumor diagnosed in fewer than 1% of patients with hypertension. The tumor is most commonly located in the adrenal glands; however, 10% to 15% of catecholamine-secreting tumors occur extra-adrenally and are called paragangliomas. The signs and symptoms of pheochromocytoma are related to the levels of epinephrine and norepinephrine secreted by the tumor. The clinical presentation consists of episodic or sustained hypertension; however, 5% to 15% of patients are normotensive. Only 40% of cases have the classic triad of symptoms consisting of episodic headaches, sweating, and tachycardia.
Pheochromocytoma is diagnosed by measuring elevated fractionated catecholamines or their metabolites (metanephrines) either in plasma or urine, followed by imaging to identify the location of the tumor. Plasma fractionated metanephrines have high sensitivity but poor specificity; 24-hour urinary fractionated metanephrines are therefore preferred to avoid false-positive results. Once the biochemical diagnosis is made, radiological evaluation with CT or MRI should be performed. Negative CT and MRI should prompt additional imaging with metaodobenzylguanidine scintigraphy or positron emission tomography.
Adrenalectomy remains the mainstay of treatment. Presurgical medical preparation with alpha-adrenergic blockade (e.g., phenoxybenzamine) followed by beta-adrenergic blockage prior to surgery is warranted to prevent unopposed alpha-action resulting in an intraoperative hypertensive emergency. Approximately 10% of adrenal tumors are malignant. Postsurgical recurrence rates are between 6% and 16%.
- Pheochromocytoma is a rare catecholamine-secreting tumor; only 40% of cases have the classic triad of symptoms consisting of episodic headaches, sweating, and tachycardia, and 5% to 15% of patients are normotensive.
- Adrenalectomy is the mainstay of treatment, and stepwise alpha- and beta-blockade are used to prevent interoperative hypertensive emergency; postsurgically, patients with pheochromocytoma are monitored regularly due to the risk of recurrence.
The authors are affiliated with the Rosalind Franklin University of Medicine and Science in Chicago and Northwestern McHenry Hospital in McHenry, Ill.
Case 5: Rapidly progressive glomerulonephritis
By Faysal Saab, MD, ACP Member
An 80-year-old woman with a history of hypertension and hypothyroidism presented with weakness, nausea, and vomiting for the past six days. She also noted that her urine was darker than usual. Her medications included hydralazine, lisinopril, metoprolol, levothyroxine, aspirin, and pentoxifylline. On presentation, she was noted to be hypertensive, with a blood pressure of 220/100 mm Hg. The rest of her vital signs and physical exam findings were unremarkable.
Laboratory workup showed a creatinine level of 5.0 mg/dL and a blood urea nitrogen level of 60 mg/dL, increased from 1.0 mg/dL and 13 mg/dL, respectively, three weeks prior. Her hemoglobin level was 11 mg/dL, decreased from 14.2 mg/dL three months prior. Her urinalysis showed 3+ blood with 27 red blood cells per high-power field (hpf), 1+ protein, and 11 white blood cells/hpf with trace leukocyte esterase. Renal ultrasound revealed mildly increased renal cortical echogenicity and thinning bilaterally, without hydronephrosis and with patent renal vessels. Chest X-ray was within normal limits. A CT of the chest showed bronchocentric nodular opacities in the right middle and bilateral lower lobes, as well as scattered solid and “ground-glass” pulmonary infiltrates.
Additional laboratory values demonstrated a positive antinuclear antibody (ANA) to 1:1,280 (homogeneous pattern) and double-stranded DNA (dsDNA) elevated to 844 IU/mL (reference range, <200 IU/mL). Complement testing (C3, C4), cytoplasmic staining anti-neutrophil cytoplasmic antigen (c-ANCA), and hepatitis serologies (A, B, and C) were all normal. Perinuclear staining ANCA titer (p-ANCA) was elevated to greater than 1:1,280 (reference range, <1:20), histone IgG was 6.1 U (reference range, <0.9 U), myeloperoxidase antibody was 121 U (reference range, <20 U), and nDNA titer was 1:80 (reference range, <1:10).
Kidney biopsy was performed (Figure 4, Figure 5). Bronchoalveolar lavage showed progressively bloody fluid over serial washouts, concerning for diffuse alveolar hemorrhage. The patient received IV methylprednisolone and plasma exchange, and despite these therapies her creatinine level remained elevated between 4 and 5 mg/dL. Hemodialysis was ultimately necessary for fluid and electrolyte optimization. She was eventually discharged in good condition to continue outpatient hemodialysis and indefinite immunosuppression with oral prednisone and cyclophosphamide.
This patient's acute kidney injury was due to a rapidly progressive glomerulonephritis (RPGN), also known as crescentic glomerulonephritis. The specific cause of this patient's RPGN was ultimately identified as microscopic polyangiitis (MPA), a pulmonary-renal syndrome. The annual incidence of RPGN in the United States is estimated to be seven cases per million. In a case series from Saudi Arabia, RPGN was reported to account for 3.2% of 233 adult renal biopsies performed. RPGN is marked by rapidly worsening renal function in the absence of precipitants, including sepsis, hypovolemic state, exposure to nephrotoxins, or urinary obstruction. Urinalysis exhibiting dysmorphic red blood cells without significant proteinuria or pyuria can further hint at the diagnosis of RPGN and should prompt evaluation for nephritis and vasculitis.
There are three types of RPGN. Type 1 shows a linear pattern of immunofluorescence due to IgG binding at the glomerular basement membrane, of which Goodpasture syndrome is a hallmark example. Type 2 is immune-complex mediated, as seen in postinfectious glomerulonephritis and IgA nephropathy. Type 3 is pauci-immune, indicating that no immune complexes are pathologically involved; MPA, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis are examples. In type 3 RPGN, ANCA is positive in up to 80% of cases.
Kidney biopsy is indicated for histologic confirmation and guidance of medical therapies, often before serologic test results are available. Treatment with IV corticosteroids should not be delayed, as this does not confound the biopsy result and is often necessary. Because pulmonary disease, such as diffuse alveolar hemorrhage, occurs concurrently in up to 45% of certain RPGN cases, CT of the chest is often indicated, as a chest X-ray may be normal in up to 20% of patients with pulmonary-renal syndromes.
Plasma exchange therapy can be considered for any RPGN subtype in cases of rapidly declining kidney function, positive anti-glomerular basement membrane autoantibodies, and pulmonary hemorrhage not responding to glucocorticoids or complicated by respiratory compromise. Long-term immunosuppression with cyclophosphamide or rituximab should be initiated in consultation with a nephrologist. Long-term prognosis is poor among adults; in one study, 32% of patients presenting with ANCA-associated glomerulonephritis were dialysis dependent at one year, and 25% had died.
- RPGN is marked by rapidly worsening renal function in the absence of precipitants including sepsis, hypovolemic states, exposure to nephrotoxins, or urinary obstruction.
- When RPGN is suspected, kidney biopsy should not be delayed while time-intensive serologic workup is still pending; early administration of IV corticosteroids should similarly not be delayed and can help salvage maximal glomerular function.
Dr. Saab is affiliated with the University of California, Los Angeles. He would like to thank W. Dean Wallace, MD, for contributing the figures and captions.