Cases from Massachusetts General Hospital

Henoch-Sch##ouml;nlein purpura in an adult, serotonin syndrome presenting as myoclonus and hyperreflexia, dengue fever, and more.


Case 1: Henoch-Schönlein purpura in an adult

By Amulya Nagarur, MD, ACP Member

The patient

A 24-year-old woman with a medical history of intravenous drug use and untreated hepatitis C infection presented at 33 weeks' gestation with fever and rigors. She was initially admitted to an outside hospital with a fever to 102.9 °F and pulse in the 140 beats/min range. All other vital signs were normal, and her physical exam was unremarkable, aside from a gravid uterus. Due to maternal and fetal tachycardia, she was transferred to our hospital. Laboratory testing revealed normal electrolytes and a creatinine level of 0.4 mg/dL, a white blood cell count of 19,400 cells/µL, erythrocyte sedimentation rate of 38 mm/h, and a C-reactive protein level of 5.8 mg/L. In blood cultures obtained prior to her transfer, multiple samples were positive for methicillin-resistant Staphylococcus aureus. Transthoracic and transesophageal echocardiograms showed no valvular vegetations. On her sixth hospital day, she had premature rupture of membranes and had a spontaneous vaginal delivery of a healthy baby without complication.

The day before the patient's delivery, repeated laboratory testing revealed worsening renal function (creatinine level, 1.19 mg/dL) and urinalysis with 3+ protein and 3+ blood without any dysmorphic red blood cells. She subsequently developed a new palpable purpuric rash, which started near her ankles and extended proximally to her thighs and lower back. She also experienced diffuse arthralgias, abdominal pain, and emesis. CT of the abdomen showed findings consistent with vasculitis. Repeat urine sediment revealed granular casts and numerous red blood cells, concerning for a glomerulonephritis. Antinuclear antibody testing was negative, cryoglobulins were not detected, and C3 and C4 levels were normal. Her creatinine level ultimately peaked at 1.7 mg/dL. Skin biopsy revealed leukocytoclastic vasculitis and direct immunofluorescence was positive for IgA immunoreactivity. She was treated with high-dose steroids with resolution of her skin lesions, arthralgias, abdominal pain, and improvement in her renal function. The patient was discharged home in good condition and lost to follow-up thereafter.

The diagnosis

This patient was diagnosed with Henoch-Schönlein purpura (HSP), a systemic small-vessel vasculitis that manifests as palpable purpura (in the absence of coagulopathy or thrombocytopenia), arthralgias/arthritis, abdominal pain, and renal dysfunction. Only approximately 10% of HSP cases occur in adults. Adults with HSP have an increased risk of significant renal disease compared to children and often have more prominent skin lesions. The pathophysiology of HSP involves deposition of IgA immune complexes in small vessels. There have been many illnesses associated with HSP, including hepatitis C virus infection, staphylococcal bacteremia, and pregnancy, all of which were present in this patient. Despite myriad described associations, no single microorganism or environmental exposure has been confirmed as a reliable precipitant of HSP. While the diagnosis of HSP is typically made on clinical suspicion, biopsy of an affected organ is sometimes required. All patients with suspicion for HSP should be evaluated with a complete blood count, coagulation parameters, and urinalysis. An elevated creatinine level, elevated blood pressure, hematuria, and/or proteinuria indicates significant renal involvement.

Most patients with HSP can be treated supportively with symptomatic relief of joint and abdominal pain. Severe arthritis and abdominal pain often improve with acetaminophen or NSAIDs; however, when these medications do not result in adequate improvement or are contraindicated, systemic glucocorticoids typically result in rapid resolution of symptoms. Renal biopsy in the setting of suspected IgA nephritis is reserved for patients with marked proteinuria or macroscopic hematuria. Evidence of crescentic glomerulonephritis is an indication for high (“pulse”)-dose corticosteroids. All patients with HSP should be seen in follow-up for a screening urinalysis and blood pressure monitoring, as progressive renal involvement should be identified early.

Pearls

  • HSP is a self-limited systemic small-vessel vasculitis that manifests with a tetrad of palpable purpura, arthralgias/arthritis, abdominal pain, and renal disease.
  • There have been many illnesses associated with HSP; however, no single microorganism or environmental exposure has been confirmed as a reliable precipitant of HSP.

Case 2: Serotonin syndrome presenting as myoclonus and hyperreflexia

By Janae K. Heath, MD, ACP Member

The patient

A 38-year-old man with a medical history of morbid obesity (body mass index, 52 kg/m2), major depressive disorder, panic disorder, and chronic low back pain presented with worsening back pain after falling out of bed. On physical examination, he was afebrile, hypertensive, and diaphoretic. Vital signs were otherwise normal. Neurologic examination revealed 3+ brachioradialis and patellar reflexes bilaterally, as well as inducible clonus of his bilateral lower extremities. His strength and sensory examinations were normal, and the remainder of his complete examination was unremarkable. Laboratory testing was notable for creatine kinase (CK) level of 1,184 U/L and white blood cell count of 11,300 cells/µL. A toxicology screen was positive for benzodiazepines and sertraline. An MRI of the spine showed cervical and thoracic spine disease, without substantial central canal or neuroforaminal stenosis or findings to suggest cord compression. Neurosurgical evaluation determined that his MRI findings did not correlate with findings on physical examination.

This patient's outpatient medication regimen notably included the following: sertraline, 100 mg twice daily; buspirone, 15 mg 4 times daily; and aripiprazole, 20 mg daily, as well as the recent addition of clonazepam in the days before his admission. He did not report taking over-the-counter or herbal medications. His findings of hyperreflexia, clonus, and mental status improved after he spent 24 hours in which supportive care was provided and his psychiatric medications were held.

The diagnosis

This patient was diagnosed with serotonin syndrome (SS), an adverse drug reaction resulting in a spectrum of clinical findings caused by increased serotonergic activity in the central nervous system. SS can be the result of therapeutic medication use, inadvertent interactions between drugs, or intentional self-poisoning. Most cases of SS present within 24 hours of a change in dose or after initiation of a serotonergic drug. SS classically presents as a triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. Mental status changes encountered include anxiety, agitated delirium, restlessness, and disorientation. Autonomic findings include diaphoresis, tachycardia, hyperthermia, hypertension, mydriasis, vomiting, and diarrhea. Neuromuscular hyperactivity can manifest as tremor, muscle rigidity, myoclonus (induced or spontaneous), hyperreflexia, and bilateral Babinski sign. Hyperreflexia and clonus are particularly common and are generally more pronounced in the lower extremities. Laboratory findings are nonspecific and include leukocytosis and elevated CK level. In more severe cases, there can be disseminated intravascular coagulation, rhabdomyolysis, metabolic acidosis, or renal failure. Management of SS depends on the severity of clinical findings and includes discontinuation of all serotonergic agents and supportive care. Benzodiazepines can be used, and severe cases of SS can be treated with serotonin antagonists.

In evaluating a patient for SS, clinicians should obtain a detailed description of prescription drugs, over-the-counter medications, illicit substances, and dietary supplements. The selective serotonin reuptake inhibitors (SSRIs) are perhaps the most commonly implicated group of medications, often in combination with other agents. Multiple other medications are associated with SS via inhibition of serotonin reuptake into the presynaptic cleft, including cocaine, MDMA, meperidine, tramadol, serotonin-norepinephrine reuptake inhibitors, dopamine-norepinephrine reuptake inhibitors (including bupropion), tricyclic antidepressants, and St. John's wort. SS can also result from increased release of serotonin (secondary to agents such as amphetamines, cocaine, MDMA, and levodopa), impaired serotonin metabolism (secondary to monoamine oxidase inhibitors), or in the setting of direct serotonin agonists (such as buspirone, triptans, fentanyl, and LSD).

Pearls

  • Serotonin syndrome (SS) is a clinical diagnosis consisting of a spectrum of neurologic findings including mental status changes, neuromuscular hyperactivity, and autonomic findings.
  • The selective serotonin reuptake inhibitors (SSRIs) are the most commonly implicated group of medications, either alone or in combination with other medications.

Case 3: Dengue fever

By Michael A. Roberts, MD

The patient

A 25-year-old woman without significant medical history presented to the hospital with fever, rash, and swelling of her hands and feet 10 days after returning from Indonesia. The patient had spent the previous 2 months working for a company in Jakarta, but with occasional travel to nearby villages. The patient received no immunizations before her travel but received all recommended childhood immunizations. In Indonesia, she drank mostly bottled water and ate well-cooked food with occasional fresh fruit or vegetables. She recalled several mosquito bites. The patient went swimming in local swimming pools and in the Indian Ocean, but not in any freshwater pools or streams. She did not have any sexual contacts in Indonesia. No one she knew had similar symptoms.

One day after returning to the United States, the patient developed a fever to 103 °F. The following day she had a moderate frontal headache and diffuse myalgias. Profound fatigue developed, and 7 days after her return she developed loose stools. She also began to menstruate with heavier than usual flow. Nine days after her return, she noted persistence of fevers to 102 °F. She presented to the hospital the following day when she noted swelling of her hands and feet and a rash on her forearms and shins. On initial exam, the patient had a temperature of 100.3 °F. She had petechiae on her soft palate, lower lip, and anterior shins. Additionally, she had non-tender cervical lymphadenopathy, mild hepatomegaly to palpation, and a diffuse, blanching, macular rash across her torso and limbs. A blood pressure cuff was inflated to 80 mm Hg and held for 2 minutes, after which new petechiae were noted in the patient's antecubital fossa. Laboratory values were notable for leukopenia (white blood cell count, 1,600 cells/µL) with lymphocytic predominance, thrombocytopenia (platelet count of 24,000 cells/µL), and abnormal aminotransferase levels (aspartate aminotransferase level, 207 U/L; alanine aminotransferase level, 147 U/L). Serological testing proved positive for dengue virus IgM. The patent's hospital course was uneventful, with resolution of her leukopenia and improvement in constitutional symptoms. One week later at outpatient follow-up, her petechiae, lymphadenopathy, edema, and myalgias were all noted to have resolved; her fatigue persisted.

The diagnosis

Dengue fever is a mosquito-borne disease now endemic to most of the world's tropical climates. Dengue fever typically presents within 3 to 14 days of the mosquito bite that introduces the virus. Travelers who develop fever more than 2 weeks after their return are unlikely to have dengue fever. Initial symptoms include a high fever, often accompanied by headaches, myalgias, arthralgias, and a morbilliform rash. Some patients will develop a second fever several days after initial defervescence, a pattern that has been called “saddleback fever.” Nausea, vomiting, diarrhea, and coryza symptoms are also frequently reported. Laboratory findings include thrombocytopenia, leukopenia, and mild transaminitis as noted in our patient.

Most cases of dengue fever are self-limited, although fatigue can last for weeks after recovery. Care for patients with dengue is largely supportive. In fewer than 5% of cases, hemorrhagic complications or shock may occur, typically 4 to 7 days into the patient's illness. Clinicians should be watchful during this period for abdominal pain, persistent vomiting, worsening hepatomegaly, lethargy, and change in hematocrit with loss of platelets. These symptoms may suggest hemorrhage or plasma leakage. Patients with systemic vascular leak syndrome may also experience pleural effusions and ascites; this plasma loss can result in the precipitous development of life-threatening hypotension.

Pearls

  • Dengue fever should remain high on the differential diagnosis for travelers with fever returning from tropical Asia, the Caribbean, and Central and South America.
  • Care for the dengue fever patient is primarily supportive, although patients should be monitored for rare but potentially life-threatening hemorrhagic complications or systemic vascular leak syndrome.

Case 4: De Quervain's thyroiditis

By Stephanie V. Sherman, MD, ACP Member

The patient

A healthy 31-year-old woman who was 8 months post-partum presented to her outpatient physician with sore throat and neck tenderness. She received a course of penicillin for presumed streptococcal pharyngitis, but her neck and throat discomfort worsened. She then developed fevers, night sweats, headaches, anxiety, insomnia, tremor, and increased frequency of bowel movements. She was referred for hospital admission when outpatient thyroid testing revealed an undetectable thyroid-stimulating hormone (TSH) level and an elevated free T4 level of 6.9 ng/dL (upper limit of normal, 1.8 ng/dL). Of note, she lived 500 miles away from the Chernobyl nuclear explosion at age 3 and underwent thyroid ultrasounds (all normal) every 2 years as a child.

On presentation, she had a sinus tachycardia to 150 beats per minute, a temperature of 100.4 °F, and normal blood pressure. There was no lid lag nor exophthalmos. The thyroid was asymmetrically enlarged and tender to palpation but without bruits or nodules. Patellar reflexes were brisk. The rest of her complete physical examination was normal. In addition to her undetectable TSH level and elevated free T4 level, she had an elevated total T3 level of 343 ng/dL (upper limit of normal 181 ng/dL) and unremarkable blood counts and chemistries. Testing for thyroid-stimulating immunoglobulin, thyroid peroxidase antibody, and thyrotropin-binding inhibitory immunoglobulin was negative. A technetium-99 thyroid uptake scan revealed diffusely low uptake (0.1% [reference range, 0.5% to 3.75%]). She received intravenous fluids, intravenous hydrocortisone, methimazole, and propranolol, and her symptoms resolved over the next 48 hours. She was discharged on propranolol and a prednisolone taper. Outpatient follow-up demonstrated normalization of thyroid indices, with transient nadir of free T4 of 0.79 ng/dL (lower limit of normal, 0.9 ng/dL) and complete symptom resolution. She never required thyroid hormone supplementation for hypothyroidism.

The diagnosis

This patient presented with thyrotoxicosis due to de Quervain's thyroiditis, also called subacute granulomatous thyroiditis. De Quervain's thyroiditis is an uncommon type of thyroiditis that affects women at least 3 times more frequently than men. The syndrome is theoretically triggered by a viral infection several weeks before onset of thyroid inflammation. Thyroid autoimmunity does not clearly contribute, but there is a genetic association with HLA-B35. De Quervain's thyroiditis is characterized by neck pain, a tender diffuse goiter, and elevated T4 and T3 levels. Classically painless causes of thyroiditis, such as lymphocytic thyroiditis, drug-induced thyroiditis, or post-partum thyroiditis, were excluded on the basis of her thyroid examination, although her recent childbirth put her at particular risk for the latter type. Similarly, pertinent negatives in her clinical history and diagnostic evaluation suggested that other causes of painful thyroiditis, such as infection, radiation, or trauma, were less likely. Hashimoto's can rarely be a painful cause of thyroiditis, but her negative auto-antibodies did not support this diagnosis.

Hyperthyroidism in de Quervain's thyroiditis can range from thyrotoxic to asymptomatic. The hyperthyroid phase is transient and lasts until thyroglobulin stores are exhausted (up to 8 weeks). Most patients experience a transient hypothyroid period before returning to euthyroid state without disease recurrence; some patients do ultimately require thyroid hormone supplementation. Our patient's childhood radiation exposure put her at more risk for thyroid malignancy or hypothyroidism than thyroiditis; she requires thyroid ultrasound screening given her exposure, but there is no known link between de Quervain's thyroiditis and subsequent thyroid malignancy.

Pearls

  • De Quervain's thyroiditis is an uncommon but important form of thyroid dysfunction that is diagnosed via common clinical characteristics (most notably neck pain) and the exclusion of other common thyroid pathologies.
  • Radiation exposure does not increase risk for thyroiditis, although surveillance for thyroid malignancy should be considered in patients with concerning radiation exposure.

Case 5: Kikuchi disease and systemic lupus erythematosus

By Adam Lurie, MD, ACP Member

The patient

A 48-year-old Nepalese woman with a distant history of typhoid presented with 6 weeks of intermittent fever, myalgias, and migratory joint pain. The patient was well until the onset of her symptoms, which began with left thumb soreness and swelling without redness or warmth, and were soon accompanied by malaise, headaches, and crippling morning body aches. She reported no joint symptoms apart from her thumb. These symptoms persisted for 3 weeks, at which point the patient developed nightly fevers to 102 °F. Laboratory evaluation revealed a positive Lyme enzyme immunoassay, for which she was treated with doxycycline by her primary care physician. However, her symptoms continued, and she was admitted to a local hospital where she was noted to have a white blood cell count of 2,600 cells/µL with neutropenia, hematocrit of 32%, negative lyme Western blot, erythrocyte sedimentation rate (ESR) of 68 mm/h, and a C-reactive protein level below 0.3 mg/dL. In addition, anti-nuclear antibody (ANA) was detectable at 1:160 dilution, anti-Ro antibody was positive, anti-La antibody was negative, anti-double stranded DNA antibody was negative, HIV enzyme-linked immunosorbent assay was negative, and cultures of blood and urine were sterile. Her symptoms improved without intervention. She was discharged but had symptom recurrence, prompting presentation to our hospital.

Further testing upon admission to our facility can be summarized as follows: Serum protein electrophoresis and free kappa/lambda ratio were normal, angiotensin-converting enzyme level was normal, C3 and C4 levels were decreased but total complement level was normal, and hepatitis serologies revealed immunity to hepatitis B and absence of exposure to hepatitis C. Cerebrospinal fluid examination, thyroid function studies, rheumatoid factor, and tests for anti-citrullinated protein antibody, human granulocytic anaplasmosis and human monocytic ehrlichiosis screening tests, and Babesia smear were unrevealing. Viral testing for influenza A/B, Epstein-Barr virus, cytomegalovirus, and parvovirus was negative. A combined PET-CT scan revealed diffuse lymphadenopathy throughout the neck, chest, abdomen, and pelvis; while the adenopathy was small (no lymph node measured >1.5 cm), all lymph nodes were fluorodeoxyglucose avid. An excisional lymph node biopsy demonstrated necrotizing lymphadenitis consistent with Kikuchi disease. She was treated with NSAIDs, and her symptoms of malaise and headaches subsequently improved.

On outpatient rheumatology follow-up 1 month later, the patient reported resolution of fevers but return of fatigue. Serologic testing revealed a positive anti-double stranded DNA antibody, meeting criteria for diagnosis of systemic lupus erythematosus (SLE). She was then started on low-dose prednisone as a bridge to hydroxychloroquine therapy, with dramatic and sustained improvement in her constitutional symptoms.

The diagnosis

Kikuchi histiocytic necrotizing lymphadenitis is a rare, benign disorder that classically presents with constitutional symptoms (fever, weight loss, sweats) and cervical lymphadenopathy. The pathogenesis of the disease is not well characterized; however, it is felt to be immune-mediated (CD8-positive T cells and histiocytes) and is normally preceded by a sentinel infectious event. Epstein-Barr virus is most commonly described as the inciting infection, although HIV, parvovirus B19, and respiratory viruses are also described. The disease is most frequently reported in women from Asia or those of Asian descent. Serologic testing is nonspecific and may demonstrate leukopenia and mild neutropenia and or mild elevations in liver aminotransferase levels. While Kikuchi disease is classified as an inflammatory syndrome, erythrocyte sedimentation rate and C-reactive protein are typically normal or minimally elevated.

The definitive diagnosis of Kikuchi disease is made by excisional lymph node biopsy, which demonstrates necrosis and infiltration of histiocytes. The differential for this disease is wide, and lymphoma, tuberculous adenitis, and lymphogranuloma venereum are included. Kikuchi disease is typically self-limited. There is no established treatment for Kikuchi disease, although symptoms normally abate over 1 to 4 months. NSAIDs, steroids, and other anti-inflammatory medications can be considered for symptom management. Finally, many patients with Kikuchi disease will ultimately develop SLE, and therefore they should be followed and assessed for the diagnostic criteria for SLE even after their initial symptoms improve or resolve.

Pearls

  • Kikuchi histiocytic necrotizing lymphadenitis is a rare, benign, and typically self-limited disease characterized by nonspecific constitutional symptoms and lymphadenopathy, most often noted in women of Asian descent.
  • Many patients with Kikuchi disease subsequently develop systemic lupus erythematosus (SLE), monitoring for which should continue even after initial symptoms abate.

Case 6: Primary biliary cirrhosis and primary sclerosing cholangitis overlap syndrome

By Emily S. Hughes, MD, ACP Member

The patient

A 26-year-old woman with a history of myeloproliferative disorder status post-splenectomy, common variable immunodeficiency, colitis not otherwise specified, and a prior diagnosis of primary biliary cirrhosis (PBC) was admitted with intermittent right upper quadrant (RUQ) abdominal pain, subjective fever, nausea and vomiting, and weight loss progressive over 1 month. On initial physical examination, she was cachectic and jaundiced. Abdominal examination was remarkable for tenderness to palpation in the RUQ with voluntary guarding and a negative Murphy's sign. Laboratory testing revealed the following abnormalities: alanine aminotransferase level, 141 U/L (reference range, 7 to 33 U/L); aspartate aminotransferase level, 180 U/L (reference range, 9 to 32 U/L); alkaline phosphatase level, 1,647 U/L (reference range, 30 to 100 U/L); total bilirubin level, 9.9 mg/dL (reference range, 0 to 1.0 mg/dL); direct bilirubin level, 5.9 mg/dL (reference range, 0 to 0.4 mg/dL), and gamma-glutamyl transpeptidase level, 742 U/L (reference range, 5 to 36 U/L). Antinuclear antibody (ANA) and antimitochondrial antibody (AMA) testing was negative, and anti-smooth muscle antibody (SMA) was positive at 1:20. Magnetic resonance cholangiography showed biliary strictures suggestive of primary sclerosing cholangitis (PSC). However, liver biopsy revealed pathology consistent with PBC. The patient was treated with ursodeoxycholic acid, which resulted in improvement in her symptoms and hepatic enzymes before discharge.

The diagnosis

This patient's diagnosis is a PBC-PSC “overlap syndrome”. Autoimmune hepatitis, PBC, and PSC are chronic cholestatic liver diseases with presumed autoimmune causes, and overlap syndrome is used to describe forms of autoimmune hepatobiliary disease that present with characteristics typical of autoimmune hepatitis, PBC, or PSC that occur in the same patient. Overlap of autoimmune hepatitis and PBC is most frequently described, and overlap between PBC and PSC is rarely reported.

The diagnosis of PBC-PSC overlap involves a combination of features of both diseases. Typically, patients with either disease in isolation present asymptomatically or report fatigue, pruritus, RUQ abdominal pain, and/or jaundice. In either PBC or PSC there can be mild to moderate elevation in aminotransferase levels, an elevated alkaline phosphatase level, and increased immunoglobulin (IgG and IgM) concentrations. However, specific autoantibodies are a point of differentiation. AMA is a serologic marker present in at least 95% of PBC patients. In contrast, there are no specific serological markers for PSC, but associated autoantibodies include ANA, SMA, and p-anti-neutrophil cytoplasmic antibody (usually in low titers); AMA is virtually absent in PSC patients. Imaging with magnetic resonance cholangiopancreatography is the gold standard for diagnosis of PSC, revealing a characteristic “bead on a string” appearance due to segmental fibrosis of intrahepatic and/or extrahepatic bile ducts with saccular dilatation of normal intervening areas. A liver biopsy is often needed to establish the diagnosis in patients with either disease, in particular for patients suspected to have PBC but with a negative AMA. The histology of patients with PBC is characterized by degenerating bile duct epithelium with ductal obliteration and often formation of a granuloma, called a “florid duct lesion.” Typical liver histology of PSC reveals progressive inflammation and concentric fibrosis of biliary ducts.

Treatment of overlap syndromes lacks clear consensus due to their rarity and the absence of large therapeutic trials. Management is therefore mainly based empirically on data from primary autoimmune hepatobiliary diseases. Ursodeoxycholic acid is the only drug option beneficial in both PBC and PSC and can delay disease progression to cirrhosis. Given the lack of data, it is also not known how the prognoses of such patients differ from those with individual component disorders and if the former group progresses more quickly to cirrhosis. However, as with primary autoimmune hepatobiliary diseases, overlap disease shows a progressive course toward end-stage liver disease and has no curative options. Liver transplantation ultimately remains the only option for such patients.

Pearls

  • “Overlap syndrome” describes forms of autoimmune hepatobiliary disease that have a combination of features of autoimmune hepatitis, primary biliary cirrhosis (PBC), or primary sclerosing cholangitis (PSC); PBC-PSC overlap is rare.
  • Treatment of PBC variants with ursodeoxycholic acid may delay disease progression to cirrhosis, but liver transplantation remains the only option in end-stage liver disease secondary to overlap syndromes.