Cases from Brown University: Rhode Island Hospital/The Miriam Hospital

Patient cases involving Benedikt's syndrome, Chikungunya fever, essential thrombocythemia, and more.


By Kristy Webster, MD; Ashley Weber, MD; Steven Schaub, MD; Thomas Ollila, MD, ACP Resident/Fellow Member; Michael Prodromou, MD, ACP Member; Manasa Ayyala, MD, ACP Resident/Fellow Member; Elizabeth Ko, MD, ACP Resident/Fellow Member; Megha Garg, MD, MPH, ACP Resident/Fellow Member; Ross Hilliard, MD, ACP Resident/Fellow Member; and Caitlin Dugdale, MD, ACP Resident/Fellow Member

Physician editor: Christopher Sankey, MD, FACP

Deputy physician editor: Benjamin Galen, MD, ACP Member

Case 1: Benedikt's syndrome

By Kristy Webster, MD, and Ashley Weber, MD

The patient

A 75-year-old woman with hypertension and hyperlipidemia presented to an outside hospital with acute onset diplopia, vertigo, and ataxia. Initial evaluation was notable for left oculomotor palsy (partial ptosis, medial rectus, and superior rectus palsies), profound ataxia, gait instability, and dysmetria on the right with finger-to-nose testing. Basic laboratory testing was unremarkable. A non-contrast head CT and brain MRI were negative for acute stroke or hemorrhage, but findings of atrophy and leukoaraiosis were noted. Magnetic resonance angiography of the head and neck were notable for dolichoectasia of the basilar, vertebral, and carotid arteries without evidence of stenosis, aneurysm, or arteriovenous malformation. Cerebrospinal fluid studies were normal.

Diffusion-weighted sequence on brain magnetic resonance imaging demonstrating left paramedian upper midbrain hyperintensity consistent with acute ischemic stroke
Diffusion-weighted sequence on brain magnetic resonance imaging demonstrating left paramedian upper midbrain hyperintensity consistent with acute ischemic stroke.

While an inpatient at the outside hospital, the patient developed a waxing and waning mental status. Repeat head CT was unremarkable. Given the negative stroke evaluation and improvement in her partial ptosis with placement of ice over her eyes for several minutes (positive ice pack test), the patient was suspected to have ocular myasthenia gravis. She was started on pyridostigmine without improvement and was transferred to our hospital given concern for myasthenic crisis. Upon transfer, our neuroradiologist reviewed all prior imaging, noting a subtle hyperintensity on the diffusion-weighted imaging sequence consistent with an acute left paramedian upper midbrain stroke (Figure 1). Anti-AChR and anti-MuSK antibody testing for myasthenia gravis returned negative.

The diagnosis

This patient was diagnosed with Benedikt's syndrome, also called “paramedian midbrain syndrome” or “inferior red nucleus syndrome.” This syndrome, first described in 1889 by Moritz Benedikt, is a constellation of symptoms including ipsilateral oculomotor palsy, cerebellar ataxia, and contralateral involuntary movements such as intention tremors, hemichorea or hemiathetosis. It results from a midbrain infarct of the penetrating branches of the posterior cerebral artery.

Although MRI is highly sensitive and specific for stroke, this case illustrates that a negative study does not exclude the diagnosis when clinical suspicion remains high, especially if the lesion localizes to the brainstem. Brainstem lesions on neuroimaging are often subtle and difficult to identify. The clinical picture was highly suggestive of an acute ischemic event, and yet imaging initially did not corroborate the diagnosis. After completing a full course of physical therapy, the patient was able to able to ambulate with the use of a walker, but her unsteadiness persisted when seen in clinic 5 months after her initial stroke.

Pearls

  • Benedikt's syndrome, the result of a ventral paramedian midbrain infarct, presents with ipsilateral oculomotor palsy, cerebellar ataxia, and contralateral involuntary movements.
  • High clinical suspicion should prompt close review of neuroimaging, as MRI findings can be subtle.

Case 2: Chikungunya fever as a cause of polyarthralgias after travel to the tropics

By Steven Schaub, MD

The patient

A 54-year-old man without significant medical history presented with 2 days of generalized malaise, arthralgia of the wrists and ankles, fever to 103° F, and a truncal rash. He also reported nausea and non-bloody emesis. Of note, 2 days before presentation, he had returned from a 1-week trip to the Dominican Republic. Two family members also had similar but less severe symptoms.

Physical examination on admission was notable for a temperature of 102.4° F, tachycardia to 115 beats/min, diaphoresis, bilateral scleral injection, an erythematous reticular rash on his chest and trunk, and symmetrically tender ankles and wrists with pain-limited range of motion. No joint effusion, erythema, or edema was noted. Laboratory data revealed mild leukopenia (white blood cell count, 3,100 to 5,300 cells/μL with lymphopenia), mild thrombocytopenia (platelet count, 100,000 to 150,000 cells/μL), and mild aminotransferase abnormalities (aspartate aminotransferase 86 U/L; alanine aminotransferase 76 U/L). Respiratory viral panel, rapid HIV test, blood cultures, and blood parasite smears were negative. Serologic samples sent to the Centers for Disease Control and Prevention (CDC) and the Rhode Island Department of Health returned positive for anti-chikungunya virus IgM antibodies. The patient was discharged home after 5 days of supportive care.

The diagnosis

Chikungunya virus is endemic to West Africa and typically presents as a mild febrile illness with polyarthralgias. The typical acute illness lasts 1 week, though arthralgias may persist for months. The first cases of chikungunya were described in Tanzania in the 1950s with the name derived from local dialect meaning “stooped walk” or “that which bends up,” owing to the debilitating nature of the arthralgias. Transmission occurs via a mosquito vector, typically Aedes aegypti or Aedes albopictus, and is more frequent in the summer months.

Cases first appeared in the Caribbean in late 2013, with increasing numbers of imported cases documented in the United States. Only 11 cases of locally transmitted disease, all in Florida, have been documented in the U.S. as of October 2014. Co-infections with dengue or yellow fever can occur due to shared vectors and typically result in prolonged infection.

Treatment is largely supportive, with anti-inflammatory medications for symptomatic relief, as antivirals or corticosteroids have not proven beneficial. No vaccine or prophylactic medicine is currently available for this disease, although use of skin barrier protection and insect repellent is recommended.

Pearls

  • Chikungunya fever is an arbovirus transmitted by Aedes mosquitoes that presents with symmetric polyarthralgias, high fevers, and malaise lasting 7 to 10 days.
  • Laboratory findings include lymphopenia, thrombocytopenia, and transaminitis, as well as IgM anti-chikungunya virus antibodies.

Case 3: Essential thrombocythemia presenting as dental bleeding

By Thomas Ollila, MD, ACP Resident/Fellow Member

The patient

A 66-year-old woman with a history of stroke and a remote bleeding episode after previous dental extraction presented with continued bleeding at the site of a recent tooth extraction. She had been in her usual state of health until presenting to an outside hospital with a sore and loose second premolar tooth. The emergency department physician removed her tooth, and she was discharged. When she returned later that day for continued bleeding from the extraction site, basic labs revealed pronounced leukocytosis and thrombocytosis; her physical examination was unrevealing for splenomegaly or lymphadenopathy. The patient was transferred to our hospital for further evaluation.

Peripheral blood smear demonstrating an abnormally large number of platelets consistent with essential thrombocythemia
Peripheral blood smear demonstrating an abnormally large number of platelets consistent with essential thrombocythemia.

Repeated labs were notable for a leukocytosis to 28,800 cells/μL and a platelet count of over 2 million cells/μL. A peripheral blood smear demonstrated striking thrombocytosis (Figure 2). Given her continued bleeding, treatment was initiated with aminocaproic acid, but suturing was required to achieve hemostasis. BCR-ABL testing for chronic myelogenous leukemia (CML) was negative, but a JAK2 mutation returned positive. Her overall clinical picture was most consistent with essential thrombocythemia. The patient was started on hydroxyurea and aspirin with eventual reduction in her platelet count.

The diagnosis

This patient's diagnosis is essential thrombocythemia (ET). Even at very elevated platelet counts, ET is a diagnosis of exclusion both of other chronic myeloproliferative disorders and of reactive thrombocytosis. While the incidence of ET is relatively low, at 2.5/100,000 persons, it is associated with a normal life expectancy and prevalence is around 2.4 per 10,000 persons. Despite a significantly elevated platelet count, this patient presented with an acute bleeding episode. Both thrombosis and hemorrhage can occur in ET, especially with platelet counts over 1 million. The increased risk of bleeding is thought to be secondary to an acquired von Willebrand deficiency from an increase in ADAMTS13 cleaving protease associated with the high platelet count. Very high platelet counts may also compromise clotting factor function even in the absence of factor deficiency. The mainstays of therapy are aspirin and hydroxyurea, both to minimize vasomotor symptoms as well as to reduce the risk of thrombosis.

Pearls

  • Essential thrombocytosis (ET) is a myeloproliferative disorder associated with acquired JAK2 mutation.
  • In ET, an elevated platelet count confers not only a clotting risk but also a bleeding risk, particularly when platelet counts exceed 1 million cells/μL.

Case 4: Autoimmune enteropathy in an elderly woman

By Michael Prodromou, MD, ACP Member

The patient

An 86-year-old woman with a history of hypothyroidism, Alzheimer's disease, and hypertension presented with 3 weeks of nonbloody, watery diarrhea, averaging 12 episodes per day. This diarrhea was associated with a 20-pound weight loss over the same period. Physical exam revealed a nontender abdomen and hyperactive bowel sounds. Infectious workup for Clostridium difficile, Shigella, Campylobacter, Escherichia coli, Salmonella, Giardia, and Isospora was negative. CT scan of the abdomen was unrevealing. Spot fecal fat was positive and thus suggestive of malabsorption, but the stool osmolar gap was equivocal.

Duodenal biopsy revealing villous blunting active inflammation and increased intraepithelial lymphocytes
Duodenal biopsy revealing villous blunting, active inflammation, and increased intraepithelial lymphocytes.

Numerous antimotility agents, including octreotide, were attempted without success. Despite a 10-day period of bowel rest, during which the patient received total parenteral nutrition, her diarrhea persisted. A small bowel enteroscopy was remarkable only for mucosal congestion in the duodenum. Biopsies revealed moderate to severe villous blunting, mild active inflammation, and increased intraepithelial lymphocytes in the duodenum and jejunum (Figure 3). The patient was placed on a gluten-free diet with improvement in her symptoms and was subsequently discharged home.

Four days later, she presented with dehydration secondary to persistent diarrhea despite gluten restriction. Anti-tissue transglutaminase, anti-endomysial antibodies, anti-gliadin antibodies, anti-enterocyte antibodies, and IgA levels returned to normal. She was ultimately started on oral prednisone and experienced significant improvement of symptoms within 1 week. One month later, she reported complete resolution of her diarrhea.

The diagnosis

This patient was diagnosed with autoimmune enteropathy (AIE), a cause of intractable diarrhea in children, with rare cases also reported in adults. The pathophysiology is not fully understood, but defects in T-cell and humoral homeostasis have been implicated in villous injury. Revised criteria for adult AIE include chronic diarrhea, malabsorption, and histology demonstrating villous blunting, increased crypt apoptotic bodies, and/or minimal intraepithelial lymphocytosis. The presence of anti-enterocyte and anti-goblet antibodies supports AIE, but their absence does not exclude the diagnosis.

Treatment of AIE should address both symptoms and the underlying disease. As many patients with AIE develop malnutrition, enteral or parenteral nutritional supplementation may be warranted. Corticosteroids remain first-line therapy for AIE. Other immunosuppressive agents, including 6-mercatopurine, azathioprine, mycophenolate mofetil, rituximab, sirolimus, and cyclosporine, may be used in refractory disease.

Pearls

  • Autoimmune enteropathy (AIE) should be considered in patients with unexplained diarrhea and malabsorption.
  • Corticosteroids and other immunosuppressive agents can be effective in treating AIE.

Case 5: Severe babesiosis

By Manasa Ayyala, MD, ACP Resident/Fellow Member

The patient

A 76-year-old woman with a history of hypertension, hypothyroidism, and recent admission 1 month before repair of left intertrochanteric femur fracture presented to the emergency department for evaluation of fevers, fatigue, and shortness of breath. Her review of systems was negative for abdominal pain, nausea, vomiting, insect bites, rashes, or joint pains. Physical examination was unremarkable apart from tachycardia to 125 beats/min. Shortly after arrival, she developed fevers to 103° F with worsening shortness of breath. Laboratory findings were notable for an initial hemoglobin level of 9.1 g/dL, which 36 hours later decreased to 6.6 g/dL. Haptoglobin level was less than the lower-limit detection, and lactate dehydrogenase level was elevated at 672 U/L (reference range, 100-220 U/L). A peripheral blood smear was sent for parasite detection and intracellular ring-form organisms were found, consistent with Babesia infection. The red blood cell infection rate was 15%.

The patient was initially started on azithromycin and atovaquone but was quickly switched to IV clindamycin and oral quinine as worsening anemia and acute kidney injury evolved. Progressive dyspnea prompted transfer to the medical ICU, where she underwent red blood cell exchange transfusion; afterward, her parasite load dropped from 15% of infected red blood cells to 2%.

The diagnosis

This patient was diagnosed with acute babesiosis and associated end-organ dysfunction. The source of her babesiosis was not immediately obvious as she had no recent tick bites or outdoor exposures, though she did receive 2 units of packed red blood cells during her hip surgery 1 month prior. Babesiosis is the most common reported cause of red blood cell transfusion-transmitted infection in the U.S., and her recent transfusion was considered to be the likely source. In 2011, babesiosis became a nationally reportable condition to the CDC. Since the first transfusion-associated babesiosis case was described in 1979, over 150 cases have been confirmed in the U.S. More than 20 cases have been reported by the state of Rhode Island, with one study on Block Island, R.I., finding that babesiosis rates were 10-fold greater than in other endemic areas around the U.S. and that babesiosis was only 25% less common than Lyme disease. While Rhode Island is the only state to screen for Babesia species prior to transfusion, this practice is limited to neonates and patients with sickle cell anemia and thalassemia undergoing exchange transfusion.

Infection with Babesia can be severe, especially in the elderly, immunocompromised, and asplenic patient populations with significant associated morbidity and mortality. Exchange transfusion is indicated for patients with significant anemia and high parasitemia (>10%) but may also be of benefit to patients with a lower parasite burden who develop end-organ dysfunction. Our patient was ultimately transitioned to oral azithromycin and atovaquone to complete a 2-week course of therapy. Her parasite load continued to decrease, with no parasites visible on peripheral smear by the time of discharge.

Pearls

  • Babesia infection is the most common cause of infection related to red blood cell transfusion in the U.S., particularly in geographic areas with higher prevalence.
  • In severe babesiosis, exchange transfusion should be considered, with a target parasite load reduction of 90%.