Cases from Maine Medical Center

Meningoencephalitis, cerebral amyloid angiopathy, tophaceous gout, and more.


Case 1: Capnocytophaga meningoencephalitis

By Katherine Garlo, MD, ACP Member; Christina DeMatteo, DO, ACP Resident/Fellow Member; Robert Smith, MD; and John Erickson, MD, FACP

The patient

Digital ischemia and ulcerative necrosis on the fingers and toes with less-thanigreater-thanCapnocytophaga canimorsusless-thanslashigreater-than meningoencephalitis Courtesy of the case authors
Digital ischemia and ulcerative necrosis on the fingers and toes with Capnocytophaga canimorsus meningoencephalitis. Courtesy of the case authors

A 63-year-old man without significant medical history was bitten on his right hand by his dog 1 week prior to presentation. He promptly cleaned the wound but did not seek medical attention. Within 2 days he developed fever, shaking chills, and headache, followed shortly by the appearance of painless, purple lesions on his fingers and toes (Figure 1). At this time, he presented to a community hospital emergency department and was noted to have fever, tachycardia, tachypnea, and leukocytosis. He developed confusion and disorientation and experienced a tonic-clonic seizure, after which he was intubated for airway protection. Blood cultures and lumbar puncture were performed. He was transferred to an intensive care unit by aeromedical evacuation. Fluids and vasopressors were necessary for hypotension, and he was given empiric antibiotics for bacterial meningitis.

Physical examination confirmed the previously described lesions on fingers and toes, without warmth, swelling, fluctuance, or exudate. There were also scattered purpura on the shins, oral mucosa, and chest. Pertinent laboratory results on presentation included: a lactate level of 5.6 mEq/L, a creatinine level of 3.33 mg/dL, an aspartate aminotransferase (AST) level of 194 U/L, an alanine aminotransferase (ALT) level of 218 U/L, an international normalized ratio (INR) of 1.4, and a D-dimer value greater than 20,000 ng/mL. The complete blood count revealed normal white and red cell counts and thrombocytopenia (platelets, 39,000/µL), and blood smear demonstrated no schistocytes. The spinal fluid had greater than 2,000 white blood cells (60% neutrophils), undetectable glucose, and a protein level of 314 mg/dL.

Head CT was normal, but MRI of the brain showed debris within the lateral ventricles and mild diffuse pachymeningeal enhancement. Cerebrospinal fluid culture was negative, and blood cultures ultimately grew Capnocytophaga canimorsus. His condition stabilized, and antibiotics were narrowed to ceftriaxone. He exhibited no further seizures, his mental status normalized, and end-organ dysfunction resolved. He was discharged home to complete a 28-day course of intravenous antibiotics.

The diagnosis

The patient's presentation, laboratory testing, and imaging were consistent with Capnocytophaga meningoencephalitis leading to septic shock and disseminated intravascular coagulation (DIC). Capnocytophaga canimorsus is the most common human pathogen associated with dog bites. The genus Capnocytophaga is a gram-negative, fastidious, capnophilic rod that thrives in carbon dioxide-enriched environments. The species canimorsus is a commensal bacteria found in the oral cavity of dogs and cats but not part of humans' normal microbiology. C. canimorsus is slow-growing in vitro and may require up to 10 days of incubation. Many laboratories are unable to presumptively identify C. canimorsus isolates and report them as “gram-negative rods.”

The chance of infection with C. canimorsus is approximately 20% following a dog bite and 50% after a cat bite. Infection severity ranges from self-limited skin lesions to fulminant septic shock with DIC, and mortality rate in DIC cases is reported to be as high as 30%. Clinical infection typically presents within 2 to 3 days of exposure and appears with cellulitis, ischemic cyanotic skin lesions, scattered purpura, and thrombocytopenia. The skin and soft tissues are the most common sites of infection, and the purpuric lesions noted in this patient occurred independent of DIC. It is hypothesized that bacterial antigens expressed on the cell surface of polymorphonuclear leukocytes trigger immune complex deposition on the vascular endothelium, leading to the scattered purpura skin lesions. Extension to the bloodstream yields septicemia and potential seeding of the central nervous system. Though rare, endocarditis has also been reported. The greatest risk factor is occupational exposure to dogs and cats, for example, through working as a veterinarian or breeder. Pet owners can also be at risk. Advanced age, asplenia, immunosuppression, and alcoholism are additional risk factors. Antibiotic choice, route, and duration of therapy depend on the site and severity of infection. Duration of antibiotic therapy is a minimum of 3 weeks, and the condition resolves in most patients without specific sequelae.

Pearls

  • Capnocytophaga is the most common human pathogen associated with dog bites and is associated with ischemic cyanotic skin lesions.
  • The severity and extent of Capnocytophaga infection range widely, from self-limited skin lesions to septic shock. Meningitis, encephalitis, and endocarditis are less common.

Case 2: Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing

By Katherine Garlo, MD, ACP Member, and Eric Dinnerstein, MD

The patient

A 33-year-old woman with a history of migraine headaches and active tobacco use presented with unilateral right-sided headache and painful swelling and lacrimation of her right eye. On the morning of admission, she had acute onset of a severe, sharp, “stabbing” headache that was intermittent, lasting only 5 to 30 seconds, and occurring 5 to 6 times every hour. This headache was different from her typical migraine symptoms. Within hours, she developed swelling, erythema, and lacrimation of the right eye. She took tramadol, diclofenac, and hydrocodone-acetaminophen without improvement, prompting her to the present to the emergency department. Review of systems was negative for vision changes, photophobia, or other focal neurological symptoms.

Of note, the patient had similar presentations 3 times in the past year and was diagnosed with preseptal cellulitis each time. She had been admitted 2 months prior, treated with intravenous antibiotics and discharged on oral sulfamethoxazole/trimethoprim with the plan to follow up with ophthalmology.

At the present admission, vital signs were normal. Eye examination was notable for erythema and swelling around the right eye, a normal pupillary reflex, intact extraocular muscles, non-injected sclera, and normal tearing. The oropharynx was clear without erythema, exudates, or edema. Neck examination showed no postauricular or mastoid tenderness to palpation and no lymphadenopathy in the cervical, supraclavicular, or axillary nodes. She was started on broad-spectrum intravenous antibiotics for presumed recurrent preseptal cellulitis.

Laboratory testing was notable for a normal complete blood count and erythrocyte sedimentation rate. An MRI of the brain with sagittal sinus venography confirmed right-eye preseptal cellulitis without postseptal involvement and no dural or cavernous sinus thrombosis. She had a normal examination under direct dilated ophthalmoscopy. She was treated with indomethacin, 25 mg 3 times daily, and received smoking cessation counseling. With treatment, her unilateral headache and conjunctivitis improved and she was discharged home.

The diagnosis

The patient was diagnosed with a rare form of trigeminal autonomic cephalalgia (TAC) known as short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). TACs are a rare group of primary headache disorders that include cluster headache, paroxysmal hemicranias, SUNCT, and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). TACs are often misdiagnosed due to their rarity and diagnostic mimicry. The International Headache Society's diagnostic criteria for TACs include unilateral head pain usually located in the orbital, supraorbital, or temporal region and ipsilateral cranial autonomic symptoms, usually in the ophthalmic distribution of the trigeminal cranial nerve, such as conjunctival injection, lacrimation, nasal congestion, rhinorrhea, ptosis, and eyelid edema.

The TAC headaches are distinguished by the duration and frequency of attacks as well as their response to treatment. SUNCT has the highest frequency of attacks, often up to 200 daily, lasting for 5 to 120 seconds. The TACs are a diagnosis of exclusion after medical (e.g., sinusitis, preseptal cellulitis, conjunctivitis, dural sinus thrombosis) and ophthalmic (e.g., acute closed-angle glaucoma) causes have been ruled out. Due to extreme pain and autonomic symptoms, they cause significant suffering and functional limitations. This patient's painful swelling and lacrimation of her right eye in combination with the frequency and duration of attacks made SUNCT the most likely diagnosis.

The treatment for SUNCT is multifactorial and patient-specific and is often overseen by a neurologist specializing in headaches. There is no abortive therapy. Paroxysmal hemicrania headaches respond to high-dose indomethacin, and cluster headaches respond to supplemental oxygen. These treatments may be attempted in patients with SUNCT, but they often have limited effect. Preventive therapy includes medications that stabilize the ion channels of the trigeminal nerve, such as antiepileptics (e.g., lamotrigine, carbamazepine, topiramate) and gabapentin. Unlike in migraine headache, beta-blockers and calcium-channel blockers have not been shown to be effective for prevention.

Pearls

  • TACs are a rare form of primary headache that should be considered in patients with unilateral periorbital headache associated with ipsilateral autonomic symptoms.
  • SUNCT, a type of TAC, can be treated with indomethacin, but care is primarily supportive.

Case 3: Cerebral amyloid angiopathy and intraparenchymal hemorrhage

By Katherine Garlo, MD, ACP Member, and Eric Dinnerstein, MD

The patient

An 82-year-old woman with Alzheimer's disease, hypertension, hyperlipidemia, and atrial fibrillation on warfarin presented 2 days after a fall at home with new speech changes and weakness in her right leg. Physical examination was notable for hypertensive emergency (blood pressure 190/110 mm Hg), expressive aphasia with dysnomia, and right leg weakness. Head CT showed left frontal and temporal subdural hematomas with a 3-cm left temporal intraparenchymal hemorrhage. INR was initially 2.4 and was promptly normalized. She was started on a nicardipine drip and transferred to the intensive care unit.

An MRI of the brain with susceptibility-weighted images demonstrated multiple areas of susceptibility artifact in both cerebral hemispheres, suggesting microvascular hemorrhages. There were no acute ischemic or hemorrhagic infarcts. Magnetic resonance angiogram was negative for flow-limiting stenosis, aneurysm, and vascular malformation. She was discharged to acute inpatient rehabilitation with strict blood pressure control with maximum doses of losartan, labetalol, and diltiazem. Her symptoms of expressive aphasia and right lower-extremity weakness improved. Upon discharge, she was maintained off warfarin, antiplatelet agents, and statins due to her increased risk for recurrent intracranial hemorrhage.

The diagnosis

This patient's diagnosis is cerebral amyloid angiopathy (CAA), with associated intracranial hemorrhage (ICH). The underlying pathophysiology of CAA is thought to be due to increased deposition of amyloid β (Aβ) protein in cerebral blood vessels and capillaries. The vessel walls become fragile and are predisposed to rupture, resulting in intraparenchymal microhemorrhages.

The mechanism for increased deposition of Aβ is under investigation. Current theories suggest increased production and abnormal clearance. Mutations in the amyloid precursor protein genes in familial forms have been linked with increased rates of cleavage into Aβ protein. Most cases are sporadic; however, familial forms in Flemish, Dutch, and other populations have been documented.

CAA is limited to the brain and spinal cord and is not related to systemic amyloidosis. CAA is diagnosed radiographically with MRI with susceptibility-weighted or gradient echo images showing low signal foci suggestive of microhemorrhages and can be missed on fluid-attenuated inversion recovery (FLAIR) imaging.

Patients with CAA have increased risk of intraparenchymal hemorrhage, which is often the initial presentation. CAA is the second most common cause of intraparenchymal hemorrhage in elderly patients (after uncontrolled hypertension), accounting for 30% to 40% of cases. There is a strong association between CAA and Alzheimer's disease. CAA most often occurs in patients over age 70 years, and the only definitive risk factor is advanced age. Cognitive decline and memory impairment often precede ICH, and 40% of patients with CAA ICHs have been previously diagnosed with dementia. Some patients with CAA ICH experience rapid cognitive decline, which has been attributed to additive effects of cortical hemorrhages and infarctions in patients with underlying accumulation of neuritic plaques and vascular deposition of amyloid.

Compared to hypertensive ICH, CAA ICH is located peripherally in lobar brain tissue rather than in the deep brain tissue of the basal ganglia. As a result, CAA ICH is associated with a lower mortality rate (11% to 32%) and better functional outcomes than hypertensive ICH. However, morbidity of CAA ICH is impacted by the high recurrence rate, which is estimated at 10% to 40% within the first year. Second CAA ICHs are associated with a higher mortality rate (up to 40%). The risk of subsequent ICH in patients with CAA is exacerbated by hypertension. Anticoagulation and antiplatelet therapy may be additional risk factors for recurrence and are hence generally avoided. The mainstay therapeutic interventions include blood pressure control combined with careful assessment of the risks versus benefits of antiplatelet agents and anticoagulation.

Pearls

  • CAA is the second most common cause of intraparenchymal hemorrhage in elderly patients; the diagnosis is made by MRI with susceptibility-weighted or gradient echo images and can be missed on fluid-attenuated inversion recovery imaging.
  • Patients with CAA intracranial hemorrhage are at increased risk for additional bleeds, and the rate of recurrent hemorrhage is approximately 10% to 40% per year; risks and benefits of antiplatelet agents and anticoagulants must be carefully weighed in such patients.

Case 4: Mycoplasma pneumoniae and cold agglutinin disease

By Katherine Garlo, MD, ACP Member, and John Erickson, MD, FACP

The patient

A 56-year-old man with no significant medical history presented with 2 weeks of worsening cough and difficulty breathing. The cough was productive of “yellow-green” sputum without blood, and he also had dyspnea on exertion. He had not traveled recently and took no medications. On admission he was afebrile with blood pressure 144/94 mm Hg, a pulse of 78 beats/min, a respiratory rate of 24 breaths/min, and oxygen saturation of 90% on room air that increased to 96% on 2 L of supplemental oxygen.

Physical examination was noteworthy for decreased breath sounds and rhonchi in the right middle and lower lung fields. Notable laboratory studies included the following: hemoglobin level, 6.9 mg/dL; hematocrit, 20.7%; markedly elevated lactate dehydrogenase level to 1,200 U/L (reference range, 94 to 250 U/L); total bilirubin level, of 1.4 mg/dL; direct bilirubin level, 0.3 mg/dL; reticulocytes, 4.3% (reticulocyte index, 0.8); and presence of 1+ schistocytes on peripheral blood smear. Admission chest X-ray demonstrated a right middle lobe infiltrate consistent with pneumonia.

Testing for influenza, Epstein-Barr virus (EBV), and Legionella was negative. Coombs testing was negative for IgG and positive for CD3, which is consistent with cold agglutinin disease related to IgM deposition on red blood cell surface. Serologic testing for Mycoplasma pneumoniae showed a high IgM titer. Negative serum and urine protein electrophoresis ruled out a paraproteinemia. With antibiotics and following blood transfusion, the patient's oxygen saturations normalized, his hemoglobin level remained stable, and his hemolysis resolved.

The diagnosis

This patient was diagnosed with autoimmune hemolytic anemia from cold agglutinin disease triggered by Mycoplasma pneumoniae respiratory infection. Cold agglutinin disease is most commonly caused by IgM antibodies directed against polysaccharide antigens on the red blood cell surface that cause agglutination of red cells at low temperatures. This triggers extravascular autoimmune hemolysis in the reticuloendothelial system of the spleen and liver. The reticulocyte index and indirect bilirubin are typically higher than seen in this case, and the schistocytes seen on peripheral blood smear are also not typical with extravascular hemolysis. However, in the context of the patient's confirmed Mycoplasma respiratory tract infection and results of the Coombs test, his diagnosis was most consistent with cold agglutinin disease.

Cold agglutinin disease is associated with lymphoproliferative disorders such as monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenstrom macroglobulinemia, lymphoma, and leukemia. It is also associated with infection, most commonly Mycoplasma pneumoniae and EBV. Cold agglutinin production occurs approximately 2 weeks after the onset of the primary disease, and clinical manifestations occur when the IgM antibody titer is greatly elevated. Antibody titers diminish as the illness resolves and return to normal within 4 months. Management consists of treatment for the underlying illness, warm environment, and the use of transfusion warmers for blood products.

Pearls

  • Cold agglutinin disease can be secondary to infection from Mycoplasma pneumoniae or EBV infection and can also be associated with lymphoproliferative diseases.
  • Cold agglutinin disease causes an extravascular, IgM-mediated autoimmune hemolytic anemia that can be diagnosed with Coombs testing.

Case 5: Acquired methemoglobinemia

By Katherine Garlo, MD, ACP Member, and John Erickson, MD, FACP

The patient

A 44-year-old woman with a medical history of diffuse large B-cell lymphoma (DLBCL) presented with 1 week of progressive shortness of breath. She previously received an allogenic bone marrow transplant that was complicated by graft-versus-host disease (GVHD). She reported no cough, sputum, fevers, chills, or wheezing but did report dyspnea on exertion. Two days before presentation, she had been started on levofloxacin by her primary care physician for presumed respiratory tract infection. No other recent medication changes were noted. Her medication regimen included immunosuppressive therapy for GVHD (tacrolimus and prednisone), valacyclovir for herpes simplex virus and cytomegalovirus prophylaxis, and dapsone for Pneumocystis jirovecii pneumonia (PJP) prophylaxis.

On physical examination, her blood pressure was 148/95 mm Hg, her pulse was 91 beats/min, her temperature was 36.8 °C (98.2 °F), her respiratory rate was 16 breaths/min, and oxygen saturation was 87% on room air, increasing to 92% on 3 L of supplemental oxygen. There was no cyanosis, and lung exam revealed normal breath sounds without wheezing or rales. Basic laboratory testing with complete blood count and metabolic profile were unrevealing. Chest X-ray was normal without infiltrate, consolidation, effusion, or vascular congestion. Blood cultures were obtained, and the patient was started on broad-spectrum antibiotics. CT angiography of the chest was normal without evidence of thrombosis, infection, or interstitial lung disease. An arterial blood gas (ABG) on room air revealed a pH of 7.5, a PaCO2 of 34 mm Hg, HCO3 of 26 mEq/L, and PaO2 of 73 mm Hg. Serum methemoglobinemia level was elevated at 11.8% (reference range, <1%).

The diagnosis

The patient was diagnosed with hypoxemia secondary to acquired methemoglobinemia from dapsone. Methemoglobin causes iron to convert from the reduced ferrous (Fe2+) to the oxidized ferric (Fe3+) form, resulting in leftward shift of the oxygen-hemoglobin dissociation curve and decreased tissue oxygen offloading. Methemoglobinemia occurs with levels higher than 1%. Symptoms are proportional to the percentage of methemoglobin and can be fatal at levels above 15% due to hypoxia-induced cardiopulmonary collapse. Methylene blue is the primary treatment for symptomatic methemoglobinemia, though it is contraindicated in glucose-6-phosphate dehydrogenase (G6PD) deficiency. Exchange transfusion and hyperbaric oxygen can also be used if patients do not respond to methylene blue or are G6PD-deficient. Treatment is indicated for levels of 15% or greater and for patients with lower levels and significant comorbidities or end-organ damage. Most cases resolve after the offending agent is discontinued.

Dapsone is a well-known oxidizing agent that triggers methemoglobinemia and accounts for approximately 40% of acquired cases. In a retrospective study of over 500 adult patients taking dapsone for PJP prophylaxis, the prevalence was 8%, and the disorder occurred at any point during treatment. In this patient, dapsone was discontinued and she was started on inhaled pentamidine for PJP prophylaxis. Her G6PD level was normal. She ultimately did not require treatment with methylene blue. A repeat ABG on the day of discharge showed that methemoglobinemia had declined to 9.6%, and her oxygen saturation improved to 90% on room air.

Pearls

  • Methemoglobinemia is a potentially fatal condition that results in a leftward shift of the oxygen-hemoglobin dissociation curve after exposure to an oxidizing agent; treatment with methylene blue is indicated if the percentage of methemoglobin is 15% or greater and for patients with comorbidities or end-organ damage.
  • Methemoglobinemia can be congenital or acquired, and the majority of acquired cases result from medications; dapsone is a common cause of acquired methemoglobinemia.