Three-Year-Old Girl With Fever and Coma

A 3-year-old Caucasian-Hispanic girl was transferred to Children’s Hospital Oakland in a coma. She was healthy until 10 days before transfer, when she developed high fever up to 39.5°C, fatigue and emesis but no diarrhea. On Day 6 of her febrile illness, she was hospitalized in another hospital with a diagnosis of acute gastroenteritis with dehydration. On Day 2 of this hospitalization she had a generalized tonic-clonic seizure. A computed tomography scan of the head was normal. Lumbar puncture revealed cerebrospinal fluid (CSF) pleocytosis with 540 white blood cells/mm3 , 90% neutrophils, 10% lymphocytes, protein of 122 mg/dl and glucose of 47 mg/dl. An electroencephalogram was normal. The patient was treated with acyclovir and Dilantin but remained febrile and intermittently lethargic. A magnetic resonance imaging scan of the head was obtained on Day 10 of her febrile illness and showed marked ventriculomegaly with patent fourth ventricle suggesting communicating hydrocephalus, and a few areas of focal increased signal within the right posterior frontal and temporal cerebral cortex. For this study the patient was sedated with chloral hydrate. Immediately after the magnetic resonance imaging scan she had another seizure, followed by somnolence, development of pinpoint pupils, loss of light and gag reflexes. She was intubated, received one dose of ceftriaxone and was transferred to the pediatric intensive care unit at Children’s Hospital Oakland. Her past medical history was unremarkable, except for a recent episode of acute otitis media, which was treated with amoxicillin for 10 days. Her mother had a history of alcohol abuse, and the patient’s primary caretakers and legal guardians were her maternal grandparents. The family history was significant for systemic lupus erythematosus in three maternal great aunts. There was a 4-year-old cat in the household, and the patient had been observed to play in the litter box. The family had recently acquired a parakeet and cockatiel, and they had an aquarium with fish. There was no history of camping or swimming. There was no known exposure history to tuberculosis, but there was exposure to a close family friend with chronic cough. Physical examination demonstrated a comatose, intubated, ventilated child. Her temperature was 38.2°C, heart rate 138 beats/min, respiratory rate 23 breaths/min and blood pressure 111/67 mm Hg. Neurologic examination revealed pinpoint pupils, which were nonreactive to light, absent gag and corneal reflexes, no response to sternal rub and withdrawal of extremities in response to painful stimuli of hands or feet. Deep tendon reflexes were hyperactive and symmetric. Head and neck examination were otherwise unremarkable; chest, cardiovascular, abdominal, external genital and skin examination were normal. The peripheral white blood cell count was 8700/mm3 with 63% segmented neutrophils, 7% band forms, 16% lymphocytes, 13% monocytes and 1% eosinophils. Hemoglobin was 10.8 g/dl. Platelet count was 340 000/mm3 . Serum electrolytes, blood urea nitrogen, creatinine, liver function tests, total protein, albumin, ammonia, coagulation studies and urinalysis were all normal. Blood and CSF cultures before treatment with ceftriaxone from the other hospital were negative. The patient had placement of an external ventricular drain to treat the hydrocephalus shortly after arrival at Children’s Hospital Oakland but had no improvement in her neurologic status. CSF analysis of the ventricular fluid revealed a white blood cell count of 3/mm3 , red blood cell count of 96/mm3 , protein of 44 mg/dl and glucose of 53 mg/dl. Repeat lumbar puncture on hospital Day 2 showed a white blood cell count of 354/mm3 with 46% neutrophils, 48% lymphocytes, 5% monocytes and 1% basophils; protein was 1247 mg/dl; glucose was 6 mg/dl; and lactic acid was 6.0 mEq/l. Multiple stains and cultures for acid-fast bacilli from CSF and respiratory secretions were negative. PCRs for Mycobacterium tuberculosis on ventricular and spinal fluid were also negative. Skin tests with purified protein derivative (PPD) and Candida antigen showed no induration and ∼5 mm induration, respectively. There were no areas of infiltrate or atelectasis on her initial chest radiograph. All household contacts had negative PPD skin tests and symptom reviews for tuberculosis. PPD skin test and chest radiography on the family friend with chronic cough were both negative. Multiple bacterial and fungal cultures from blood and CSF were negative. Serologic tests for Toxoplasma gondii, Coccidioides immitis, Mycoplasma pneumoniae, Bartonella henselae and quintana, and human immunodeficiency virus were all negative. Antigen testing for Cryptococcus neoformans on blood and CSF was negative. PCR for human herpes simplex virus on CSF was negative. Serum concentrations of very long chain fatty acids and copper were normal. Serum arsenic level was <10 μg/l. Antinuclear antibodies were negative; erythrocyte sedimentation rate (Westergren) was 38 mm/h. Ophthalmologic examination revealed normal fundi and cornea. The patient was empirically treated for tuberculous meningitis with isoniazid, rifampin, ethambutol and pyrazinamide via nasogastric tube, as well as intravenous methylprednisolone. Ceftriaxone and acyclovir were continued for 14 and 3 days, respectively. The patient defervesced on Hospital Day 2 but continued to be comatose. On Day 24 of her illness an electroencephalogram documented electrocerebral silence consistent with the clinical diagnosis of brain death. Supportive care was withdrawn the following day, in agreement with her family. Shortly before her death another blood test and lumbar puncture revealed the diagnosis, which was confirmed by autopsy.