The diagnostic conundrum and treatment dilemma of a patient with a rapidly progressive encephalopathy.

A 45-year-old man of the Yakama Nation tribe without significant medical history had an abrupt onset headache that progressed over a week. He presented to an emergency department and a noncontrast head computerized tomography (CT) was unremarkable except for mild ethmoid sinus disease. One week later, the patient developed neck stiffness, fever to 101.6 degrees F, chills, and body aches. The patient’s partner reported episodes of confusion with auditory and visual hallucinations, seeing things on the wall, and thinking he was covered in chocolate. After 2.5 weeks into the course of illness, the patient sought care from his primary care physician who referred him to a local emergency department. In the emergency department, the patient was afebrile though ill appearing with diaphoresis. He had fluent speech, normal comprehension, and intact memory and concentration. He was noted to have an unsteady tandem gait and positive Romberg sign. The rest of the neurologic examination was unremarkable. He was admitted to the hospital where cerebrospinal fluid (CSF) analysis revealed a significant neutrophil-predominant pleocytosis with a low glucose (Table 1, column Day of Illness 17). An infectious etiology was suspected, and empiric treatment was initiated with intravenous administration of ceftriaxone, vancomycin, acyclovir, and dexamethasone. Extensive serum and CSF infectious and autoimmune workup was unrevealing (Table 2). Repeat imaging with a contrast-enhanced brain magnetic resonance imaging (MRI) about 3 weeks after symptom onset demonstrated hyperintensities in the deep gray and white matter as well as basal leptomeningeal enhancement (Figure 1). An atypical viral meningoencephalitis was presumed and antibiotics, antivirals, and steroids were discontinued. Table 1. Cerebrospinal Fluid Analysis. Table 2. Blood, Urine, and Cerebrospinal Fluid Testing. Figure 1. Magnetic resonance imaging (MRI) scans of the brain on day 27 of illness. A and B, Fluid attenuated inversion recovery (FLAIR) axial images of the lesions in the medial right temporal lobe (thin long arrow), right basal ganglia (short thick arrow), inferior ... The hospital course was characterized by a progressive encephalopathy, and approximately 1 month after initial symptom onset, the patient began having episodes of unresponsiveness concerning for seizures and required intubation. In between the episodes, he was drowsy and followed simple commands. His clinical progression and episodes of depressed consciousness prompted transfer to our institution for further evaluation. On arrival, repeat CSF analysis revealed a persistent neutrophilic pleocytosis and hypoglycorrhachia (Table 1, column Day of Illness 27). Intravenous acyclovir, ceftriaxone, vancomycin, and enteral doxycycline were initiated. As CSF cultures, antibody tests, and viral polymerase chain reactions (PCRs) returned negative, these treatments were again discontinued. Continuous electroencephalogram (EEG) monitoring over a 3-day period revealed diffuse slowing but no epileptiform activity. Contrast-enhanced CT of the chest, abdomen, and pelvis and testicular ultrasound were normal. Whole-body [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scan from the base of skull to upper thighs revealed no evidence of primary malignancy or metastases. A nonlesional brain biopsy from the right frontal lobe demonstrated nonspecific findings of scattered rare perivascular lymphocytic infiltrates with no evidence of neoplasm or a specific infection (Figure 2). Figure 2. Nonlesional brain biopsy. A-D, Hematoxylin and eosin-stained sections show activated microglia (black arrowheads). B, Background neurons (white arrowheads) are identified. Scale bar in A = 250 µ; B-D = 100 µ. Due to the persistent CSF pleocytosis, hypoglycorrhachia, and elevated protein, as well as brain imaging with basal leptomeningeal enhancement, antituberculous medications and dexamethasone were started and continued for an 8-week course. The patient had no known exposure to tuberculosis (TB). The CSF fungal cultures and broad-based PCR tests for fungal elements and TB were negative (Table 2). Six weeks after the symptom onset, the patient progressed to a deep coma, unresponsive to both verbal and painful stimuli and with no purposeful movements. He also began exhibiting limb and orofacial choreoathetoid movements with dystonia. He had severe dysautonomia, including hyperthermia, tachycardia, and hypertension. Multiple medications were trialed—including benzodiazepines, propranolol, baclofen, trihexyphenidyl, and botulinum toxin injections to the masticatory muscles—which had little improvement. A diagnostic test result was obtained.