A 46-year-old African American female presented to an outside hospital in late November 2017 due to altered mentation and flu-like symptoms. Her past medical history was significant for bipolar disorder, 1 seizure episode at age 17, and psoriatic arthritis treated with rituximab infusions since 2014. Her last known rituximab infusion was July 2017. Prior to seeking medical care, the patient tried multiple doses of Theraflu (acetaminophen, dextromethorphan, and phenylephrine) because she attributed her symptomatology to influenza.
She complained of a subjective tactile fever, myalgias, and cough. Initial physical exam revealed the patient to be normotensive and afebrile, but she did have nuchal rigidity, was obtunded and showed generalized stiffness with her arms flexed and legs extended. Initial emergency department workup included a CT scan of the brain without contrast that showed no mass effect or hemorrhages and normal gray-white differentiation. Complete blood count (CBC) on admission showed a leukocytosis of 18,000/uL with an absolute neutrophil count of 15,600/uL. C-reactive protein (CRP) was elevated at 156.8 mg/L. A lumbar puncture showed a high WBC count of 161/uL with 70% lymphocytes, 25% PMNs, 98 mg/dL protein, and 55 mg/dL glucose. The patient was placed on isolation precautions and empirically started on ceftriaxone, vancomycin, and acyclovir. A CSF BioFire Meningitis/Encephalitis Panel revealed the presence of enterovirus. As a result, empiric antimicrobials were discontinued. On subsequent hospital days, the patient continued to have generalized stiffness, was unable to follow commands, and remained nonverbal. She experienced recurrent febrile episodes as well as multiple witnessed generalized tonic-clonic seizures. An EEG showed abnormal bihemispheric slowing suggestive of nonspecific diffuse encephalopathy. Attempted brain MRI on hospital day 5 was not successful. The patient did not improve, had recurrent febrile episodes with leukocytosis, and frequent seizures. A brain MRI under sedation revealed restricted diffusion in the bilateral cortical and subcortical regions of the parietal and posterior temporal lobes, splenium of the corpus callosum, and bilaterally in the posterior thalamus (Fig. 1). These findings raised concern for posterior reversible encephalopathy syndrome (PRES) at the outside facility.
The patient was transferred to our tertiary care facility. On arrival, the patient remained altered with disorientation to person, place, and time. She showed left gaze preference and was unable to follow simple one-step commands. Her reflexes, muscle tone, and sensorium were normal. CRP was elevated at 64.2 mg/L. Her liver function studies and pancreatic studies were unremarkable. Intracranial and extracranial CT angiography showed no abnormalities. Brain MRI showed restricted diffusion in the splenium of the corpus callosum. Left greater than right restricted diffusion in the temporoparietal cortex was present. Subtle leptomeningeal enhancement on the left was also observed. Folate, vitamin B12, vitamin B1, and TSH levels were all within the normal reference ranges.
The patient improved clinically and was able to follow one-step commands. However, she had intermittent episodes of agitation requiring four-point restraints. She was placed on olanzapine as needed with haloperidol for breakthrough agitation. Follow-up brain MRI two weeks later showed stable FLAIR and T2 signal abnormalities within the splenium of the corpus callosum and thalami with no residual hypointensity on ADC map images, indicating no persisting restricted diffusion in these locations. Previous temporoparietal diffusion hyperintensities also had returned to normal and no new areas of signal abnormalities were identified (Fig. 2). At this point, the patient was awaiting placement in a skilled nursing facility. Her mentation and orientation continued to improve. Her episodes of aggression and agitation lessened.
A month after admission, the patient complained of decreased visual acuity. She was found to have decreased bilateral blink-to-threat reflexes with left-gaze preference. However, she was able to distinguish colors and track around the room. As a result, a repeat brain MRI was done on January 10, 2018. New cortical-restricted diffusion was present in the bilateral parietal and occipital lobes. Stable abnormal diffusion abnormality within the splenium of the corpus callosum and thalami remained (Fig. 3). These findings were concerning for Creutzfeldt-Jakob Disease but a 14-3-3 protein analysis was found to be within the normal reference range and real-time quaking-induced conversion failed to detect abnormal prion proteins.
Repeat CSF PCR for enterovirus was negative as well as a swab of the oropharynx. Cerebrospinal fluid testing for California (La Crosse) encephalitis, John Cunningham virus, Mycobacterium tuberculosis, Eastern equine encephalitis virus, Cryptococcus neoformans, VZV, HSV-1, HSV-2, CMV, VDRL for neurosyphilis, and angiotensin converting enzyme for neurosarcoidosis all proved to be negative. An India ink stain was performed and proved to be negative. Serum and plasma testing for hepatitis B virus, hepatitis C virus, HIV-1, HIV-2, John Cunningham virus, Borrelia burgdorferi, Borrelia mayonii, Borrelia Garinii, and Borrelia afzelii were all negative. The prior hospital had tested a CSF sample for West Nile virus and Streptococcus pneumoniae antigen, both of which were negative. Blood and CSF cultures showed no growth for bacteria or fungi. The patient did have a positive QuantiFERON-TB Gold test. However, a follow-up chest X-ray was negative, AFB sputum culture ultimately showed no growth for 42 days, and sputum PCR for Mycobaterium tuberculosis was negative.
A serum Epilepsy Autoimmune Evaluation (Mayo Clinic Laboratories) failed to reveal any of the 19 autoantibodies tested. A serum NeoCerebellar Degeneration Paraneoplastic Profile with Recombx (Quest Diagnostics) was unremarkable for any autoantibodies indicative of cerebellar degeneration. CSF and serum paraneoplastic autoantibody evaluations were negative. The patient's IgM, IgG, and IgA levels were all within the normal reference ranges. She ultimately received a five-day course of 400 mg/kg/day IVIG. Although the patient was not at baseline, she was discharged in an improved clinical condition with decreased visual acuity. She was instructed to follow-up as an outpatient with neurology, psychiatry, and infectious disease.