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Powassan virus (POWV) is a rare but increasingly recognized tick-borne flavivirus that can lead to life-threatening encephalitis. Immunocompromised patients, particularly those on rituximab or Bruton's Tyrosine Kinase (BTK) inhibitors, may experience impaired viral clearance and worsened disease severity. We report a case of fatal POWV encephalitis (POWVE) in a patient with chronic lymphocytic leukemia (CLL) on zanabrutinib. 

Case Presentation: A 68-year-old male with a history of hypertension, thyroid cancer, renal cell carcinoma, and  CLL treated with rituximab and zanabrutinib presented with four days of progressive weakness, difficulty ambulating, and a  fall. He reported a tick bite  2–3 weeks prior to symptom onset. Initial examination revealed bilateral upper extremity resting tremors and a wide-based gait.  Labs showed leukopenia, thrombocytopenia, and elevated creatine- kinase. The patient’s  cerebellar syndrome progressed with severe dysarthria, bilateral sixth cranial nerve  palsy, horizontal nystagmus, and limb ataxia. Brain MRI revealed interval T2 cerebellar hyperintensities and leptomeningeal enhancement, consistent with cerebellitis. Cerebral spinal fluid (CSF) showed elevated proteins (604mg/dL) and 19 lymphocytes. POWV serum IgM and total antibodies were negative, but serum, CSF and urine tested positive for POWV by PCR with prolonged viremia over several weeks. Despite treatment with dexamethasone, IVIG, and high dose remdesivir, the patient's condition worsened, and he expired. 

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 POWVE is an emerging disease with cases now being identified from April to December, likely due to human related changes in tick habitat and increase in ticks geographic activity. Targeted testing for POWV in patients who are on B-cell depleting therapies is important because, in addition to the poor outcome, these patients will present not only with negative serological testing but with prolonged viremia and viruria on molecular testing. Characteristic MRI findings such as signal abnormalities in the thalami, basal ganglia, brainstem, and cerebellum — should prompt high suspicion for tick-borne encephalitis.