Fatal Powassan Encephalitis (Deer Tick Virus, Lineage II) in a Patient With Fever and Orchitis Receiving Rituximab

Abstract

IMPORTANCE Powassan virus is a rare but increasingly recognized cause of severe neurological disease. OBJECTIVE To highlight the diagnostic challenges and neuropathological findings in a fatal case of Powassan encephalitis caused by deer tick virus (lineage II) in a patient with follicular lymphoma receiving rituximab, with nonspecific anti-GAD65 antibodies, who was initially seen with fever and orchiepididymitis. DESIGN, SETTING, AND PARTICIPANTS Comparison of clinical, radiological, histological, and laboratory findings, including immunohistochemistry, real-time polymerase chain reaction, antibody detection, and unbiased sequencing assays, in a single case report (first seen in December 2016) at an academic medical center. EXPOSURE Infection with Powassan virus. MAIN OUTCOMES AND MEASURES Results of individual assays compared retrospectively. RESULTS In a 63-year-old man with fatal Powassan encephalitis, serum and cerebrospinal fluid IgM antibodies were not detected via standard methods, likely because of rituximab exposure. Neuropathological findings were extensive, including diffuse leptomeningeal and parenchymal lymphohistiocytic infiltration, microglial proliferation, marked neuronal loss, and white matter microinfarctions most severely involving the cerebellum, thalamus, and basal ganglia. Diagnosis was made after death by 3 independent methods, including demonstration of Powassan virus antigen in brain biopsy and autopsy tissue, detection of viral RNA in serum and cerebrospinal fluid by targeted real-time polymerase chain reaction, and detection of viral RNA in cerebrospinal fluid by unbiased sequencing. Extensive testing for other etiologies yielded negative results, including mumps virus owing to prodromal orchiepididymitis. Low-titer anti-GAD65 antibodies identified in serum, suggestive of limbic encephalitis, were not detected in cerebrospinal fluid. CONCLUSIONS AND RELEVANCE Owing to the rarity of Powassan encephalitis, a high degree of suspicion is required to make the diagnosis, particularly in an immunocompromised patient, in whom antibody-based assays may be falsely negative. Unbiased sequencing assays have the potential to detect uncommon infectious agents and may prove useful in similar scenarios.

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy

“…Although the testis is thought to be an immunologically privileged site protected from autoimmunity, adoptive transfer of T lymphocytes was shown to cause autoimmune orchitis in animal models [31]. In this case, given the symptom profile, we also posited that the inhibition of PD-1 could have amplified the inflammatory manifestations of an otherwise minimally symptomatic virus (e.g., mumps, EBV, or Powassan virus) [32] but found no evidence of active viral infection in the CSF, despite testing with a clinical metagenomic sequencing assay that is able to detect a broad range of pathogens. However, viral or other environmental triggers of irAEs should be explored on a larger scale.…”

Diagnostic Testing in Central Nervous System Infection

“…For pathogens that are commonly diagnosed by serology, metagenomic sequencing can offer a faster turnaround time 118 and can achieve a diagnosis in patients in whom antibodies are unreliable, e.g., due to treatment with rituximab. 119 For pathogens that can be detected by PCR, metagenomic sequencing offers advantages of high sensitivity and independence from pathogen-specific primers. Highlighting the benefit of using an unbiased approach, metagenomic sequencing has yielded unexpected findings in immunocompromised patients including coronavirus, 120 Cache Valley virus, 121 and mumps vaccine-associated encephalitis.…”

Jamestown Canyon virus in Massachusetts: clinical case series and vector screening

“…Laboratory diagnosis of JCV is made by serology, but due to cross-reactivity with other arboviruses, diagnosis requires a screening antibody-capture ELISA and a confirmatory JCV-specific plaque reduction neutralization test (PRNT) [16]. Serology can be negative in patients treated with B-cell depleting agents, an increasingly recognized limitation for both JCV (Solomon et al, in preparation) and other arboviruses [17][18][19]. To assess the utility of viral RNA detection for JCV diagnostics, we designed a JCV RT-qPCR assay and screened available residual sera.…”