A novel cause of chronic viral meningoencephalitis: Cache Valley virus

Abstract

Objective: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients.

Methods: We present the case of a 34-year-old man with X-linked agammaglobulinemia from Australia suffering from 3 years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen.

Results: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue.

Interpretation: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in 3 immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multiorgan failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. Ann Neurol 2017;82:105-114.

Figure 1

Neuroimaging from acute presentation. (A) Coronal T2‐weighted/fluid‐attenuated inversion recovery brain magnetic resonance imaging (MRI) demonstrating T2 hyperintensity in the right hippocampus and amygdala (arrow). (B) Axial diffusion‐weighted imaging brain MRI demonstrating restricted diffusion in the right hippocampus and amygdala (arrow). (C, D) Sagittal (C) and coronal (D) T1‐weighted postcontrast brain MRI demonstrating contrast enhancement 2 weeks after the acute presentation (arrows).

Figure 2

Neuroimaging at 3‐year follow‐up. (A, B) Axial T1‐weighted brain magnetic resonance imaging (MRI) at the acute presentation (A) and at 3‐year follow‐up (B) with interval development of severe, diffuse cerebral atrophy, ex vacuo hydrocephalus, and focal atrophy of the right hippocampus (arrow). (C, D) Sagittal T1‐weighted brain MRIs at the acute presentation (C) and at 3‐year follow‐up (D) with interval development of severe, diffuse cerebral atrophy, and ex vacuo hydrocephalus.

Figure 3

Neuropathology. (A) Leptomeningeal thickening and inflammation. (B) Microglial nodule in the cortex. (C) Perivascular and interstitial lymphocytic infiltrate in the cortex. (D) Perivascular and interstitial lymphocytic infiltrates of predominantly CD8⁺ T lymphocytes visualized by means of immunolabeling with anti‐CD8 antibody.

Figure 4

Immunohistochemistry. (A) Strong intracytoplasmic immunostaining in ovine fetal brain using anti–Cache Valley virus (CVV) polyclonal antibody (Ab) and stained with brown 3,3′‐diaminobenzidine chromogen (positive control). (B) No immunostaining in noninfected human brain using anti‐CVV polyclonal Ab (negative control). (C, D) Intracytoplasmic immunostaining in subject's brain using anti‐CVV polyclonal Ab. Scale bar = 20 µm (A–C) and 13 µm (D).