A 42 year-old man with chronic lymphocytic leukemia underwent allogeneic bone marrow transplant in September 2013.
The graft was mismatched at a single human leukocyte antigen allele (DQB1), and was T-cell depleted using in vivo alemtuzumab.
He engrafted on day 12 after transplant.
Aside from persistent lymphopenia and diarrhea from norovirus infection, his posttransplant course was unremarkable until mid-October when he developed tinnitus and rapidly progressive sensorineural deafness, resulting in subtotal hearing loss bilaterally (>95 dB) over 2–3 weeks.
Brain magnetic resonance imaging (MRI) was unremarkable, as was cerebrospinal fluid (CSF) analysis (4 leukocytes/µL with 50% neutrophils and 50% lymphocytes, 6 red blood cells/µL, glucose 2.4 mmol/L [normal range, 2.2–4.7 mmol/L], protein 61 mg/dL [normal range, 15–45 mg/L], absence of oligoclonal bands).
Viral polymerase chain reaction (PCR) testing of CSF was negative for enterovirus and herpesvirus infection.
The patient was treated empirically with high-dose valacyclovir, broad-spectrum antibiotics, and 2 g/kg intravenous immunoglobulin (IVIG).
Despite these interventions, he developed new symptoms of central dyspnea, postural hypotension, nausea, and gradually worsening balance.
Repeat neurological assessment confirmed persistent vestibulocochlear dysfunction 6 weeks after symptom onset.
By mid-December, the patient had become increasingly withdrawn, irritable, and intermittently agitated.
He remained lymphopenic (lymphocytes 0.54 × 106/μL [normal range, 1.2–3.6 × 106/μL]).
MRI scans of the brain were unremarkable, as was serum testing for antineuronal antibodies; an electroencephalogram revealed only diffuse encephalopathy.
Given continued suspicion for a viral etiology, the patient was treated with high-dose glucocorticoids and again with IVIG.
He began refusing fluids, food, and medication, and was detained under the UK Mental Health Act.
Repeat MRI scanning showed interval development of new, nonenhancing signal abnormalities in both thalami and midbrain with cranial nerve involvement but no meningeal enhancement (Figure ​1A).
Near the end of December, a frontal lobe biopsy was performed.
Histology revealed reactive gliosis and diffuse infiltration with CD3+/8+ lymphocytes (Figure 1B).
Extensive microbiological testing of the biopsy tissue for an infectious etiology was negative (Supplementary Table 1).
Given the absence of a diagnosis and the patient's progressive neurological deterioration, CSF and brain biopsy tissue were analyzed in January 2014 by metagenomic next-generation sequencing (NGS) [2].
NGS analysis of the brain biopsy, genome assembly, and in situ hybridization revealed findings of neuroinvasive astrovirus (AstV) infection.
Despite lack of approved therapies, the patient was treated with ribavirin and IVIG.
However, he did not respond to these interventions, and remained in a minimally conscious state following withdrawal of sedation in March 2014.
He eventually died at the end of May, 4 months after the NGS diagnosis and approximately 7.5 months after onset of symptoms.