Neurologic Complications of Smallpox and Monkeypox: A Review.

Importance: Orthopox viruses include smallpox virus, a once feared but now eradicated virus, as well as monkeypox virus. Monkeypox is an emerging virus initially isolated in 1958, previously unrecognized outside sub-Saharan Africa until a worldwide outbreak in May 2022. It is important to review known neurologic consequences of both these viruses, as complications of smallpox may be relevant to monkeypox, though complications of monkeypox may be rarer and perhaps less severe. Observations: This was a literature review of the known neurologic complications of smallpox, which include encephalitis, transverse myelitis, and acute disseminated encephalomyelitis among others; historical complications of smallpox vaccination, including postvaccinal encephalomyelitis; and the known neurologic complications of monkeypox, which include headaches and mood disturbances, as well as rare presentations of encephalitis, transverse myelitis, and seizures. Of concern is the possibility of viral persistence and systemic complications in immunocompromised individuals. Also provided were considerations for diagnosis, current treatment, and prevention of monkeypox. Conclusions and Relevance: Monkeypox should be considered in high-risk populations who present with neurologic syndromes. Diagnosis may require serology and polymerase chain reaction testing of blood and spinal fluid. Antiviral therapy should be initiated early in the course of the illness.

Cross-sectional Neuromuscular Phenotyping Study of Patients With Arhinia With SMCHD1 Variants.

BACKGROUND AND OBJECTIVES: Facioscapulohumeral muscular dystrophy type 2 (FSHD2) and arhinia are 2 distinct disorders caused by pathogenic variants in the same gene: SMCHD1. The mechanism underlying this phenotypic divergence remains unclear. In this study, we characterize the neuromuscular phenotype of individuals with arhinia caused by SMCHD1 variants and analyze their complex genetic and epigenetic criteria to assess their risk for FSHD2. METHODS: Eleven individuals with congenital nasal anomalies, including arhinia, nasal hypoplasia, or anosmia, underwent a neuromuscular examination, genetic testing, muscle ultrasound, and muscle MRI. Risk for FSHD2 was determined by combined genetic and epigenetic analysis of 4q35 haplotype, D4Z4 repeat length, and methylation profile. We also compared expression levels of pathogenic DUX4 mRNA in primary myoblasts or dermal fibroblasts (upon myogenic differentiation or epigenetic transdifferentiation, respectively) in these individuals vs those with confirmed FSHD2. RESULTS: Among the 11 individuals with rare, pathogenic, heterozygous missense variants in exons 3-11 of SMCHD1, only a subset (n = 3/11; 1 male, 2 female; age 25-51 years) met the strict genetic and epigenetic criteria for FSHD2 (D4Z4 repeat unit length <21 in cis with a 4qA haplotype and D4Z4 methylation <30%). None of the 3 individuals had typical clinical manifestations or muscle imaging findings consistent with FSHD2. However, the patients with arhinia meeting the permissive genetic and epigenetic criteria for FSHD2 displayed some DUX4 expression in dermal fibroblasts under the epigenetic de-repression by drug treatment and in the primary myoblasts undergoing myogenic differentiation. DISCUSSION: In this cross-sectional study, we identified patients with arhinia who meet the full genetic and epigenetic criteria for FSHD2 and display the molecular hallmark of FSHD-DUX4 de-repression and expression in vitro-but who do not manifest with the typical clinicopathologic phenotype of FSHD2. The distinct dichotomy between FSHD2 and arhinia phenotypes despite an otherwise poised DUX4 locus implies the presence of novel disease-modifying factors that seem to operate as a switch, resulting in one phenotype and not the other. Identification and further understanding of these disease-modifying factors will provide valuable insight with therapeutic implications for both diseases.

BK virus-specific T cells for immunotherapy of progressive multifocal leukoencephalopathy: an open-label, single-cohort pilot study.

BACKGROUND: Progressive multifocal leukoencephalopathy, a rare disease of the CNS caused by JC virus and occurring in immunosuppressed people, is typically fatal unless adaptive immunity is restored. JC virus is a member of the human polyomavirus family and is closely related to the BK virus. We hypothesised that use of partly HLA-matched donor-derived BK virus-specific T cells for immunotherapy in progressive multifocal leukoencephalopathy would be feasible and safe. METHODS: We did an open-label, single-cohort pilot study in patients (aged 18 years or older) with clinically definite progressive multifocal leukoencephalopathy and disease progression in the previous month at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Overlapping peptide libraries derived from large T antigen and major capsid protein VP1 of BK virus with high sequence homology to JC virus counterparts were used to generate polyomavirus-specific T cells cross-recognising JC virus antigens. Polyomavirus-specific T cells were manufactured from peripheral blood mononuclear cells of first-degree relative donors aged 18 years or older. These cells were administered to patients by intravenous infusion at 1 × 106 polyomavirus-specific T cells per kg, followed by up to two additional infusions at 2 × 106 polyomavirus-specific T cells per kg. The primary endpoints were feasibility (no manufacturing failure based on meeting release criteria, achieving adequate numbers of cell product for clinical use, and showing measurable antiviral activity) and safety in all patients. The safety monitoring period was 28 days after each infusion. Patients were followed up with serial MRI for up to 12 months after the final infusion. This trial is registered at ClinicalTrials.gov, NCT02694783. FINDINGS: Between April 7, 2016, and Oct 19, 2018, 26 patients were screened, of whom 12 were confirmed eligible and received treatment derived from 14 matched donors. All administered polyomavirus-specific T cells met the release criteria and recognised cognate antigens in vitro. 12 patients received at least one infusion, ten received at least two, and seven received a total of three infusions. The median on-study follow-up was 109·5 days (range 23-699). All infusions were tolerated well, and no serious treatment-related adverse events were observed. Seven patients survived progressive multifocal leukoencephalopathy for longer than 1 year after the first infusion, whereas five died of progressive multifocal leukoencephalopathy within 3 months. INTERPRETATION: We showed that generation of polyomavirus-specific T cells from healthy related donors is feasible, and these cells can be safely used as an infusion for adoptive immunotherapy of progressive multifocal leukoencephalopathy. Although not powered to assess efficacy, our data provide additional support for this strategy as a potential life-saving therapy for some patients. FUNDING: Intramural Research Program of the National Institute of Neurological Disorders and Stroke of the NIH.

HHV-6 and hippocampal volume in patients with mesial temporal sclerosis.

OBJECTIVE: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS). BACKGROUND: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies. DESIGN/METHODS: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B. RESULTS: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results. INTERPRETATION: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies.

Imaging spinal cord atrophy in progressive myelopathies: HTLV-I-associated neurological disease (HAM/TSP) and multiple sclerosis (MS).

OBJECTIVE: Previous work measures spinal cord thinning in chronic progressive myelopathies, including human T-lymphotropic virus 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers. METHODS: Spinal cord cross-sectional area was measured in individuals (24 healthy controls [HCs], 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 relapsing-remitting MS [RRMS], 17 secondary progressive MS [SPMS], and 40 primary progressive MS [PPMS]) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross-sectional area regions at the C2 to C3, C4 to C5, and T4 to T9 levels. In 2 HAM/TSP patients, spinal cord cross-sectional area was measured over 3 years. RESULTS: All spinal cord regions are thinner in HAM/TSP (56 mm2 [standard deviation, 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (Expanded Disability Status Scale [p = 0.009] and Instituto de Pesquisas de Cananeia [p = 0.03]) and CD8+ T-cell frequency (p = 0.04) correlate with T4 to T9 spinal cord cross-sectional area in HAM/TSP. Higher cerebrospinal fluid HTLV-1 proviral load (p = 0.01) was associated with thinner spinal cord cross-sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning. INTERPRETATION: Group average spinal cord cross-sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize in HAM/TSP that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. Ann Neurol 2017;82:719-728.