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Neuro-ID Update [January '25]
iStock 1483285950 Neuroinfectious Brain

Neuro-ID Update [January '25]

6 Jan 2025

B. Jeanne Billioux, MD, and Avindra Nath, MD

For this Neuro-ID update, we review recent developments in neuroinfectious diseases across the globe, including potential complications of Oropouche virus, new discoveries regarding the pathophysiology of MIS-C in COVID-19, and reports on Chandipura virus.

Oropouche virus (OROV) has been in the news recently, given an outbreak in the region of the Americas in 2024, and reports of vertical transmission with related effects on fetuses.  Oropouche virus is an arthropod-born Orthobunyavirus initially identified in 1955 in Trinidad and Tobago.  Until recently, it had caused small outbreaks in areas of the Caribbean and Central and South America, typically beginning in rural areas.. This year over 11,000 confirmed cases have been reported in the region of the Americas, with Brazil reporting over 9,500 cases (WHO Disease Outbreak News Dec 2024).  It is typically transmitted through biting midges (particularly Culicoides paraensis) and some Aedes, Culex, and Coquillettidia mosquito species.

While most people (up to 60%) develop  fever, headache, fatigue, myalgias, arthralgias, conjunctival injection, and anorexia, patients may also exhibit gastrointestinal symptoms, uncommonly have rash, and rarely develop hemorrhagic manifestations such as petechiae, gingival bleeding, epistaxis, and melena.  Neurologic manifestations , include encephalitis and meningitis; neurological symptoms such as encephalopathy, vertigo, hearing loss, visual symptoms, seizures; and Guillain-Barré syndrome (Pastula 2024).   Intriguingly, recent reports have associated OROV infection with vertical transmission and subsequent fetal consequence.  

A case report in the New England Journal of Medicine confirmed a case of vertical transmission of OROV from mother to fetus, with 3rd trimester fetal demise (Fiho 2024). Additionally, a study from Brazil in Lancet Infectious Diseases described six cases of congenital microcephaly that tested positive for OROV. In this study, infant CSF and serum and maternal serum samples from microcephaly cases were analyzed, including 65 cases from between 2015 and 2021 (initially thought related to Zika, but were negative), and three cases from 2024.  All 68 cases were analyzed for multiple causes of microcephaly (including Zika serology/PCR, TORCH infections, other arboviral infections), as well as OROV serology and PCR.  Of the 65 retrospective cases, three were found to have positive CSF IgM serology for OROV without other obvious causes for microcephaly.

The three cases of microcephaly from 2024 were all from babies born in the state of Acre, Brazil.  All three cases tested negative for other arboviruses and TORCH infections.  In addition to microcephaly, two of these 2024 cases also had arthrogryposis and other fetal malformations. All three were positive for OROV IgM in both serum and CSF.  The third case was also positive for OROV by PCR in the CSF, and died  at postnatal day 47. On autopsy of this case, ex vacuo hydrocephalus was found, with small remnants of brain tissue.  Meninges and brain tissue changes were found to be consistent with a severe meningoencephalitis with brain necrosis and inflammatory infiltration.  OROV RNA and antigen were detected in brain tissue, as well as in multiple other body tissues including lung and kidney (das Neves Martins 2024).

These reports indicate that the neurotropic Oropouche virus has potential to cause major fetal malformations during maternal intrapartum infection, warranting additional surveillance and research. This is particularly concerning since this virus has the potential of becoming the next big outbreak in South America. This comes on the heels of outbreaks of Dengue and Chikungunya in these regions this year. This rapid spread of several vector-borne illness in these regions is of major concern.

In COVID-19 related news, a recent report has described a new potential pathway underlying  multisystem inflammatory syndrome in children (MIS-C).  MIS-C is a severe post-infectious inflammatory syndrome which affects a minority of children infected with SARS-CoV2, which may lead to a wide variety of clinical symptoms including neurologic, cardiac, renal, gastrointestinal, dermatologic, pulmonary, or hematologic abnormalities (CDC 2023). Until recently, the cause of MIS-C was unclear, but thought to possibly be related to an autoimmune condition.

In a recent Nature article, investigators have identified molecular mimicry as a potential cause for this severe complication.  The authors used custom phage immunoprecipitation and sequencing (PhIP-Seq) in samples from 199 children with MIS-C compared to 45 control children (with COVID-19 but without MIS-C), and found several autoantibodies in MIS-C patients, most notably to the protein SNX8 which is normally expressed in a wide variety of tissues including the heart, brain, GI tract, skin, kidneys, and immune cells. The most immunoreactive peptide sequence of the SNX8 protein was very similar to a region of the SARS-CoV-2 nucleocapsid protein. Interestingly, this particular protein (the MIS-C associated domain of SARS-CoV-2, or MADS protein) had a differentially enriched (higher) antibody response in children with MIS-C compared to controls.

When the autoantibodies to SNX8 were evaluated against the MADS protein, they were also found to cross-react; indeed, CD8+ T-cells from a small group of MIS-C patients were also found to be cross-reactive to both proteins, while this response was absent in control patients’ T-cells (Bodansky 2024).  While cross reactivity to the SNX8 and MADS proteins only accounts for a subset of the MIS-C patients that were studied, this account of molecular mimicry leading to autoreactivity provides key clues to the pathophysiology of MIS-C.

In other neuroinfectious disease news, there has been an outbreak of Chandipura virus (CHPV) in India this year, leading to at least 78 cases of encephalitis, with a total suspected case number of 245 and a 33% case fatality rate (CFR). CHPV is a negative sense single-strand RNA virus in the Rhabdoviridae family, and is transmitted by sandflies in the Phlebotomus and Sergentomyia species as well as Aedes aegypti mosquitoes, more commonly in the monsoon seasons in India.

Since being identified as a cause of encephalitic outbreaks in 2003, there have been seven CHPV encephalitis outbreaks with CFR ranging from 20-78%. Although favipiravir and ribavirin have shown some degree of efficacy in animal models, there are currently no treatments or vaccines for CHPV approved for human use. (Brisse 2024).  There is an urgent need for development of vaccines and treatments for these (re)emerging vector-borne illnesses which are causing some of the devastating outbreaks in modern history resulting in untold human suffering and socioeconomic devastation in regions where resources are limited.

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