Neurological complications of Orthopoxvirus infections: neurotropism and neurovirulence

Abstract

With the declaration of monkeypox virus (MPXV) infection as a global health emergency in 2022 by the World Health Organization and its ongoing presence, orthopoxviruses have garnered increasing attention, including their capacity to cause neurological disease. Indeed, the mpox syndrome caused by MPXV infection is recapitulated in humans for several other orthopoxviruses, including variola (VARV, the cause of smallpox), vaccinia (VACV), camelpox (CMPX) and cowpox (CPXV) viruses, albeit with variable disease severities. In addition to prototypic signs and symptoms of Orthopoxvirus infections, such as fever, swollen lymph nodes, malaise and skin lesions, MPXV-infected individuals also develop neurological syndromes such as headaches, myalgias, seizures, altered consciousness and encephalopathy/encephalitis. MRI of the brains of MPXV-infected persons can display hyperintensities consistent with brain oedema. Pleocytosis has also been reported in the CSF from persons with MPXV infections, implying active infection of the CNS. Of note, newborn rodents, or animals with severe combined immune deficiency, were found to be susceptible to MPXV infection with evidence that the virus can cross the blood–brain barrier. In the present review, we highlight the current understanding of Orthopoxvirus neuropathogenesis together with germane diagnostic and therapeutic considerations.