Is Monkeypox Neuroinvasive?

As human monkeypox cases rise, neurologists should be prepared to recognize, diagnose, and treat potentially neuroinvasive disease or other neurologic symptoms, experts said.

Monkeypox virus has the potential to be neuroinvasive based on animal models, case series from previous outbreaks, and preliminary reports currently under investigation, reported Kenneth Tyler, MD, and Daniel Pastula, MD, MHS, both of the University of Colorado School of Medicine, in an overview published in Annals of Neurology.

“Although neurological manifestations are exceedingly rare, they can occur,” Tyler told MedPage Today. “It’s a numbers game, and prior studies of outbreaks with hundreds of cases did include rare neurological events like seizures and encephalitis.”

“The current case numbers are orders of magnitude greater than the case series reported before, increasing the likelihood that rare events will emerge,” Tyler added.

Current media reports have indicated that in some monkeypox cases, encephalitis may have occurred. “There are also unpublished discussions of possible transverse myelitis-like disease in patients with monkeypox virus,” Tyler observed.

In addition, “evidence from related orthopox viruses including smallpox, vaccinia, and vaccinia vaccination suggest the possibility of things like encephalitis, myelitis, or acute disseminated encephalomyelitis-like events,” he pointed out.

Most reports of related viruses suggest the majority of neurologic complications may be post-infectious or para-infectious immune-mediated processes, Tyler noted. “However, animal studies with monkeypox suggest it can be directly neuroinvasive as well,” he said.

In the current monkeypox outbreak, rare reports of possible neuroinvasive disease are being investigated.

“For instance, the Spanish Ministry of Health has recently reported two fatal cases of neuroinvasive monkeypox virus disease in two adult men (ages 31 and 44) diagnosed with encephalitis (Ministerio de Sanidad de España 2022),” Tyler and Pastula wrote. Both men were presumed immunocompetent. Monkeypox virus nucleic acid and anti-orthopox virus immunoglobulin (Ig) M were detected in the cerebrospinal fluid of both.

The neurotropic potential of monkeypox has also been suggested by animal models, they pointed out. “Infectious virus has been repeatedly detected in the brain in various animals by viral plaque assays,” Tyler and Pastula wrote.

“A survey of tissues from a variety of pet rodents (e.g., prairie dog, rat, hamster, chinchilla, etc.) exposed to monkeypox virus during the 2003 Midwest United States outbreak also found amplifiable monkeypox virus DNA in the brains of ~8% of 52 tested animals using real-time polymerase chain reaction (PCR) assays,” they added.

Past research about monkeypox outbreaks, summarized in a preprint meta-analysis from British researchers on medRxiv, suggested a wide range of neurologic and psychiatric presentations in humans. The meta-analysis, which has not yet been peer-reviewed, is based on 1,512 individuals in mostly cohort studies and case series and shows headache (53.8%) as a common neurologic manifestation, with seizures (2.7%), confusion (2.4%), and encephalitis (2.0%) occurring rarely.

These frequencies may be influenced by reporting bias in some studies that favored more severe or hospitalized patients, Tyler and Pastula noted.

During the current outbreak, there has also been reports of neuropathic pain and pruritis in areas of rash for which neurologists may be consulted, they added.