MonkeyPox and Neurology Update [November '22]

For this month's update, we present some pertinent updates in the literature and news regarding Neurologic complications of Monkeypox.

The large multinational Monkeypox virus (MPXV) outbreak that began in spring 2022 is the first of its kind outside of Central and West Africa, and with over 77,000 cases worldwide, is the largest MPXV outbreak to date (https://www.cdc.gov/poxvirus/monkeypox/response/2022/ ⧉ ). It was declared a Public Health Emergency of International Concern (PHEIC) by the World Health Organization in July 2022. This outbreak has disproportionately affected men who have sex with men, with significant person-to-person transmission occurring in a sexual context. Of note, many patients who have contracted MPXV during this current outbreak also have preexisting HIV, with a CDC report noting a rate of 41% in a cohort reported in May-July 2022 (Philpott 2022).  Recent data suggests that the incidence of new infections is decreasing likely due to a combination of public health measures and vaccination. However, it is still important not to put the guard down, for the infection can become endemic and re-emerge in greater numbers. Clinically, MPXV is characterized by a pustular, centrifugal rash (starting on face and extremities and spreading to body) that typically presents after a viral prodrome of fever, myalgias, and lymphadenopathy. During this current outbreak, MPXV has had some notable differences in clinical presentation, including rash sometimes presenting without prodrome, rash localized to the genital areas, and complications including proctitis.

Although neurological manifestations tend to be uncommon in MPXV, patients can rarely present with severe neurologic issues which are worth noting.  In prior outbreaks, headaches have been noted to be common, with occasional mood disturbances and neuralgia also reported; severe manifestations such as encephalitis and seizures were noted to occur rarely (Billioux 2022). During the current outbreak, a number of neurologic complications have been reported, and are likely to grow given the extent of the outbreak.  Severe pain, though unclear if neuropathic in nature, has been often reported to be associated with MPXV lesions, and may lead to hospitalization for management.  Although most cases of MPXV have been self-limited, a recent report from the CDC detailed over 50 cases of severe MPXV, largely occurring in patients with HIV (82%).  Of these cases, 4 had neurologic manifestations, including one patient with disseminated MPXV who developed seizures, coma, and subsequently died (Miller 2022).  Several additional cases of encephalitis have been reported which include two Spanish patients in whom MPXV DNA was detected in the CSF, indicating direct viral invasion; both of these patients subsequently died (Pastula, Ann Neurol 2022).

Encephalomyelitis has also been reported during this outbreak, counting two patients in the U.S. Both cases occurred in immunocompetent young men who had developed MPXV-related rash 5 and 9 days prior to developing neurologic symptoms and were diagnosed with MPXV via lesion swab. The first patient developed upper and lower extremity weakness and numbness as well as bowel and bladder symptoms, and was found to have multifocal demyelinating lesions throughout the brain and spinal cord, including a longitudinally extensive cord lesion; on CSF examination, he had a predominantly lymphocytic pleocytosis (WBC of 155, 60% lymphs), normal glucose (64 mg/dL), elevated protein (273 mg/dL), and was negative for MPXV DNA by PCR.  The second patient developed flaccid weakness and bowel and bladder incontinence, followed by altered mental status requiring intubation for airway protection; he had nonenhancing lesions throughout the brainstem as well as partially enhancing lesions involving the spinal cord.  CSF analysis of this patient also revealed a lymphocytic pleocytosis, (WBC of 30, 89% lymphs), normal glucose (65 mg/dL), elevated protein (60 mg/dL), and was negative for MPXV DNA by PCR.  Both patients underwent extensive workup to rule out alternative etiologies (NMO Ab, Mog Ab, other infectious etiologies, etc), and were treated with a varying combination of tecovirimat, pulsed IV methylprednisolone, IVIG, and plasma exchange.  Both patients recovered well over subsequent weeks, and were able to ambulate with walking devices on follow-up (Pastula MMWR 2022). Given the delayed onset of neurologic symptoms, lack of MPXV DNA in CSF, and improvement with immunotherapy, it is reasonable to suspect that these two cases were related to para-infectious/immune-mediated complications of MPXV.

Little is known about potential mechanisms of neuropathogenesis of MPXV.  However, a group in Thailand recently showed that iPSC-derived neural progenitor cells and astrocytes were both able to be productively infected by MPXV (Chailangkarn 2022).  While the full extent of neurologic manifestations and sequelae of MPXV remains unknown, it is important as neurologists to remain vigilant for these potential issues, particularly in immunocompromised patients. Many patients in this epidemic have had dual infection with HIV, putting them at greater risk for complications. Further, due to the wide use of immunosuppressive drugs in patients with autoimmune conditions and cancer, one needs to have a high index of suspicion for the infection in those who may have been exposed. In these patients the typical rash may not be apparent. Fortunately, treatments such as tecovirimat are available for those at risk, and some degree of prevention from MPXV may be obtained with smallpox vaccinations including Jynneos and ACAM2000.  

References and further reading

1. David Philpott, MD; Christine M. Hughes, MPH; Karen A. Alroy, et al. Epidemiologic and Clinical Characteristics of Monkeypox Cases — United States, May 17–July 22, 2022. Morbidity and Mortality Weekly Report. August 12, 2022. https://www.cdc.gov/mmwr/volumes/71/wr/mm7132e3.htm?s_cid=mm7132e3_w ⧉
2. Billioux BJ, Mbaya OT, Sejvar J, Nath A. Neurologic Complications of Smallpox and Monkeypox: A Review. JAMA Neurol. 2022 Sep 20. doi: 10.1001/jamaneurol.2022.3491.  https://jamanetwork.com/journals/jamaneurology/fullarticle/2796513 ⧉
3. Miller MJ, Cash-Goldwasser S, Marx GE, et al.  Severe Monkeypox in Hospitalized Patients — United States, August 10–October 10, 2022. Morbidity and Mortality Weekly Report. October 26, 2022. https://www.cdc.gov/mmwr/volumes/71/wr/mm7144e1.htm ⧉  
4. Pastula DM, Tyler KL. An Overview of Monkeypox Virus and Its Neuroinvasive Potential. Ann Neurol. 2022 Aug 6. doi: 10.1002/ana.26473.
5. Daniel M. Pastula, MD; Matthew J. Copeland, DO; Markus C. Hannan, MD, et al. Two Cases of Monkeypox-Associated Encephalomyelitis — Colorado and the District of Columbia, July–August 2022. Morbidity and Mortality Weekly Report. September 23, 2022 / 71(38);1212–1215. https://www.cdc.gov/mmwr/volumes/71/wr/mm7138e1.htm ⧉
6. Chailangkarn T, Teeravechyan S, Attasombat K, Thaweerattanasinp T, Sunchatawirul K, Suwanwattana P, Pongpirul K, Jongkaewwattana A. Monkeypox virus productively infects human induced pluripotent stem cell-derived astrocytes and neural progenitor cells. J Infect. 2022 Oct 19:S0163-4453(22)00613-2. doi: 10.1016/j.jinf.2022.10.016. https://www.journalofinfection.com/article/S0163-4453(22)00613-2/fulltext ⧉