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Neurologic Complications of Smallpox and MonkeypoxA Review

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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.

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Article Information

Accepted for Publication: August 25, 2022.

Published Online: September 20, 2022. doi:10.1001/jamaneurol.2022.3491

Corresponding Author: Avindra Nath, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Dr, Bldg 10, Room 7C-103, Bethesda, MD 20892 (natha@ninds.nih.gov).

Author Contributions: Dr Nath had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Billioux, Mbaya, Nath.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Billioux, Mbaya, Nath.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: All authors.

Supervision: Sejvar.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported in part by the National Institutes of Health (Drs Billioux, Mbaya, and Nath) and the Center for Disease Control and Prevention (Dr Sejvar).

Role of the Funder/Sponsor: These organizations have approved the manuscript for publication. The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation or review of the manuscript; and decision to submit the manuscript for publication. The funding sources approved the manuscript for publication.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Centers for Disease Control and Prevention. 2022 Monkeypox outbreak global map. Accessed August 22, 2022. https://www.cdc.gov/poxvirus/monkeypox/response/2022/world-map.html
Diaz  JH .  The disease ecology, epidemiology, clinical manifestations, management, prevention, and control of increasing human infections with animal orthopoxviruses.   Wilderness Environ Med. 2021;32(4):528-536. doi:10.1016/j.wem.2021.08.003PubMedGoogle ScholarCrossref
Ruffer  MA , Ferguson  AR .  Note on an eruption resembling that of variola in the skin of a mummy of the twentieth dynasty (1200-1100 BC).   J Pathol Bacteriol. 1911;15:1-3. doi:10.1002/path.1700150102Google ScholarCrossref
Thèves  C , Crubézy  E , Biagini  P .  History of smallpox and its spread in human populations.   Microbiol Spectr. 2016;4(4). doi:10.1128/microbiolspec.PoH-0004-2014PubMedGoogle ScholarCrossref
Strassburg  MA .  The global eradication of smallpox.   Am J Infect Control. 1982;10(2):53-59. doi:10.1016/0196-6553(82)90003-7PubMedGoogle ScholarCrossref
Moore  ZS , Seward  JF , Lane  JM .  Smallpox.   Lancet. 2006;367(9508):425-435. doi:10.1016/S0140-6736(06)68143-9PubMedGoogle ScholarCrossref
McEntire  CRS , Song  KW , McInnis  RP ,  et al.  Neurologic manifestations of the World Health Organization’s list of pandemic and epidemic diseases.   Front Neurol. 2021;12:634827. doi:10.3389/fneur.2021.634827PubMedGoogle ScholarCrossref
Breman  JG , Henderson  DA .  Diagnosis and management of smallpox.   N Engl J Med. 2002;346(17):1300-1308. doi:10.1056/NEJMra020025PubMedGoogle ScholarCrossref
Cann  JA , Jahrling  PB , Hensley  LE , Wahl-Jensen  V .  Comparative pathology of smallpox and monkeypox in man and macaques.   J Comp Pathol. 2013;148(1):6-21. doi:10.1016/j.jcpa.2012.06.007PubMedGoogle ScholarCrossref
Rao  AR .  Smallpox. Kothari Book Depot; 1972.
Marsden  JP , Hurst  EW .  Acute perivascular myelinoclasis (“acute disseminated encephalomyelitis”) in smallpox.   Brain. 1932;55(2):181-225. doi:10.1093/brain/55.2.181Google ScholarCrossref
Murphy  OC , Messacar  K , Benson  L ,  et al; AFM working group.  Acute flaccid myelitis: cause, diagnosis, and management.   Lancet. 2021;397(10271):334-346. doi:10.1016/S0140-6736(20)32723-9PubMedGoogle ScholarCrossref
Bozzola  E , Bozzola  M , Tozzi  AE ,  et al.  Acute cerebellitis in varicella: a 10-year case series and systematic review of the literature.   Ital J Pediatr. 2014;40:57. doi:10.1186/1824-7288-40-57PubMedGoogle ScholarCrossref
Miravalle  A , Roos  KL .  Encephalitis complicating smallpox vaccination.   Arch Neurol. 2003;60(7):925-928. doi:10.1001/archneur.60.7.925PubMedGoogle ScholarCrossref
Booss  J , Davis  LE .  Smallpox and smallpox vaccination: neurological implications.   Neurology. 2003;60(8):1241-1245. doi:10.1212/01.WNL.0000063319.64515.6BPubMedGoogle ScholarCrossref
Lillie  RD .  Smallpox and vaccinia: the pathologic histology.   Arch Pathol (Chic). 1930;10:241-291.Google Scholar
Sejvar  JJ , Labutta  RJ , Chapman  LE , Grabenstein  JD , Iskander  J , Lane  JM .  Neurologic adverse events associated with smallpox vaccination in the US, 2002-2004.   JAMA. 2005;294(21):2744-2750. doi:10.1001/jama.294.21.2744PubMedGoogle ScholarCrossref
Von Magnus  P , Andersen  EK , Petersen  KB , Birch-Andersen  A .  A pox-like disease in cynomologous monkeys.   Acta Pathol Microbiol Scand. 1959;46:156. doi:10.1111/j.1699-0463.1959.tb00328.xGoogle ScholarCrossref
Prier  JE , Sauer  RM .  A pox disease of monkeys.   Ann N Y Acad Sci. 1960;85:951-959. doi:10.1111/j.1749-6632.1960.tb50015.xPubMedGoogle ScholarCrossref
Sklenovská  N , Van Ranst  M .  Emergence of monkeypox as the most important orthopoxvirus infection in humans.   Front Public Health. 2018;6:241. doi:10.3389/fpubh.2018.00241PubMedGoogle ScholarCrossref
Thomassen  HA , Fuller  T , Asefi-Najafabady  S ,  et al.  Pathogen-host associations and predicted range shifts of human monkeypox in response to climate change in central Africa.   PLoS One. 2013;8(7):e66071. doi:10.1371/journal.pone.0066071PubMedGoogle ScholarCrossref
Alakunle  E , Moens  U , Nchinda  G , Okeke  MI .  Monkeypox virus in Nigeria: infection biology, epidemiology, and evolution.   Viruses. 2020;12(11):1257. doi:10.3390/v12111257PubMedGoogle ScholarCrossref
Antinori  A , Mazzotta  V , Vita  S ,  et al; INMI Monkeypox Group.  Epidemiological, clinical, and virological characteristics of 4 cases of monkeypox support transmission through sexual contact, Italy, May 2022.   Euro Surveill. 2022;27(22):2200421. doi:10.2807/1560-7917.ES.2022.27.22.2200421PubMedGoogle ScholarCrossref
Peiró-Mestres  A , Fuertes  I , Camprubí-Ferrer  D ,  et al; Hospital Clinic de Barcelona Monkeypox Study Group.  Frequent detection of monkeypox virus DNA in saliva, semen, and other clinical samples from 12 patients, Barcelona, Spain, May to June 2022.   Euro Surveill. 2022;27(28). doi:10.2807/1560-7917.ES.2022.27.28.2200503PubMedGoogle ScholarCrossref
Sale  TA , Melski  JW , Stratman  EJ .  Monkeypox: an epidemiologic and clinical comparison of African and US disease.   J Am Acad Dermatol. 2006;55(3):478-481. doi:10.1016/j.jaad.2006.05.061PubMedGoogle ScholarCrossref
Happi  C , Adetifa  I , Mbala  P ,  et al.  Urgent need for a nondiscriminatory and nonstigmatizing nomenclature for monkeypox virus.   PLoS Biol. 2022;20(8):e3001769. doi:10.1371/journal.pbio.3001769PubMedGoogle ScholarCrossref
Isidro  J , Borges  V , Pinto  M ,  et al.  Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virus.   Nat Med. 2022;28(8):1569-1572. doi:10.1038/s41591-022-01907-yPubMedGoogle ScholarCrossref
Iñigo Martínez  J , Gil Montalbán  E , Jiménez Bueno  S ,  et al.  Monkeypox outbreak predominantly affecting men who have sex with men, Madrid, Spain, 26 April to 16 June 2022.   Euro Surveill. 2022;27(27):2200471. doi:10.2807/1560-7917.ES.2022.27.27.2200471PubMedGoogle ScholarCrossref
Girometti  N , Byrne  R , Bracchi  M ,  et al.  Demographic and clinical characteristics of confirmed human monkeypox virus cases in individuals attending a sexual health centre in London, UK: an observational analysis.   Lancet Infect Dis. 2022;22(9):1321-1328. doi:10.1016/S1473-3099(22)00411-XPubMedGoogle ScholarCrossref
Thornhill  JP , Barkati  S , Walmsley  S ,  et al; SHARE-net Clinical Group.  Monkeypox virus infection in humans across 16 countries—April-June 2022.   N Engl J Med. 2022;387(8):679-691. doi:10.1056/NEJMoa2207323PubMedGoogle ScholarCrossref
Parker  S , Nuara  A , Buller  RML , Schultz  DA .  Human monkeypox: an emerging zoonotic disease.   Future Microbiol. 2007;2(1):17-34. doi:10.2217/17460913.2.1.17PubMedGoogle ScholarCrossref
Jezek  Z , Szczeniowski  M , Paluku  KM , Mutombo  M .  Human monkeypox: clinical features of 282 patients.   J Infect Dis. 1987;156(2):293-298. doi:10.1093/infdis/156.2.293PubMedGoogle ScholarCrossref
Orviz  E , Negredo  A , Ayerdi  O ,  et al.  Monkeypox outbreak in Madrid (Spain): clinical and virological aspects.   J Infect. Published online July 10, 2022. doi:10.1016/j.jinf.2022.07.005PubMedGoogle ScholarCrossref
Whitehouse  ER , Bonwitt  J , Hughes  CM ,  et al.  Clinical and epidemiological findings from enhanced monkeypox surveillance in Tshuapa Province, Democratic Republic of the Congo during 2011-2015.   J Infect Dis. 2021;223(11):1870-1878. doi:10.1093/infdis/jiab133PubMedGoogle ScholarCrossref
Yinka-Ogunleye  A , Aruna  O , Dalhat  M ,  et al; CDC Monkeypox Outbreak Team.  Outbreak of human monkeypox in Nigeria in 2017-18: a clinical and epidemiological report.   Lancet Infect Dis. 2019;19(8):872-879. doi:10.1016/S1473-3099(19)30294-4PubMedGoogle ScholarCrossref
Adler  H , Gould  S , Hine  P ,  et al; NHS England High Consequence Infectious Diseases (Airborne) Network.  Clinical features and management of human monkeypox: a retrospective observational study in the UK.   Lancet Infect Dis. 2022;22(8):1153-1162. doi:10.1016/S1473-3099(22)00228-6PubMedGoogle ScholarCrossref
Ogoina  D , Iroezindu  M , James  HI ,  et al.  Clinical course and outcome of human monkeypox in Nigeria.   Clin Infect Dis. 2020;71(8):e210-e214. doi:10.1093/cid/ciaa143PubMedGoogle ScholarCrossref
Sejvar  JJ , Chowdary  Y , Schomogyi  M ,  et al.  Human monkeypox infection: a family cluster in the midwestern US.   J Infect Dis. 2004;190(10):1833-1840. doi:10.1086/425039PubMedGoogle ScholarCrossref
Faus  J . Spain reports second monkeypox-related death in Europe. Accessed July 30, 2022. https://www.reuters.com/world/europe/spain-confirms-first-monkeypox-related-death-country-reports-2022-07-29/
The Daily Star. Kerala reports India’s first monkeypox-related death. Accessed August 5, 2022. https://www.thedailystar.net/health/disease/news/kerala-reports-indias-first-monkeypox-related-death-3084831
Pastula  DM , Tyler  KL .  An overview of monkeypox virus and its neuroinvasive potential.   Ann Neurol. Published online August 6, 2022. doi:10.1002/ana.26473PubMedGoogle ScholarCrossref
World Health Organization. Clinical management and infection prevention and control for monkeypox: Interim rapid response guidance, 10 June 2022. Accessed August 22, 2022. https://www.who.int/publications/i/item/WHO-MPX-Clinical-and-IPC-2022.1
Parker  S , Handley  L , Buller  RM .  Therapeutic and prophylactic drugs to treat orthopoxvirus infections.   Future Virol. 2008;3(6):595-612. doi:10.2217/17460794.3.6.595PubMedGoogle ScholarCrossref
Jordan  R , Tien  D , Bolken  TC ,  et al.  Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor.   Antimicrob Agents Chemother. 2008;52(5):1721-1727. doi:10.1128/AAC.01303-07PubMedGoogle ScholarCrossref
SIGA Technologies, Inc. FDA advisory committee briefing document: tecovirimat for the treatment of smallpox disease. Accessed June 30, 2022. https://www.fda.gov/media/112808/download
US Food and Drug Administration. Highlights of TPOXX prescribing information. Accessed June 30, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208627s000lbl.pdf
Centers for Disease Control and Prevention. Monkeypox signs and symptoms. Accessed July 5, 2022. https://www.cdc.gov/poxvirus/monkeypox/index.html
US Food and Drug Administration. FDA approves drug to treat smallpox. Accessed June 30, 2022. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-smallpox
Hutson  CL , Kondas  AV , Mauldin  MR ,  et al.  Pharmacokinetics and efficacy of a potential smallpox therapeutic, brincidofovir, in a lethal monkeypox virus animal model.   mSphere. 2021;6(1):e00927-e20. doi:10.1128/mSphere.00927-20PubMedGoogle ScholarCrossref
Neyts  J , Snoeck  R , Schols  D , Balzarini  J , De Clercq  E .  Selective inhibition of human cytomegalovirus DNA synthesis by (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG).   Virology. 1990;179(1):41-50. doi:10.1016/0042-6822(90)90271-RPubMedGoogle ScholarCrossref
De Clercq  E , Holý  A , Rosenberg  I .  Efficacy of phosphonylmethoxyalkyl derivatives of adenine in experimental herpes simplex virus and vaccinia virus infections in vivo.   Antimicrob Agents Chemother. 1989;33(2):185-191. doi:10.1128/AAC.33.2.185PubMedGoogle ScholarCrossref
Akazawa  D , Ohashi  H , Hishiki  T ,  et al.  Potential antimonkeypox virus activity of atovaquone, mefloquine, and molnupiravir, and their potential use as treatments.   bioRxiv. Published online August 2, 2022. https://www.biorxiv.org/content/10.1101/2022.08.02.502485v1Google Scholar
Sklenovska  N . Monkeypox virus. In: Malik  YS , Singh  RK , Dhama  K , eds.  Animal-Origin Viral Zoonoses Livestock Diseases and Management. Springer; 2020:39-68. doi:10.1007/978-981-15-2651-0_2
Rao  AK , Petersen  BW , Whitehill  F ,  et al.  Use of JYNNEOS (smallpox and monkeypox vaccine, live, nonreplicating) for preexposure vaccination of persons at risk for occupational exposure to orthopoxviruses: recommendations of the advisory committee on immunization practices—US, 2022.   MMWR Morb Mortal Wkly Rep. 2022;71(22):734-742. doi:10.15585/mmwr.mm7122e1PubMedGoogle ScholarCrossref
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