A recent JAMA Neurology study provides an overview of existing literature on the complications of infection with both smallpox and monkeypox virus (MPXV). Here, the researchers primarily focus on the neurological manifestations that develop following recovery from these infections.
Study: Neurologic Complications of Smallpox and Monkeypox. Image Credit: Kateryna Kon / Shutterstock.com
Background
Several pandemics have emerged over the past few decades due to the emergence of the human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS), as well as Dengue, Zika, Ebola, and West Nile viruses. Most recently, the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the coronavirus disease 2019 (COVID-19) pandemic. Many of these infections precipitate acute symptoms associated with long-term neurologic complications, such as long COVID.
Recently, MPXV has emerged as a looming threat for another pandemic following COVID-19, the latter of which continues to claim hundreds of deaths each day worldwide. In the aftermath of these VIRAL OUTBREAKS and the lingering symptoms of these infections and their associated psychological impacts are responsible for long-term public health and socioeconomic burden.
Due to the lack of information available on the long-term impacts of many viral infections, the current review describes the post-acute neurological complications following infection with smallpox and MPXV. MPXV and smallpox are zoonotic viruses that belong to the genus orthopoxvirus. Thus, the post-infection neurological complications of both viruses may be similar, although differing in severity and frequency.
Orthopox viruses
The orthopoxvirus genus comprises zoonotic viruses with 17 known species, eight of which have been shown to infect humans from animal contact, whereas five can be transmitted between humans. Infections in humans are often caused by contact with contaminated fomites, skin lesions, and respiratory droplets.
Most orthopox viruses do not cause disease in humans; however, MPXV accounts for most human infections. Rodents are the natural reservoirs of MPXV, thus making its eradication difficult.
In May 2022, the global outbreak of MPXV throughout non-endemic regions in Europe, North America, and Australia began. The West African (WA) clade of MPXV, which has since been renamed Clade II, appears to be the dominant circulating strain during the current outbreak.
MPXV has primarily been detected among men who have sex with men (MSM), which has led to speculations on the sexual transmission route. As of September 25, 2022, over 65,000 MPXV cases have been detected worldwide.
Smallpox virus
Global eradication of the smallpox virus was acknowledged in 1980 by the World Health Organization (WHO) after centuries of the epidemic on different continents. Smallpox virus has two variants, including variola major and minor, with major variola infection often associated with greater severity and a high mortality rate.
Infection with the smallpox virus is characterized by a prodromal phase typically associated with fever, backache, and headache. After that, the eruptive phase is marked by the development of erythematous mucous membrane lesions within the mouth, tongue, and oropharynx. Subsequently, the exanthema phase is associated with skin lesions affecting the face and extremities, spreading within one or two days.
The pathognomonic feature of smallpox infection is its centrifugal pattern of skin lesions. Therefore, all types of lesions, such as macule, papule, vesicle, pustule, umbilication, crusting, and desquamation, will be present simultaneously at the same stage.
The WHO classifies smallpox infection into five clinical subtypes: ordinary, modified, variola sine eruption, flat, and hemorrhagic. The ordinary subtype, the most common smallpox infection, is associated with a 30% mortality rate.
The variola sine eruption and modified subtypes are mild infections that often arise in vaccinated individuals. Conversely, hemorrhagic and flat subtypes of smallpox, both of which are rare, are associated with a very high fatality rate of 97%. Complications of smallpox infection may include viral keratitis, bronchopneumonia, and arthritis.
Neurological complications of smallpox at different stages of the disease include headaches, backaches, encephalopathy, delirium, and seizures. Rarely encephalitis occurs as a complication with culture-negative neutrophilic cerebrospinal fluid (CSF). Normal-to-mild elevation in protein levels and normal glucose levels are also detected when the nervous system is affected.
Older smallpox vaccines were associated with several neurological side effects, like post vaccinal encephalomyelitis (PVEM) in adults, with a fatality rate of 25%. Importantly, these vaccines are no longer used because of these side effects, with newer smallpox vaccines associated with a superior biosafety profile.
MPXV
MPXV was first isolated in 1958 in Denmark from the lesions of cynomolgus monkeys. By 1970, the first human MPXV infection was recorded in Africa.
MPXV infection is most frequently diagnosed in certain African countries, particularly those within West Africa and the Democratic Republic of Congo. However, several MPXV outbreaks have been reported in the United States, United Kingdom, and Israel between 2003 and 2018, as well as the current 2022 outbreak that has been reported in over 100 locations worldwide.
Most MPX human infections occur through direct contact with an infected animal, exposure to their body fluids, or contact with contaminated materials. MPXV transmission through the consumption of undercooked meat of an infected animal has also been documented.
In addition to Clade II, there is a second MPXV clade known as the Congo Basin (CB), or Clade I. Both MPXV clades differ clinically and demographically, with CB responsible for more severe disease with a fatality rate of 11% and commonly diagnosed in pediatric patients. A third MPXV clade, known as Clade III, is a subset of Clade II and has also been recently described.
The clinical presentation of MPXV disease is similar to that of smallpox. More specifically, there is a prodromal phase characterized by submandibular, inguinal, cervical, and/or axillary lymphadenopathy, as well as fever, chills, headache, sweat, myalgia, sore throat, and prostration. Lymphadenopathy is the characteristic feature of this disease.
MPXV skin lesions progress at a similar rate as smallpox lesions. In addition, MPXV disease is also associated with gastrointestinal manifestations. Nevertheless, about 30% of MPXV-infected patients remain asymptomatic.
The concurrence of MPXV infection with dehydration can predispose an infected individual to numerous complications, including myocarditis, proctitis, and epiglottitis. Several common adverse effects of MPXV infection include ocular damage, sepsis, and neurologic impairment.
A considerable percentage of MPXV-infected patients are also HIV-positive and on antiretroviral therapy. Furthermore, MPXV disease often co-occurs with various sexually transmitted infections.
The recent MPXV outbreak has primarily been associated with a mild form of the disease, with localized skin lesions reported at the area of infection. These lesions, which can be asynchronous in some cases, maybe the initial symptom of infection.
Neurologic effects of MPXV
Neurologic complications following recovery from MPXV infection include headache, depression, mood swings, anxiety, and neuropathic pain. Meanwhile, skin lesions may lead to painful sores causing dysphagia, anal fissures, and rectal pain. Conjunctivitis may lead to reduced eyesight and exacerbate an infection involving the central nervous system (CNS).
It is vital to investigate the presence of any other sexually transmitted infection. All suspected cases should undergo polymerase chain reaction (PCR) testing and serology of vesicular fluid at local health departments. Cerebrospinal fluid (CSF) should be tested if neurological involvement is suspected.
In the case of acute neurological involvement, the etiological agent should be determined through biological tests. Orthopox virus immunoglobulin (Ig)M and PCR testing of CSF should be done for the DNA of MPXV.
Treatment
To date, various antiviral drugs have been evaluated in both in vitro and in vivo studies for their efficacy in treating MPXV infection; however, none of these agents have been tested in clinical settings. Tecovirimat (ST-246), which is currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, is a promising drug that has the potential also to be used to treat MPXV infection.
ST-246 can be administered orally or intravenously, with the current recommended dose for adults being 600 mg twice daily for two weeks. This drug inhibits the orthopox virus envelope-wrapping protein (p37).
Brincidofovir, approved by the FDA to treat smallpox disease caused by the variola virus, inhibits the orthopox virus nucleotide analog DNA polymerase. Although this drug has been shown to improve survival against smallpox, its efficacy in treating MPXV remains unclear.
Symptomatic and supportive care is an essential aspect in the management of MPXV infection. Treating painful lesions, for example, can be achieved through topical agents, oral medications, or nerve blocks.
Certain neurological complications of MPXV, such as transverse myelitis and acute disseminated encephalomyelitis (ADEM), should be treated with a high dose of corticosteroids. In addition, intravenous immunoglobulin (Ig) or plasmapheresis should be used to treat Guillain-Barre syndrome.
First-generation smallpox vaccines appear to successfully protect against MPXV with an efficacy of about 85%. Despite these benefits, the live vaccinia virus vaccine is associated with severe side effects that can affect the CNS. Furthermore, the live smallpox vaccine is contraindicated in immunocompromised patients, pregnant women, and patients with eczema.
In addition to this first-generation smallpox vaccine, two other vaccines have been developed, including ACAM2000 and Jynneos. Both vaccines are recommended for preexposure prophylaxis for those at risk of exposure to orthopoxviruses.
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