The recent global emergence of monkeypox has raised fears of another pandemic on the heels of the COVID-19 pandemic. Although the COVID-19 pandemic is the worst pandemic in a century, several major pandemics have occurred in the recent past, including Zika, Ebola, dengue, West Nile, and AIDS.
A common thread of these pandemics is long-term neurological complications , such as post-COVID-19 conditions, congenital Zika syndrome, post-Ebola syndrome, West Nile encephalitis, and neurocognitive disorders associated with HIV. These complications have important socioeconomic effects and are feared by the public.
However, these manifestations often go unnoticed, initially masked by the acute systemic involvement of the infection and later attributed to target organ damage or psychosocial stress related to the pandemic. For these reasons, we have reviewed the literature on orthopox viruses.
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 of sub-Saharan Africa until a global outbreak in May 2022.
It is important to review the known neurological consequences of these two viruses, as smallpox complications may be relevant to monkeypox, although monkeypox complications may be rarer and perhaps less severe.
Observations
This was a literature review of known neurological complications of smallpox, including encephalitis, transverse myelitis, and acute disseminated encephalomyelitis , among others; historical complications of smallpox vaccination, including post-vaccine encephalomyelitis; and the known neurological complications of monkeypox, including headaches and mood disturbances, as well as rare presentations of encephalitis, transverse myelitis, and seizures.
The possibility of viral persistence and systemic complications in immunocompromised individuals is worrying. Considerations for the diagnosis, current treatment, and prevention of monkeypox were also provided.
Neurological complications of smallpox
Smallpox can cause a variety of neurological complications, although reports are scarce. Headaches at the beginning are very common. Back pain is typical in the prodrome, affecting up to 90% of patients. Delirium or encephalopathy may accompany the illness in about 15% of patients during the febrile stage. Febrile seizures may occur in approximately 7% of children under 5 years of age.
Encephalitis may occur in approximately 1 in 500 cases of smallpox, characterized by reduced levels of consciousness. Cerebrospinal fluid (CSF) is characterized by elevated opening pressure, mild lymphocytic pleocytosis, which may be neutrophilic at first, normal glucose level, and normal to slightly elevated protein level. No virus could be cultured from CSF. However, it is still unknown whether techniques based on polymerase chain reaction (PCR) would be more sensitive for viral detection.
Marsden and Hurst published a case series of what they described as acute perivascular myelinoclasis, or acute disseminated encephalomyelitis (ADEM), in patients with smallpox. Additionally, they described several historical cases of smallpox with neurological manifestations, including cases of transverse myelitis and one case of concurrent optic neuritis and transverse myelitis during smallpox infection.
Although there were variable presentations of spinal cord involvement, individuals with transverse myelitis had more motor than sensory involvement, with sphincter dysfunction, and when pathology was available, gray matter was more affected than white matter. Both ADEM and transverse myelitis can be triggered by a wide variety of viral infections and produce longitudinally extensive lesions that often predominantly involve the white matter.
Both Rao and Marsden and Hurst noted an interesting phenomenon in patients recovering from smallpox-related encephalitis, as they often had dysarthria and an ataxic gait that would improve over time, indicating possible cerebellar involvement. Similar features have been reported with varicella-zoster virus infection. In these cases, magnetic resonance imaging (MRI) shows a hyperintense signal in the cerebellum and patients respond to high doses of corticosteroids. Because smallpox cases predate the availability of MRIs, it is not yet known whether a similar pattern can be seen with smallpox.
Neurological complications with smallpox vaccination
Although there is an effective vaccine against smallpox virus, similar to most other vaccines, it is not without some risks. Neurological complications have been associated with older forms of the vaccine, such as Dryvax (Wyeth Laboratories), used to eradicate the disease. These older vaccines are no longer used due to the associated complications. These neurological complications occur more frequently in adults and can present as post-vaccine encephalomyelitis (PVEM). PVEM is characterized by multifocal inflammatory demyelinating lesions that occur 7 to 14 days after vaccination. Patients developed altered consciousness, headache, and neck and back pain, with progression to aphasia, seizures, paresis or paralysis of extremities, bladder dysfunction, cranial nerve palsies, and worsening mental status, sometimes leading to coma. The mortality rate from PVEM was around 25%. Despite this, pathological descriptions are scarce.
Neurological complications of monkeypox
Very few neurological complications of monkeypox have been described. Headache is a common presenting feature in clades 1 and 2. Mood disorders, including depression and anxiety, and neuropathic pain are common. The skin lesions themselves can cause painful sores and, depending on the affected site, can cause dysphagia, rectal pain with anal fissures, etc.
It is unclear whether some of the pain may be dermatomal, similar to that seen with varicella zoster, but the pain may be severe. Conjunctivitis occurred in approximately 20% of patients in a recent outbreak in the Democratic Republic of the Congo, which could lead to decreased vision. This could also be a potential site for virological seeding in the central nervous system. Monkeypox rarely causes encephalitis.
Prevention
Smallpox vaccines induce cross-reactive antibodies that protect against infection by other Orthopoxvirus species. The live vaccinia virus vaccine (first generation), used during the smallpox eradication program, was 85% effective against monkeypox. This vaccine can cause serious adverse effects (including neurological adverse effects, as detailed above) and is contraindicated in pregnant women, immunocompromised people, and people with eczema.
The second (ACAM2000) and third (Jynneos, also known as Imvanex or Imvammune) vaccinia vaccines have reduced adverse effects and simplified administration; However, it would not be surprising if mass inoculation resulted in some cases with neuroinflammatory manifestations, such as Guillain-Barré syndrome, myelitis, or encephalitis.
The Advisory Committee on Immunization Practices (ACIP) recommended pre-exposure prophylaxis with ACAM2000 in 2015. Jynneos, a live replication-deficient vaccinia virus, was licensed in the US in 2019. On November 3, 2021, ACIP recommended pre-exposure prophylaxis with Jynneos as an alternative to ACAM2000 for people at risk of exposure to orthopoxvirus.
Conclusions In the wake of the current multinational monkeypox outbreak, it is evident that many aspects of this disease are understudied. This includes neurological complications and sequelae and their management. Therefore, it is important to review the literature not only for MPXV but also for other orthopoxviruses, such as smallpox virus, to better understand the potential for these complications. To date, few major neurological complications have been reported with the current clade outbreak. However, based on the known neurological complications of orthopoxviruses, we must be prepared for the possibility of viral encephalitis, myelitis, ADEM, Guillain-Barré syndrome, neuropathic pain, and others, and treat them accordingly. Special attention should be paid to patients with immunocompromising conditions, such as HIV/AIDS, as viral neuroinvasion may be facilitated and neurological complications are to be expected. Preventive measures, including third-generation vaccinia vaccines, are available but scarce. Although safer than previous vaccines, healthcare providers should be alert for potential adverse neurological reactions as these vaccines are reaching a wide population. |
Final message
Monkeypox should be considered in high-risk populations presenting with neurological syndromes. Diagnosis may require serological and polymerase chain reaction testing in blood and cerebrospinal fluid. Antiviral therapy should be started early in the course of the disease.
