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Orthopoxviruses, a genus of viruses that include smallpox (variola virus) and a monkeypox, are known primarily for their dermatological manifestations, such as pustular skin eruptions and systemic illness. While smallpox was declared eradicated in 1980, monkeypox continues to be a significant health concern, particularly in regions of Africa, but with increasing global spread. Although most attention has focused on the cutaneous and systemic features of these diseases, recent evidence suggests that neurological complications can occur, adding to the morbidity associated with orthopoxvirus infections [1].

This article explores the neurological manifestations of smallpox and monkeypox, shedding light on the mechanisms by which these viruses affect the nervous system, the types of complications that can arise, and the importance of recognizing these issues for patient care and public health.

Overview of orthopoxvirus infections

• Smallpox (variola virus): Smallpox was a highly contagious and deadly disease that claimed millions of lives before its eradication. The variola virus primarily spread through respiratory droplets, entering the body and replicating in the lymphatic system before disseminating to the skin, causing characteristic pustular lesions. While eradicated, concerns over bioterrorism or accidental release of stored viral samples maintain interest in smallpox research.
• Monkeypox: Monkeypox is an emerging zoonotic virus closely related to smallpox but typically less severe. It is transmitted to humans through direct contact with infected animals or through human-to-human transmission via bodily fluids or respiratory droplets. The disease presents similarly to smallpox, with fever, malaise, and rash, but is generally less lethal. Recent outbreaks outside Africa have drawn increased attention to the global health risks posed by monkeypox [2].

Neurological Complications of Orthopoxvirus Infections

Historically, the neurological complications of smallpox and monkeypox have been underreported, possibly due to the overwhelming focus on the visible dermatological and systemic aspects of these diseases. However, evidence from case reports and emerging outbreaks suggests that the nervous system can be significantly impacted by these viral infections. Neurological manifestations can range from mild, transient symptoms to severe, life-threatening conditions, including encephalitis, myelitis, and neuropathy.

1. Smallpox and the Nervous System

Although smallpox primarily attacked the skin and mucous membranes, neurological complications were recognized in a subset of patients, especially during severe cases. The nervous system could be affected in various ways:

• Post-Vaccinal Encephalitis: One of the most significant neurologic complications of smallpox was related to vaccination. The live-attenuated vaccinia virus, used in the smallpox vaccine, occasionally led to post-vaccinal encephalitis, a condition marked by brain inflammation, seizures, and altered mental status. This rare but severe adverse event occurred in approximately 1 in 100,000 vaccine recipients and could result in long-term neurological deficits or death.
• Encephalomyelitis: In rare cases of smallpox infection itself, patients developed encephalomyelitis, an inflammation of the brain and spinal cord. This condition was likely immune-mediated, triggered by the body’s response to the virus rather than direct viral invasion of the central nervous system (CNS). Symptoms included confusion, paralysis, and seizures, which could be fatal in severe cases.
• Guillain-Barré Syndrome (GBS): Another rare but recognized complication was GBS, an autoimmune disorder where the immune system attacks the peripheral nervous system, leading to muscle weakness and, in severe cases, paralysis [3].

2. Monkeypox and Neurological Complications

While the neurological complications of monkeypox are less well-documented than those of smallpox, emerging data from recent outbreaks indicate that the nervous system can be involved:

• Encephalitis: Several case reports have described encephalitis (inflammation of the brain) as a complication of monkeypox infection. Symptoms of monkeypox-related encephalitis include headache, fever, altered mental status, and seizures. This condition can be life-threatening and requires immediate medical intervention.
• Seizures: Some individuals with monkeypox have developed seizures, which may be associated with encephalitis or other forms of CNS involvement. The exact mechanism is unclear, but it may involve immune-mediated inflammation or direct viral effects on the brain.
• Meningitis: Monkeypox can also lead to aseptic meningitis, an inflammation of the meninges (the membranes surrounding the brain and spinal cord) that is typically less severe than bacterial meningitis but can still cause significant discomfort, with symptoms such as headache, neck stiffness, and fever.
• Myelitis: Although rare, myelitis (inflammation of the spinal cord) has been reported in some cases of monkeypox, resulting in muscle weakness, paralysis, and sensory disturbances.
• Cognitive and Psychological Symptoms: In addition to physical neurological symptoms, some individuals recovering from monkeypox have reported cognitive impairments, such as difficulty concentrating and memory issues, as well as psychological effects like depression and anxiety [4]. These symptoms may persist even after the acute infection resolves, suggesting potential long-term neurological impacts.

Mechanisms of Neurological Involvement in Orthopoxvirus Infections

The exact mechanisms by which orthopoxviruses affect the nervous system are not fully understood, but several pathways have been proposed:

• Direct Viral Invasion: In some cases, orthopoxviruses may invade the CNS directly, crossing the blood-brain barrier and infecting neural tissues. While this is likely rare, it could explain cases of encephalitis or myelitis where viral particles are detected in the brain or spinal cord.
• Immune-Mediated Inflammation: A more likely explanation for most neurological complications is an immune-mediated response. The body’s immune system may overreact to the virus, resulting in widespread inflammation that affects not only the skin and organs but also the CNS. This hyperactivation of the immune system can lead to conditions like encephalitis or Guillain-Barré syndrome.
• Vaccine-Related Neurological Effects: In the case of smallpox, neurological complications have also been linked to vaccination. The vaccinia virus used in the vaccine is a live virus, which, in rare cases, can trigger adverse immune responses or directly infect neural tissues. While modern versions of the vaccine have improved safety profiles, the risk of neurological complications remains a concern, especially in individuals with weakened immune systems.

Management of Neurological Complications

Managing neurological complications associated with orthopoxvirus infections is challenging and requires a multidisciplinary approach [5]. Early recognition of symptoms is crucial for timely intervention. Key management strategies include:

• Supportive Care: In cases of encephalitis or meningitis, supportive care, such as fluids, antipyretics, and anti-seizure medications, is essential. Patients may require intensive care in severe cases.
• Antiviral Therapy: Antiviral medications, such as tecovirimat (approved for the treatment of smallpox and under investigation for monkeypox), may help reduce viral replication and limit disease severity. However, the effectiveness of these treatments in preventing or mitigating neurological complications is still being studied.
• Immunotherapy: For immune-mediated complications, such as Guillain-Barré syndrome or post-vaccinal encephalitis, treatments like intravenous immunoglobulin (IVIG) or plasma exchange may be beneficial in reducing inflammation and improving outcomes.

Future Research Directions

Given the emerging understanding of neurological complications in orthopoxvirus infections, several areas of research are crucial for improving patient care:

1. Epidemiological Studies: Large-scale epidemiological studies are needed to determine the true prevalence of neurological complications in both smallpox and monkeypox infections. Understanding the risk factors for developing these complications could help identify vulnerable populations and guide preventive measures.
2. Mechanistic Studies: Further research into the mechanisms by which orthopoxviruses affect the nervous system is essential for developing targeted therapies. This includes studies on the role of immune-mediated inflammation and direct viral invasion of the CNS [6-8].
3. Vaccine Safety: As monkeypox vaccination efforts expand, especially in response to outbreaks, continued monitoring of vaccine safety is critical. Identifying individuals at risk of vaccine-related neurological complications will help improve vaccine protocols and minimize adverse outcomes.

Conclusion

Orthopoxvirus infections, including smallpox and monkeypox, pose not only dermatological and systemic risks but also significant neurological challenges. While rare, complications such as encephalitis, myelitis, and post-vaccinal encephalitis can have severe and lasting impacts on patients. Ongoing research into the mechanisms of these complications and improved diagnostic and therapeutic strategies will be key to reducing the neurological burden of orthopoxvirus infections and ensuring better outcomes for affected individuals.

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