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Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but severe condition associated with SARS-CoV-2 infection. First reported during the COVID-19 pandemic, MIS-C is characterized by systemic hyperinflammation affecting multiple organs, including the heart, lungs, kidneys, gastrointestinal tract, and central nervous system (CNS). Neurological manifestations, though less common than cardiovascular or gastrointestinal involvement, have emerged as a significant component of the syndrome, including headache, altered mental status, seizures, encephalopathy, and cerebrovascular events. Understanding the neuropathophysiology of MIS-C is critical for timely diagnosis, appropriate management, and prevention of long-term neurological sequelae [1,2].

Discussion

The neuropathophysiology of MIS-C is multifactorial, involving immune dysregulation, systemic inflammation, endothelial dysfunction, and hypercoagulability. Unlike primary viral encephalitis, SARS-CoV-2 is rarely detected in the cerebrospinal fluid (CSF) of affected children, suggesting that neurological complications are primarily mediated by an indirect immune response rather than direct viral invasion. The systemic cytokine storm observed in MIS-C plays a central role, with elevated levels of interleukin-6, interleukin-1β, tumor necrosis factor-alpha, and other pro-inflammatory mediators leading to widespread inflammation. These cytokines can disrupt the blood–brain barrier (BBB), promoting neuroinflammation, edema, and altered neuronal signaling [3-6].

Endothelial activation and vascular injury further contribute to neurological manifestations. MIS-C is associated with a prothrombotic state, leading to microvascular thrombosis and, in rare cases, ischemic or hemorrhagic strokes. In addition, endothelial dysfunction may impair cerebral autoregulation, increasing susceptibility to hypoxic or metabolic injury. Magnetic resonance imaging (MRI) of affected children sometimes reveals features such as white matter lesions, signal changes in the thalamus or basal ganglia, and cortical edema, consistent with cytokine-mediated injury rather than direct viral cytopathy [7,8].

Another contributing factor is immune-mediated autoimmunity. Molecular mimicry between viral antigens and host neural proteins may trigger autoimmune responses, leading to conditions such as acute disseminated encephalomyelitis (ADEM)-like lesions in some MIS-C patients. Seizures, altered consciousness, and behavioral changes are thought to result from both direct inflammatory effects on neurons and secondary metabolic disturbances caused by systemic illness.

The clinical implications of MIS-C neuropathophysiology are significant. Early recognition of neurological involvement is crucial for initiating anti-inflammatory therapies such as intravenous immunoglobulin (IVIG), corticosteroids, and, in severe cases, biologic agents targeting specific cytokines. Supportive care, including seizure management, cerebral edema control, and monitoring for stroke, is also essential. Long-term follow-up may be needed for children who develop persistent cognitive, motor, or behavioral deficits [9,10].

Conclusion

Neurological manifestations in MIS-C arise primarily from immune-mediated processes rather than direct viral invasion. Hyperinflammation, cytokine dysregulation, endothelial dysfunction, and autoimmune mechanisms collectively contribute to CNS involvement. Understanding these pathways is critical for early diagnosis, targeted therapy, and minimizing long-term neurological sequelae in affected children. Continued research into the precise mechanisms of neuroinflammation in MIS-C will inform future therapeutic strategies and improve outcomes for this vulnerable population.

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