During the COVID-19 pandemic in the past few years, parainfectious encephalopathy has become a key focus in neuroinfectious and neuroimmunological research. For neurologists, the initial clinical issue is whether SARS-CoV-2 causes viral encephalitis or possesses neuroinvasive properties. Accumulating evidence from systematic and in-depth research has progressively clarified our understanding of the underlying mechanisms.

COVID-19-associated Encephalopathy is driven primarily by systemic inflammatory cascades rather than direct viral invasion of the central nervous system (CNS). Zamani et al. (1) analyzed 182 COVID-19 cases with CNS involvement, finding no clinical or ancillary evidence of direct neural infection. Neuropathological studies support this conclusion: autopsies from the United States and Germany detected SARS-CoV-2 only in vascular endothelial cells in the brain, with no evidence of viral invasion into neurons or glial cells. Other pathological findings included glial activation, microglial nodules, and mild inflammatory infiltration (predominantly by monocytes and T lymphocytes) (2, 3). A Chinese cohort study demonstrated blood-brain barrier disruption (reflected by reduced GFAP immunoreactivity) without neuronal viral RNA detection (4). These changes resemble influenza virus-associated encephalopathy, where GFAP staining shows clasmatodendrosis—fragmentation and loss of astrocytic processes. Additionally, cerebral edema, necrosis, and hemorrhage were prominent, yet inflammatory cell infiltration was minimal (5).

Encephalopathy caused by respiratory viruses such as SARS-CoV-2 is distinct from viral encephalitis caused by neurotropic viruses or autoimmune encephalitis mediated by specific antibodies. Instead, it is best categorized as a distinct third type—parainfectious encephalopathy. Respiratory viral infections can trigger a rapid innate immune response, leading to cytokine storms and systemic inflammatory syndrome. These conditions reflect CNS involvement in systemic inflammatory responses (6) ( Figure 1 ). In the 1990s, Japan reported a series of influenza A–associated parainfectious encephalopathies, including acute necrotizing encephalopathy (ANE), which showed similarities to COVID - 19-related parainfectious encephalopathy in clinical presentation, neuroimaging features, and neuropathology (7). In recent years, we have encountered a range of parainfectious encephalopathy cases in clinical practice. Based on accumulating experience and literature review, we propose a preliminary classification of parainfectious encephalopathy subtypes.

Intensive immunotherapy is crucial in severe parainfectious encephalopathies, particularly ANE and FIRES-C. First-line treatment typically includes high-dose glucocorticoid pulse therapy combined with intravenous immunoglobulin (IVIG). Our data confirm this regimen significantly improves neurological recovery in COVID - 19-associated ANE (14). Tocilizumab, an IL - 6 receptor antagonist, serves as a cornerstone therapeutic agent for COVID - 19-associated inflammatory syndromes. Given that parainfectious encephalopathy manifests as a component of systemic inflammatory response, this biologic agent demonstrates emerging therapeutic potential in severe encephalopathy subtypes, with expanding clinical applications (24). Our systematic review of tocilizumab-treated ANE cases revealed significantly improved neurological outcomes when administered within 24 hours of hospital admission (PROSPERO, ID CRD420251017817).

Parainfectious encephalopathy stems from early innate immune dysregulation and typically does not require long-term immunotherapy. Long-term therapies targeting adaptive immunity (e.g., rituximab, mycophenolate mofetil) have shown limited benefit in FIRES-C (12). Prolonged tocilizumab treatment may be effective for seizure control in some cases of FIRES-C; however, this requires further validation through cohort studies. The optimal dosing, frequency, and duration of tocilizumab remain under investigation. Based on our clinical experience, we have shortened the dosing interval from every four weeks to every two weeks to achieve a more rapid therapeutic effect.

The sequelae of parainfectious encephalopathy may be mechanistically associated with long neuro-COVID-19 syndrome. The long-term neurological complications of SARS-CoV-2 infection impose a substantial burden on affected patients. Proposed mechanisms include immune dysregulation, persistent inflammation, vascular dysfunction, and neurotransmitter imbalance (25). Notably, even patients with mild initial neurological symptoms demonstrate brain changes on structural MRI, particularly in white matter regions, which correlate with specific cognitive deficits (26). Recent studies by Schwabenland et al. have further demonstrated persistent neuroinflammation with distinct microglia-T-cell interactions in COVID - 19 brains (27).

Although parainfectious encephalopathy typically presents as acute or transient neurological damage, its sequelae may share similarities with many symptoms of long COVID - 19, including anxiety, memory loss, and cognitive impairment (“brain fog”). In clinical practice, we have observed that some FIRES-C patients with disease courses exceeding 6 months continue to respond well to tocilizumab, suggesting that sustained inflammatory activation may persist beyond the acute phase of parainfectious encephalopathy.

In summary, parainfectious encephalopathy is a group of autoinflammatory encephalopathy closely related to innate immune response. Its pathogenic mechanism, clinical phenotype, and immunotherapy are different from those of autoimmune encephalitis mediated by adaptive immune response. Parainfectious encephalopathy comprises a spectrum of acute encephalopathy syndromes triggered by systemic infections, characterized by heterogeneous clinical manifestations. For severe parainfectious encephalopathy cases, early diagnosis followed by aggressive immunotherapy is critical to improve outcomes. As research advances, accumulating clinical evidence will pave the way for a deeper, evidence-based consensus on its diagnosis and management.