Abstract
The neurological sequelae of SARS-CoV-2 infection have emerged as among the most disabling manifestations of post-acute sequelae of COVID-19 (PASC), commonly known as Long COVID. While cognitive dysfunction, dysautonomia, headache syndromes, and neuropsychiatric symptoms have received substantial attention, increasing reports describe new-onset seizure disorders following acute infection and, less commonly, following COVID-19 vaccination. Among these presentations are absence (petit mal) seizures and other transient disturbances of consciousness. The mechanistic relationship between SARS-CoV-2 infection, vaccination, neuroimmune activation, and epileptogenesis remains incompletely understood. Current evidence suggests that persistent immune dysregulation, endothelial dysfunction, microvascular injury, autoantibody production, mitochondrial impairment, viral persistence, and neuroinflammation may converge to create conditions favoring neuronal hyperexcitability. This review examines contemporary findings concerning Long COVID, COVID-19 vaccination, and seizure disorders, with emphasis on absence seizures, genomic susceptibility, neuropathology, pathophysiology, clinical progression, treatment strategies, and long-term prognosis.
Introduction
The COVID-19 pandemic has produced an unprecedented burden of chronic illness. Estimates suggest that millions worldwide continue to experience persistent symptoms months or years following acute infection. Neurological manifestations are among the most common and debilitating features of Long COVID and include cognitive dysfunction, memory impairment, dysautonomia, sleep disturbance, headaches, neuropathic symptoms, movement disorders, and seizures. Recent investigations have increasingly implicated persistent neuroimmune activation and cerebrovascular dysfunction as central drivers of these symptoms.¹⁻⁴
Seizures occurring after SARS-CoV-2 infection have attracted growing attention because they may represent evidence of sustained central nervous system involvement. Although generalized tonic-clonic seizures are more readily recognized, absence seizures may remain underdiagnosed because their clinical manifestations are subtle and easily mistaken for cognitive dysfunction, “brain fog,” dissociative episodes, or psychiatric symptoms.
Neuropathological Foundations of Long COVID
Accumulating evidence indicates that Long COVID is not attributable to a single pathological mechanism. Rather, multiple overlapping biological processes appear responsible.
Viral Persistence
Several investigations have identified persistent viral proteins and viral RNA within tissues months after acute infection. Persistent viral reservoirs may continue to stimulate innate and adaptive immune responses, resulting in chronic inflammation and neuroimmune activation.¹⁻⁴
Neuroinflammation
Microglial activation appears to be a central feature of Long COVID neuropathology. Activated microglia release inflammatory mediators including interleukin-1β, interleukin-6, tumor necrosis factor-alpha, interferon-gamma, and various chemokines capable of altering neuronal excitability and synaptic transmission.² ⁵ ⁶
Chronic neuroinflammation is a recognized contributor to epileptogenesis and may lower seizure thresholds in genetically susceptible individuals.
Endothelial Dysfunction and Microvascular Injury
Emerging research increasingly implicates endothelial dysfunction as a fundamental pathological mechanism. SARS-CoV-2 infects endothelial cells and disrupts vascular homeostasis through ACE2-mediated pathways. Persistent endothelial injury promotes microthrombus formation, impaired cerebral perfusion, blood-brain barrier disruption, and chronic tissue hypoxia.² ⁴
Blood-brain barrier dysfunction permits infiltration of inflammatory mediators and immune cells into neural tissue, potentially facilitating epileptic activity.
Mitochondrial Dysfunction
Multiple omics-based studies have identified abnormalities involving mitochondrial energy production, oxidative phosphorylation pathways, and cellular bioenergetics. Mitochondrial dysfunction may impair neuronal energy homeostasis and increase susceptibility to seizure generation.¹ ³
Genomic Susceptibility
Host genomic factors appear to influence susceptibility to both Long COVID and seizure disorders.
Several candidate pathways have emerged:
- HLA-related immune regulation genes
- Interferon signaling pathways
- Cytokine regulatory loci
- Complement activation genes
- Mitochondrial metabolism genes
- Neuronal ion channel genes
Particular interest has focused on variants affecting sodium, potassium, and calcium channels because these genes are already known contributors to generalized epilepsies and absence seizure syndromes.
Network analyses performed in 2025 further identified mitochondrial regulators, inflammatory signaling pathways, and neurovascular genes as potential determinants of persistent neurological symptoms.¹
Absence Seizures and Long COVID
Absence seizures traditionally consist of brief episodes of impaired awareness lasting seconds, frequently accompanied by staring, eyelid fluttering, or subtle automatisms.
In Long COVID patients, distinguishing absence seizures from cognitive dysfunction can be challenging.
Reported symptoms include:
- Sudden lapses in awareness
- Brief staring episodes
- Episodic memory gaps
- Transient speech arrest
- Intermittent confusion
- Visual fixation episodes
- Brief behavioral arrest
Case reports and patient registries increasingly describe seizure-like episodes emerging months after SARS-CoV-2 infection, although epidemiological data remain limited. Online patient communities and specialty epilepsy centers have documented individuals developing absence-like events despite no prior seizure history. These observations remain hypothesis-generating rather than definitive evidence of causality.
COVID-19 Vaccination and Seizure Risk
The relationship between COVID-19 vaccination and seizures remains an area of active investigation.
Large pharmacovigilance studies have generally found that serious neurological adverse events are rare. Most analyses conclude that the benefits of vaccination substantially outweigh the risks. Nevertheless, rare post-vaccination seizures have been reported and continue to be studied.
Several theoretical mechanisms have been proposed:
Cytokine-Mediated Neuroexcitation
Transient post-vaccination immune activation may elevate cytokine levels, potentially lowering seizure thresholds in susceptible individuals.
Fever-Associated Mechanisms
Vaccination-related fever may provoke seizures among predisposed patients, particularly children and individuals with preexisting epilepsy.
Autoimmune Mechanisms
Molecular mimicry and immune activation have been hypothesized to contribute to autoimmune neurological syndromes. However, convincing evidence linking vaccination to chronic absence epilepsy remains lacking.
Genetic Predisposition
Individuals carrying epilepsy-associated channelopathies may possess lower thresholds for seizure provocation by infection, fever, inflammation, or immune activation.
Importantly, epidemiological evidence generally indicates that SARS-CoV-2 infection itself poses a substantially greater neurological risk than vaccination.
Neurophysiology of Epileptogenesis in Long COVID
Current models suggest that epileptogenesis in Long COVID may arise through convergence of several biological processes:
- Persistent neuroinflammation
- Blood-brain barrier disruption
- Cerebral microvascular injury
- Autoantibody production
- Mitochondrial dysfunction
- Glutamate-GABA imbalance
- Chronic oxidative stress
These processes may alter cortical-thalamic circuitry responsible for absence seizure generation.
The thalamocortical network is particularly vulnerable to inflammatory and metabolic disturbances. Dysregulation within these circuits may produce the characteristic synchronized oscillatory activity associated with absence epilepsy.
Clinical Presentation
Patients presenting with Long COVID-associated absence seizures may exhibit:
- Episodic staring spells
- Memory lapses
- Impaired concentration
- Cognitive slowing
- Episodic unresponsiveness
- Visual fixation
- Fatigue
- Dysautonomia
- Headaches
- Sleep disturbance
Because these symptoms overlap considerably with Long COVID cognitive impairment, EEG monitoring often becomes essential for diagnosis.
Diagnostic Evaluation
Recommended investigations include:
- Routine EEG
- Ambulatory EEG
- Prolonged video EEG monitoring
- Brain MRI
- Autoimmune encephalitis panels
- Inflammatory biomarkers
- Neuropsychological testing
- Autonomic function testing
Long-duration EEG monitoring may reveal generalized spike-wave discharges characteristic of absence epilepsy that are not detected during routine recordings.
Therapeutic Strategies
Treatment remains individualized.
Potential approaches include:
Conventional Antiseizure Medications
- Ethosuximide
- Lamotrigine
- Valproate
- Levetiracetam
Neuroinflammatory Management
Experimental approaches include:
- Corticosteroids
- Intravenous immunoglobulin
- Plasmapheresis
- Cytokine-modulating therapies
Evidence remains preliminary.
Long COVID Directed Care
Management frequently includes:
- Autonomic rehabilitation
- Sleep optimization
- Physical reconditioning
- Cognitive rehabilitation
- Management of endothelial dysfunction and vascular risk factors
Prognosis
Current evidence suggests highly variable outcomes.
Some patients demonstrate gradual improvement over months, whereas others continue to experience persistent neurological symptoms for years. Prognosis likely depends upon:
- Severity of initial infection
- Degree of neuroinflammation
- Genetic susceptibility
- Presence of autoimmunity
- Extent of vascular injury
- Comorbid neurological disease
The long-term risk of chronic epilepsy following Long COVID remains unknown.
Conclusion
Current evidence supports the existence of persistent neurobiological abnormalities in Long COVID involving immune dysregulation, neuroinflammation, endothelial dysfunction, microvascular injury, mitochondrial impairment, and autonomic dysregulation. These mechanisms provide biologically plausible pathways through which epileptogenesis and absence seizures may emerge after SARS-CoV-2 infection. Although rare seizure events have been reported following COVID-19 vaccination, available epidemiological evidence has not established a causal association between vaccination and chronic absence epilepsy. Future prospective cohort studies integrating genomics, proteomics, neuroimaging, electrophysiology, and immunophenotyping will be required to determine whether distinct Long COVID seizure syndromes represent a unique post-viral epileptogenic disorder.
References
- da Silva M, et al. Advances in Understanding Long COVID: Pathophysiological Mechanisms and the Role of Omics Technologies in Biomarker Identification. Mol Diagn Ther. 2025.
- Fekete M, et al. Cerebromicrovascular Mechanisms Contributing to Long COVID. GeroScience. 2025.
- Mueller MR, et al. Long COVID: Emerging Pathophysiological Mechanisms. Minerva Med. 2025.
- Skevaki C, et al. Long COVID: Pathophysiology, Current Concepts, and Future Directions. J Allergy Clin Immunol. 2025.
- Popa SL, et al. Molecular Mechanisms of Cognitive Dysfunction in Long COVID. Int J Mol Sci. 2025.
- Moen JK, Baker CA, Iwasaki A. Neuroimmune Pathophysiology of Long COVID. Psychiatry Clin Neurosci. 2025.
- Ko HY, et al. Risk of New-Onset Seizures Following Immunization Against COVID-19: A Self-Controlled Case-Series Study. Epidemiol Health. 2025.