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Clinical Context

Although COVID-19 is a respiratory illness, all clinicians have grown accustomed to the protean patient presentation of COVID-19. A review by Harapan and Yoo, which appeared in the September 2021 issue of the Journal of Neurology, characterized neurological symptoms of COVID-19.^[1]

More than 90% of patients with COVID-19 identified at least 1 subjective neurological symptom, with headache, confusion, and dizziness being the most common neurological symptoms. Earlier during the pandemic, disturbances of taste and smell were common acute manifestations of COVID-19, with prevalence rates of 38.5% and 35.8% of cases, respectively. However, the rates of anosmia and dysgeusia have declined since Omicron became the dominant variant of SARS-CoV-2.

The incidence of stroke among patients with COVID-19 was estimated at 2.3%, although this rate should be kept in context. The incidence of stroke among patients hospitalized for any severe infection approaches 6%. Finally, the report found that COVID-19 was associated with new onset of epilepsy in 0.9% of patients. The current study further explores the relationship between COVID-19 and seizures/epilepsy.

Study Synopsis and Perspective

Individuals who have had COVID-19 are more likely to develop seizures or epilepsy after being infected than their peers who have had influenza, new research suggests.

In an analysis of more than 300,000 individuals, those who had COVID-19 were 66% more likely than those with influenza to develop epilepsy or seizures during the 6 months after infection.

The risk was highest in children and in those who had not been hospitalized for COVID-19, the researchers report.

“While the overall risk of developing seizures or epilepsy was low--less than 1% of all people with COVID-19--given the large number of people who have been infected with COVID-19, this could result in increases in the number of people with seizures and epilepsy,” senior investigator Arjune Sen, MD, PhD, associate professor and head of the Oxford Epilepsy Research Group, University of Oxford, United Kingdom, said in a news release.

The findings were published online November 16 in Neurology.^[2]

“Confusing” Literature

The literature on seizures after COVID-19 “has been somewhat confusing,” Dr Sen told Medscape Medical News.

“There have been, especially early on in the pandemic, small case reports or small case series suggesting that seizures could occur following COVID-19, but we weren’t seeing a dramatic increase in seizures in the clinic in people who had been infected,” he said.

Therefore, the investigators set out to “define whether or not there actually was an association between COVID-19 and epilepsy and seizures,” Dr Sen noted.

They turned to an electronic health record (EHR) network encompassing 81 million people and compared patients who had had COVID-19 with those who had had influenza. In each cohort, the researchers analyzed the incidence and hazard ratios (HRs) of seizures and epilepsy. They stratified the data by age and by whether the patient had been hospitalized during the acute infection.

They also “explored time-varying HRs to assess temporal patterns of seizure or epilepsy diagnoses,” the investigators report.

Of 860,934 EHRs, they arrived at 2 cohorts (n = 152,754 each) that were “closely matched” for demographic characteristics and comorbidities, both psychiatric and medical. Covariates included age, sex, race, ethnicity, comorbidities, and lifestyle factors.

The primary outcome was 6-month incidence of the composite endpoint of epilepsy or seizures, whereas secondary outcomes included seizures and epilepsy separately.

Secondary analyses divided the overall group into pediatric (≤16 years) vs adult (>16 years) participants and those who were hospitalized for COVID-19 vs those who were not hospitalized for it.

Be Alert for Even Mild Seizures

Results showed an increase in the incidence of the composite endpoint of seizures or epilepsy in the COVID-19 vs the influenza cohort. When seizures and epilepsy were assessed separately, there was also an increased risk for each outcome.

When the researchers stratified their analysis by age, they found an increased risk for the composite endpoint in children as well as adults, but the increase in risk was greater in children.

The risk for epilepsy after COVID-19 was “significantly moderated by age and more marked among children than adults” in comparison with influenza (moderation coefficient, 0.68; 95% CI, 0.23-1.13; P = .0031), the researchers report.

Risk for the composite endpoint was also greater after COVID-19 vs influenza among those who had not been hospitalized vs those who had been.

Hospitalization status was not a significant moderator (moderation coefficient, 0.12; 95% CI, −0.10 to 0.35; P=.28) for the composite endpoint.

In contrast, hospitalization status was a significant moderator for the association between COVID-19 and epilepsy, with a “more marked” association among nonhospitalized patients (moderation coefficient, 0.52; 95% CI, 0.11-0.93; P=.012).

A post hoc analysis showed that the peak time for the HR of the composite endpoint between COVID-19and influenza was 23 days postinfection, with 21 days in adults only and 50 days in children. However, at 50 days postinfection, children were almost 3 times more likely to have the composite endpoint after COVID-19 vs influenza.

There were also important differences between hospitalized and nonhospitalized individuals, with the HR for the composite endpoint peaking at 9 vs 41 days, respectively. At that point, nonhospitalized participants were more than twice as likely to have seizures or a diagnosis of epilepsy after COVID-19 vs after influenza.

“We found that the overall rate of seizures after COVID is low, which would match what we’ve been seeing in clinic; but, although low, it’s still significantly more than after influenza,” Dr Sen said.

He suggested that clinicians “should be aware that this can happen and that it may manifest as milder seizures where people don’t lose consciousness or have unusual symptoms.”

The findings also “highlight the increased risk in children,” Dr Sen said. He noted that children should be vaccinated “because, even if the COVID infection is relatively mild, there may be unwanted sequelae.”

Continued Prevention, Greater Attention

Commenting for Medscape Medical News, Wyatt Bensken, PhD, adjunct assistant professor of population and quantitative health sciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, said that “assessing the scope and severity of the consequences of COVID-19 is critical to inform efforts to mitigate lasting effects and continue to advocate for preventive measures.”

Dr Bensken, who is coauthor of an accompanying editorial, was not involved in the study.^[3]

Awareness of the long-term risk of developing seizures among individuals who have had COVID-19 “should motivate continued prevention of infection, as well as greater attention to lasting neurological symptoms and disease,” he noted.

“Importantly, we must also acknowledge that the risk of COVID-19 infection has been, and continues to be, inequitably distributed in the population,” said Dr Bensken.

“Studies like these that highlight the neurological consequences of COVID-19 infection reinforce efforts to address the drivers of these inequities,” he added.

The study was funded by the National Institute for Health and Care Research Oxford Health Biomedical Research Centre. The investigators report no relevant financial relationships. Dr Bensken serves on the editorial board for the journal Neurology and has received research funding from the National Institute on Minority Health and Health Disparities of the National Institutes of Health. The other editorialist’s disclosures are listed in the original article.

Neurology. Published online November 16, 2022.

Clinical Implications

• A prior review found that more than 90% of patients with COVID-19 identified at least 1 subjective neurological symptom, with headache, confusion, and dizziness being the most common neurological symptoms. Earlier during the pandemic, disturbances of taste and smell were common acute manifestations of COVID-19, with prevalence rates of 38.5% and 35.8% of cases, respectively, through mid-2021.
• In the current study, the incidence of both seizures and epilepsy were higher after infection with COVID-19 vs influenza, and this difference was more pronounced among children and patients who had not been hospitalized. The peak time for incident seizures or epilepsy after infection in both the influenza and COVID-19 groups was 23 days after infection.
• Implications for the healthcare team: Although the overall risk is low, the healthcare team should be aware of a higher risk for seizures after infection with COVID-19 vs influenza.

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