Management of COVID-19 in Patients with Seizures: Mechanisms of Action of Potential COVID-19 Drug Treatments and Consideration for Potential Drug-Drug Interactions with Anti-Seizure Medications

Abstract, originally published in Epilepsy Research

In regard to the global pandemic of COVID-19, it seems that persons with epilepsy (PWE) are not more vulnerable to get infected by SARS-CoV-2, nor are they more susceptible to a critical course of the disease. However, management of acute seizures in patients with COVID-19 as well as management of PWE and COVID-19 needs to consider potential drug-drug interactions between antiseizure drugs and candidate drugs currently assessed as therapeutic options for COVID-19.

Repurposing of several licensed and investigational drugs is discussed for therapeutic management of COVID-19. While for none of these approaches, efficacy and tolerability has been confirmed yet in sufficiently powered and controlled clinical studies, testing is ongoing with multiple clinical trials worldwide. Here, we have summarized the possible mechanisms of action of drugs currently considered as potential therapeutic options for COVID-19 management along with possible and confirmed drug-drug interactions that should be considered for a combination of antiseizure drugs and COVID-19 candidate drugs.

Our review suggests that potential drug-drug interactions should be taken into account with drugs such as chloroquine/hydroxychloroquine and lopinavir/ritonavir while remdesivir and tocilizumab may be less prone to clinically relevant interactions with ASMs.

COVID-19 EEG Studies: The Other Coronavirus Spikes We Need to Worry About

Commentary, originally published in Epilepsy Currents

By now it is well-known that neurological manifestations occur in ?35% of COVID-19 patients, and potentially in a majority of patients with more severe infections. Results of electroencephalogram (EEG) in these patients are of particular interest: How frequently is epileptiform activity seen in this patient population, and are the underlying risks for epileptiform activity different from other critically ill patients? Are there novel EEG features specific to COVID-19? Is the EEG informative in guiding the understanding of the pathophysiology of the frequently observed altered mental status, or prognosis, in COVID-19?

We are now starting to see the early COVID-19 EEG studies in the literature.

The 3 papers included in this collection are peer-reviewed studies that systematically assessed EEGs in patients with COVID-19, as of July 26, 2020. That the study authors, clinicians engaged in the momentous task of treating these patients in high prevalence hospitals, were able to quickly disseminate this information is a noteworthy and commendable achievement.

Influence of COVID-19 Pandemic on Quality of Life in Patients With Epilepsy – Follow-Up Study

Abstract, originally published in Epilepsy & Behavior

Objective: To perform a follow-up study of the quality of life in patients with epilepsy in the era of the COVID-19 crisis.

Methods: Two months before the first case of the COVID-19 in Serbia, we obtained the Serbian Version of Quality of Life Inventory for Epilepsy 31 (SVQOLIE-31) and Neurological Disorders Depression Inventory for Epilepsy scores (SVNDDI-E) for another study. We retested the same patients one year after in COVID-19 pandemic. In addition to SVQOLIE-31, and SVNDDI-E we used a generic questionnaire compiled from items related to the COVID-19.

Results: We retested 97 out of 118 patients (82.2%) for the follow-up analysis. The average age was 36.1 ± 12.2 (range: 18-69), and 49 were women (50.5%). The median duration of epilepsy was 13 years (range: 1.5-48). The structural etiology of epilepsy was noted in 41 (42.3%), unknown etiology in 41 (42.3%), and genetic etiology in 15 (15.4%) patients. Fewer patients (27.8%) experienced at least one seizure three months before follow-up testing when compared to patients who experienced at least one seizure three months in initial testing (36.0%) (p = 0.15). All patients reported full compliance with anti-seizure medication in the follow-up. The SVQOLIE-31 score during the COVID-19 pandemic visit (64.5 ± 14.6) was significantly lower than the SVQOLIE-31 score before the pandemic (p < 0.001). The SVNDDI-E score during the COVID-19 pandemic (10.5 ± 3.5) was significantly higher than the SVNDDI-E score before it (p < 0.001). Multiple linear regression analyses revealed fear of seizures, and fear of a reduction in household income, significantly associated with SVQOLIE-31 and SVNDDI-E overall score. These variables accounted for 66% and 27% of the variance of SVQOLIE-31 and SVNDDI-E overall score.

Significance: Lower quality of life, higher prevalence of depression, healthcare availability issues, and perceived fears during pandemic all suggest COVID-19 has negatively impacted lives of patients with epilepsy.

Medium-Term Effects of COVID-19 Pandemic on Epilepsy: A Follow-Up Study

Abstract, originally published in Acta Neurologica Scandinavica

Objective: To analyze the medium-term impact of the COVID-19 pandemic on epilepsy patients, focusing on psychological effects and seizure control.

Methods: Prospective follow-up study to evaluate the medium-term effects of the COVID-19 pandemic on a cohort of epilepsy patients from a tertiary hospital previously surveyed during the first peak of the pandemic. Between July 1, 2020, and August 30, 2020, the patients answered an online 19-item questionnaire, HADS, and PSIQ scales. Short- and medium-term effects of the pandemic confinement and the perception of telemedicine were compared.

Results: 153 patients completed the questionnaire, mean ± SD age, 47.6 ± 19.3 years; 49.7% women. Depression was reported by 43 patients, significantly more prevalent than in the short-term analysis (29.2% vs. 19.7%; p = .038). Anxiety (38.1% vs. 36.1%; p = 0.749) and insomnia (28.9% vs. 30.9%, p = .761) remained highly prevalent. Seventeen patients reported an increase in seizure frequency (11.1% vs. 9.1%, p = .515). The three factors independently associated with an increase in seizure frequency in the medium term were drug-resistant epilepsy (odds ratio [OR] = 8.2, 95% CI 2.06-32.52), depression (OR = 6.46, 95% CI 1.80-23.11), and a reduction in income (OR = 5.47, 95% CI 1.51-19.88). A higher proportion of patients found telemedicine unsatisfactory (11.2% vs. 2.4%), and a lower percentage (44.8% vs. 56.8%) found it very satisfactory (p = .005).

Conclusions: Depression rates increased significantly after the first wave. Depression, drug-resistant epilepsy, and a reduction in family income were independent risk factors for an increased seizure frequency. Perception of telemedicine worsened, indicating need for re-adaptation.

Risk Estimation of SUDEP During COVID-19 Pandemic Era in a Tertiary Referral Center

Abstract, originally published in Epilepsy Research

Objective: No data exist regarding the impact of the lockdown due to the COVID-19 pandemic on the risk factors of sudden unexpected death in epilepsy (SUDEP). This study aimed to stratify risk factors of SUDEP in relation to COVID-19 lockdown, among patients with epilepsy (PWE) in Cairo University epilepsy unit (CUEU). Therefore, we can detect risk factors and mitigate such factors in the second wave of the virus.

Methods: an observational, cross-sectional study carried on 340 Egyptian patients with active epilepsy. Individual risk identification and stratification was done by using The SUDEP and seizure Safety Checklist, after which sharing risk knowledge to PWE and their caregivers was undertaken.

Results: The mean age of patients was 29.72 ± 12.12. The median of the static factors was 4 (IQR 3-5) whereas, the median of the modifiable factors was 2 (IQR 1-3). Epilepsy emergencies (serial seizures or status epilepticus) were reported in 24.1 % of patients, for which non-compliance was the commonest cause, followed by deferral of epilepsy surgery for patients with drug resistant epilepsy (DRE). Stepwise logistic regression analysis showed that use of anxiolytic medications, non-compliance, keeping patients with DRE on dual anti-seizure medications (ASMs), or adding third medication increased the odds of increased seizure frequency by 2.7, 3.5, 16.6 and 6.1 times, respectively.

Conclusion: Some COVID-19 related issues had influenced the risk of seizure worsening including postponing epilepsy surgery for patients with DRE, non-compliance, and psychiatric comorbidities. Special attention should be paid to these issues to mitigate the risk of SUDEP.

a graphic of the COVID-19 virus

Epilepsy During the COVID-19 Pandemic Lockdown: A US Population Survey

Abstract, originally published in Epileptic Disorders

Objective: This study sought to understand issues facing people with epilepsy (PWE) during the lockdown period of the COVID-19 pandemic in the United States.

Methods: We conducted a cross-sectional study using a 20-question survey that used SeziureTracker.com, sent to eligible PWE and their caregivers on May 6th, 2020. Questions about demographics and medical history were used to calculate COVID mortality risk odds ratios (OR) compared to a low baseline risk group.

Results: In total, 505 responses were collected. Of these, 71% reported no change in seizure rates and 25% reported an increase in seizures, which they attributed primarily to disrupted sleep (63%) and decreased exercise (42%). Mortality risks from COVID-19 had median OR of 1.67, ranging 1.00-906.98. Fear about hospitalization (53%) and concern for loved ones (52%) were prominent concerns. Of the respondents, 5% reported stopping or reducing anti-seizure medications due to problems communicating with doctors, access or cost. Lower-risk COVID patients reported more fear of hospitalization (55% versus 38%, p<0.001) and anxiety about medication access (43% versus 28%, p=0.03) compared with higher-risk COVID patients. Increased anxiety was reported in 47%, and increased depression in 28%. Ten percent without generalized convulsions and 8% with did not know anything about epilepsy devices (VNS, RNS, DBS).

Significance: The COVID-19 pandemic presents unique challenges to PWE, including increased seizure rates, problems with access and cost of life-saving medications. Those with lower COVID-19 risk may have been marginalized more than those with higher risk. Efforts to protect PWE during major public health emergencies should take these findings into account.

Click here for more information and resources related to COVID-19 and epilepsy.

COVID-19-Associated Seizures May Be Common, Linked to Higher Risk of Death

Study Featuring Former CURE Epilepsy Grantee Dr. Moushin Shafi

COVID-19 can have damaging effects on multiple organs in the body, including the brain. A new study led by investigators at Massachusetts General Hospital (MGH) and Beth Israel Deaconess Medical Center (BIDMC) indicates that some hospitalized patients with COVID-19 experience non-convulsive seizures, which may put them at a higher risk of dying. The findings are published in the Annals of Neurology.

“Seizures are a very common complication of severe critical illness. Most of these seizures are not obvious: Unlike seizures that make a person fall down and shake, or convulse, seizures in critically ill patients are usually nonconvulsive,” explains co-senior author M. Brandon Westover, MD, PhD, an investigator in the Department of Neurology at MGH and director of Data Science at the MGH McCance Center for Brain Health. “There is increasing evidence that non-convulsive seizures can damage the brain and make outcomes worse, similar to convulsions.”

Westover notes that there have been only a few small reports of seizures in patients with severe COVID-19 illness, and it was previously unclear whether such seizures primarily occur in patients who already have a seizure disorder or whether they can arise for the first time because of COVID-19. The effects of such seizures on patients’ health was also unknown.

“We found that seizures indeed can happen in patients with COVID-19 critical illness, even those without any prior neurologic history, and that they are associated with worse outcomes: higher rates of death and longer hospital stay, even after adjusting for other factors,” says co-senior author Mouhsin Shafi, MD, PhD, an investigator in the Department of Neurology at BIDMC, medical director of the BIDMC EEG laboratory, and director of the Berenson-Allen Center for Noninvasive Brain Stimulation. “Our results suggest that patients with COVID-19 should be monitored closely for nonconvulsive seizures. Treatments are available and warranted in patients at high risk; however, further research is needed to clarify how aggressively to treat seizures in COVID-19.”

Status Epilepticus and COVID-19: A Systematic Review

Abstract, originally published in Epilepsy & Behavior

Purpose: In March 2020, the World Health Organization declared the SARS-CoV-2 infection-related coronavirus Disease (COVID-19) a pandemic. During the first and second waves of the pandemic spread, there have been several reports of COVID-19-associated neurological manifestations, including acute seizures and status epilepticus (SE). In this systematic review, we summarized the available data on clinical features, diagnosis, and therapy of COVID-19-related SE.

Methods: We performed a systematic search of the literature to identify data on demographics, clinical, neurophysiological, and neuroradiological data of patients with COVID-19-related SE. We used regression models (linear or logistic) with a stepwise forward method to identify features associated with mortality or severity of SE.

Results: Thirty-nine articles were included with a total of 47 cases of SE associated with COVID-19. Age, time between the acute respiratory phase of SARS-CoV-2 infection and SE onset, and hospitalization correlated with a higher SE severity as assessed by quantitative validated scales.

Conclusions: SE can be a neurological manifestation of SARS-CoV-2 infection. Although a possible association between SE and COVID-19 has been reported, the exact mechanisms are still not fully understood. Systemic inflammatory syndrome due to cytokine release could play a role in COVID-19-related SE.

The Impact of the Coronavirus Disease (COVID-19) Pandemic on Outpatient Epilepsy Care: An Analysis of Physician Practices in Germany

Abstract, originally published in Epilepsy & Behavior

Objective: To gain insight into epilepsy care during coronavirus disease (COVID-19) pandemic, we analyzed prescription data of a large cohort of persons with epilepsy (PWE) during lockdown in Germany.

Methods: Information was obtained from the Disease Analyzer database, which collects anonymous demographic and medical data from practice computer systems of general practitioners (GP) and neurologists (NL) throughout Germany. We retrospectively compared prescription data for anti-seizure medication (ASM) and physicians’ notes of “known” and “new” PWE from January 2020 until May 2020 with the corresponding months in the three preceding years 2017-2019. Adherence was estimated by calculating the proportion of patients with follow-up prescriptions within 90 days after initial prescriptions in January or February. We additionally analyzed hospital referrals of PWE. The significance level was set to 0.01 to adjust for multiple comparisons.

Results: A total of 52,844 PWE were included. Anti-seizure medication prescriptions for known PWE increased in March 2020 (GP + 36%, NL + 29%; P < 0.01). By contrast, a decrease in prescriptions to known and new PWE was observed in April and significantly in May 2020 ranging from -16% to -29% (P < 0.01). The proportion of PWE receiving follow-up prescriptions was slightly higher in 2020 (73.5%) than in 2017-2019 (70.7%, P = 0.001). General practitioners and NL referred fewer PWE to hospitals in March 2020 (GP: -30%, P < 0.01; NL: -12%), April 2020 (GP: -29%, P < 0.01; NL: -37%), and May 2020 (GP: -24%, P < 0.01; NL: -16%).

Conclusion: Adherence of known people with epilepsy to anti-seizure medication treatment appeared to remain stable during lockdown in Germany. However, this study revealed findings which point to reduced care for newly diagnosed PWE as well as fewer hospital admissions. These elements may warrant consideration during future lockdown situations.

COVID-19 Presentations and Outcome in Patients With Epilepsy

Abstract, originally published in Acta Neurologica Scandinavica

Objective: To determine whether patients with epilepsy (PWE) are particularly over-represented in a very large cohort of patients with COVID-19. We also investigated whether COVID-19 is associated with a different clinical picture or a more severe course of illness in PWE (compared with others).

Methods: All consecutive patients who referred to and admitted at healthcare facilities anywhere in Fars province (located in the south of Iran with a population of 4,851,000 people) from February 19, 2020 until November 20, 2020 were included.

Results: A total of 37,968 patients were studied. Eighty-two patients (0.2%) had pre-existing epilepsy. Seizures were significantly more frequent among PWE as a presenting manifestation of COVID-19 compared with that in people without epilepsy (Odds Ratio = 27; p = 0.0001). Furthermore, PWE less often reported cough (significantly) and more often had gastrointestinal symptoms (vomiting and anorexia; as trends) compared with those in people without epilepsy. Patients with epilepsy were not differently likely to be intubated or admitted at ICUs. Case fatality rates were not different between the two groups [9.8% in PWE and 8.5% in people without epilepsy; p = 0.690].

Conclusion: Patients with epilepsy are not susceptible to contracting COVID-19 more than other individuals. Furthermore, COVID-19 in PWE is not associated with a more severe illness or a poorer prognosis. However, PWE and COVID-19 may present somewhat differently than others with such an illness. Why PWE less often present with cough and more often present with gastrointestinal symptoms is not clear yet and should be investigated and clarified in the future studies.