Safety and adverse events following COVID-19 vaccination among people with epilepsy: A cross-sectional study

1.1 Background

Epilepsy is a non-communicable disease contributing to an inevitable local and global burden on public health. More than 50 million people worldwide are identified with epilepsy, costing more than 13 million disability-adjusted life years (DALYs) globally. The lives of people with epilepsy (PWE) are often impacted by negativity, such as stigma and discrimination.¹ It is reported by Cabezudo-Garc ́ıa and colleagues that active epilepsy was associated with increased prevalence of severity and fatality of COVID-19 infection.^2-4 The more comorbidities one has, the greater is the risk of more severe COVID-19 infection.^{2, 3, 5} Providentially, vaccinations against the coronavirus were successfully developed, massively produced, and administered globally. In spite of that, the concerns of the adverse events following immunization (AEFI) among PWE have been unequivocal.

Vaccines that were approved by the Food and Drug Administration (FDA) for emergency use in the United States against COVID-19 include the Pfizer-BioNtech vaccine, followed by AstraZeneca, and Johnson and Johnson. The preliminary evidence from the safety and efficacy trials of these vaccines has been favorable.^6-8 According to the International League Against Epilepsy (ILAE), PWE are encouraged to receive the COVID-19 vaccine as the benefits outweigh the risks, namely the impact of COVID-19 infection and its complications are more severe than the AEFI. The seizures developed are more likely due to fever following COVID-19 vaccination, the risks of which can be reduced by taking antipyretics regularly for 48 hours after the vaccination. According to the ILAE, there is currently no evidence proving that having epilepsy has a strong relation to the increased risk of AEFI from any COVID-19 vaccines.⁹ As a matter of fact, as per the Clinical Guidelines on COVID-19 Vaccination in Malaysia, PWE are classified under vaccine priority groups as the underlying medical condition may increase the risk of severe illness from COVID-19. CanSinoBio vaccine is by far the only COVID-19 vaccine that has clear contraindications for people with uncontrolled epilepsy and other progressive neurological diseases, which is not available in Malaysia. In Malaysia, the three approved COVID-19 vaccines are the Pfizer-BioNtech, AstraZeneca and Sinovac.¹⁰

As COVID-19 variants with the potential to compromise vaccine efficacy continue to develop globally, additional data on the real-world safety and efficacy of our present mass immunization initiatives is required especially in patients with chronic disorders like PWE. The real-world data on its efficacy focusing on certain priority groups are still relatively low given the period the mass vaccination programme began. Therefore, we conducted a study to assess the safety and AEFI of COVID-19 vaccination among PWE focusing on neurological AEFI in relation to the socio-demographic, epilepsy, and vaccination factors. We aimed to share a baseline reference with our data as a novel study in Malaysia.

1.2 Operational definition

According to the ILAE, epileptic seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a chronic neurological disorder characterized by an enduring predisposition to generate epileptic seizures. The diagnosis of epilepsy usually requires the occurrence of at least two seizures more than 24 hours apart.¹¹

Based on the World Health Organization (WHO) Global Manual on Surveillance of Adverse Events (2014), an adverse event following immunization (AEFI) is any untoward medical occurrence which follows immunization and does not necessarily have a causal relationship with the usage of the vaccine. The adverse event may be any unfavorable or unintended sign, abnormal laboratory finding, symptom or disease. Reported adverse events can either be true adverse events i.e., resulting from the vaccine or immunization process, or coincidental events that are not due to the vaccine or immunization process but are temporarily associated with immunization. A serious AEFI is an AEFI which results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or requires intervention to prevent permanent impairment or damage.¹²

According to a nationwide descriptive study in Mexico by García-Grimshaw and colleagues in 2021, neurologic AEFI was defined as any sign or symptom of AEFI potentially related to central or peripheral nervous system dysfunction, which includes headache, motor symptoms, sensory symptoms (paraesthesia, dysesthesia, numbness, pinprick, tingling, or a combination thereof), focalising signs, altered mental status (including syncope), and weakness (paresis, weakness, diminished strength, lack of strength, paralysis, or a combination thereof). Headache, sensory symptoms, weakness, and syncope were considered non-serious neurologic adverse events unless otherwise defined by the medical personnel or if fulfilling the definition of serious AEFI.¹³

2.1 Sampling

This was a cross-sectional study conducted at the Neurology Clinic, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), which is a tertiary hospital in Malaysia. Around 500 PWE are regularly followed up at our hospital. The sample size for this study was determined using a two-tailed z-test of proportions between two groups with 80% power and a 5% level of significance. In reference to Massoud and colleagues, the prevalence of vaccination adverse effects among PWE on single anti-seizure medication (ASM) therapy was 36.4%, with an attrition rate of 20% for wrong entries or poor mobile signals. For our study, 120 samples were required.¹⁴

2.2 Data collection

Patients with epilepsy coming to our clinic between November 8, 2021 and January 12, 2022 were invited to participate in the study. We only recruited PWE, who fulfilled the following criteria: Malaysian nationality, aged at least 18 years old in 2021, having a definite diagnosis of epilepsy according to the ILAE Guidelines, able to communicate in Malay/English/Mandarin/Tamil, having completed at least two doses of COVID-19 vaccination. The first 120 PWE fulfilling the criteria were invited to join the study via asynchronous hardcopy consent-taking during their consultation session at the clinic or synchronously over the phone consent-taking, both of which were followed by a phone call interview session. The interviews were held based on a scripted measure, formatted on Microsoft Forms and only accessible by the authors. All over-the-phone consent-taking and interviews were recorded. For those who were unable to partake in the interview due to speech limitations including mutism and presence of speech disturbance, impaired cognitive status, fatigue, and weakness, or in a comatose state, the caregiver or next-of-kin was allowed to proceed with the consent-taking and interview on behalf of the PWE.

2.3 Instrument

A scripted and standardized online measure was developed on the Microsoft Forms portal. The measure consisted of three sections: socio-demographic information, epilepsy-related variables, and vaccination-related variables. Socio-demographic information of the PWE included gender, race, age, body mass index (BMI) in accordance with the Malaysian Clinical Practice Guideline on Management of Obesity 2004 (BMI <18.5 kg/m² is underweight; 18.5–22.9 kg/m² is normal; ≤23 kg/m² is overweight; 23.0–27.4 kg/m² is overweight or pre-obese; 27.5–34.9 kg/m² is Obese I; 35.0–39.9 kg/m² is Obese II; ≥40 kg/m² is Obese III), education level in accordance with the education system of the Malaysian Ministry of Education and Higher Education (Pre-school education: education programme for students aged 4-6; Primary education: 6 years of primary level course of study; Secondary education: consists of lower and upper secondary education; Pre-university: Form 6, matriculation, International Baccalaureate or other equivalent; Undergraduate: bachelor degree levels; Postgraduate: master degrees and PhD levels), marital status, employment status, allergy history, other medical illnesses (congenital diseases, metabolic syndromes, mental disorders), history of surgery, and alternative medications (conventional medicine that is not fully integrated into the dominant health-care system in Malaysia; also includes traditional medicine).^15-17

Epilepsy-related variables included the age of first onset of seizure, age of definite diagnosis of epilepsy, type of epilepsy, pre-vaccination seizure frequency, difference in seizure frequency between pre-vaccination and post-vaccination, history of status epilepticus within 3 months before the first dose of vaccination, number, and type of current antiseizure medication (ASM), and medication adherence. Patients' latest diagnosis and electroencephalographic findings were collaboratively assessed and classified according to the epilepsy types stated in the ILAE Classification of the Epilepsies 2017.¹⁸ The subjects were interviewed about their monthly, 6-monthly, and yearly frequency of seizures before the first dose of vaccination. The frequency was accessed and further classified into seizure-free, lower seizure frequency (≤10 seizures per year), and higher seizure frequency (>10 seizures per year), using the Revised Seizure-based Outcome Classification System (Duke).¹⁹ Adherence to medication was accessed using the Medication Adherence Rating Scale (MARS) that required the patient to answer 10 questions (≤5 is not adherent; ≥6 is adherent). Vaccination-related variables included history of pre-vaccination confirmed COVID-19 infection, type of COVID-19 vaccine (Cominarty®; ChAdOx1-S®; CoronaVac®), duration of onset and outcome of AEFI. The vaccination details were clarified via the participants' national COVID-19 mobile application–MySejahtera, which was developed by the Malaysian government to facilitate the management of COVID-19 with individualized vaccination profiles. Local AEFI included injection site pain or tenderness, redness, swelling, and pruritus. Systemic AEFI included fever, fatigue, chills, nausea, vomiting, dysphagia, anorexia, constipation, diarrhea, abnormal skin, and mucosa at non-injection site, new or worsened myalgia at non-injection site, new or worsened arthralgia at non-injection site, sore throat, acute allergy reaction, and use of antipyretic or analgesia. Non-serious neurological AEFI included headache, sensory symptoms, weakness, and syncope. Serious neurological AEFI included Guillain-Barré syndrome (GBS), acute transverse myelitis, seizure, acute palsy, or paralysis. The presentation of each AEFI was further categorized into none, requiring no hospital admission, or requiring hospital admission.

2.4 Statistical analyses

Data analysis of this study was performed using the Statistical Package for the Social Sciences (SPSS) version 28. Categorical data were expressed as frequencies and percentages, while continuous data were expressed in means and standard deviations. Fisher’s exact test (FE), Pearson’s chi-square (PCS), and independent t-test were used for univariate comparison. The associations between pre-existing epilepsy and other variables were determined using the logistic regression analysis; the variables with P < 0.05 from the univariate analyses were entered into the multiple logistic regression analysis model. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. A P-value less than 0.05 (2-sided) was considered significant.

3.1 Characteristics of PWE

The characteristics of the 120 PWE are shown in Table 1. The socio-demographic characteristics along with epilepsy-related and vaccines-related variables are included.

3.2 Frequency and duration of onset of AEFI following COVID-19 vaccination

Overall, 75.8% of the participants experienced AEFI of COVID-19 vaccination. The highest prevalence of AEFI was systemic AEFI (64.2%). The lowest prevalence of AEFI was serious neurological AEFI (3.3%). Local AEFI was the quickest to develop, with an average onset within a day requiring no hospital admission. Serious neurological AEFI was the slowest to present, with an average onset of 4 days with one index requiring hospital admission. The cumulative prevalence and duration of onset of AEFI of COVID-19 vaccination are shown in Table 2.

3.3 Clinical presentation of AEFI of COVID-19 vaccination in PWE

The analytical clinical presentation of AEFI is shown in Table 3. People with epilepsy after the CoronaVac® vaccination reported the lowest prevalence of systemic AEFI, while PWE following the ChAdOx1-S® vaccination had the highest prevalence of systemic AEFI (P = 0.03). The most common local AEFI was injection site pain or tenderness. Regardless of the vaccination brands, it was equally high in prevalence for PWE to take antipyretics or analgesics to relieve their presenting AEFI. The two most common non-serious neurological AEFI were headache and weakness. Furthermore,  those who were administered the CoronaVac® vaccine also reported the lowest prevalence of non-serious neurological AEFI (P = 0.005). However, that particular patient required hospital admission for the presenting complaint.

3.4 Association of characteristics of AEFI and COVID-19 vaccination

Females had significantly more local or systemic AEFI than males (P = 0.02 and P = 0.007, respectively). The age group that developed systemic or non-serious neurological AEFI was significantly younger than those who did not develop (P = 0.045 and P = 0.001, respectively). Most of the PWE, who developed either local or systemic AEFI, had significantly normal body mass index (P = 0.001 and P = 0.004, respectively). Race, education level, marital status, employment status, allergy history, other medical illnesses, history of surgery and alternative medications were not associated with any AEFI of COVID-19 vaccination.

Serious neurological AEFI were significantly more frequent among PWE with a history of status epilepticus within 3 months before the first dose of COVID-19 vaccination (P = 0.049). The time interval from the first onset of seizure to the diagnosis of epilepsy ranged from 0.25 to 1.29 years. The difference in seizure frequency between pre-vaccination and post-vaccination was insignificant. Otherwise, there was no significant association between other variables and AEFI of COVID-19 vaccination. The detailed information and association between the characteristics and AEFI of COVID-19 vaccination are summarized in Table 4.

All the characteristics and variables with a P-value <0.05 were further analyzed with each category of the AEFI in a multiple logistic regression analysis model. The findings of the multivariate analyses indicated that there was no significant association between all characteristics of PWE with non-serious neurological and serious neurological AEFI. The logistic regression multivariate analysis of the significant associations between characteristics of PWE and AEFI are shown in Table 5. Gender, age, history of status epilepticus within 3 months before the first dose of vaccination, and brand of COVID-19 vaccine were not found to be associated with local or systemic AEFI. However, body mass index was found to be a significant factor associated with local or systemic AEFI. Only normal body mass index showed statistically significant association with systemic AEFI, compared to underweight PWE.

3.5 Characteristics of PWE associated with serious AEFI

Out of the 120 PWE, only four patients developed serious AEFI following COVID-19 vaccination. All patients were younger than 45 years of age. Three patients were vaccinated with Cominarty® and one patient was vaccinated with CoronaVac®. The serious neurological AEFI experienced was seizure, and it occurred within 1-8 days after vaccination. It is important to emphasize that all patients had at least one systemic or non-serious neurological AEFI. The detailed characteristics and variables with a P value of <0.05 were tabulated in Table 6.