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Psychological impact of the COVID-19 pandemic for patients with epilepsy: A systematic review and meta-analysis

Objective To investigate psychological comorbidities in patients with epilepsy during the coronavirus disease 2019 (COVID-19) pandemic. Method A systematic review and meta-analysis approach was used to comprehensively search MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov databases for relevant studies. Studies that reported psychological stress in patients with epilepsy during the COVID-19 pandemic were included. Psychological comorbidities were defined as anxiety, depression, and sleep disturbance. Pooled proportions of psychological comorbidities with 95% confidence intervals (CIs) were assessed using a random-effects model. The quality of assessment for each study, heterogeneity between the studies, and publication bias were also evaluated. Results A total of 28 studies with 7959 patients/caregivers were included in the meta-analysis. The pooled proportions of anxiety/worry, depression/bad mood, and sleep disturbance were 38.9% (95% CI: 31.3–46.7); I2 = 97%; p < 0.01, 30.9% (95% CI: 23.3–38.9), I2 = 97%; p < 0.01, and 36.5% (95% CI: 28.3–45.1), I2 = 97%, p < 0.01, respectively. Conclusion Although the heterogeneity was high, our results showed a relatively high incidence of psychological comorbidities. Therefore, clinicians need to intervene early in the stress of patients with epilepsy to prevent worsening of stress, which can result in seizure worsening.


Introduction
Epilepsy is a chronic neurological disorder that causes recurrent, unprovoked seizures. It is known that 20-30% of patients with epilepsy experience symptoms of depression [1]. Compared to healthy people, patients with epilepsy have a 40-50% higher suicide rate [2]. Coronavirus disease 2019 (COVID- 19) initially occurred in Wuhan, China, in late 2019, before its global outbreak [3]. The COVID-19 pandemic has been stressful for people worldwide, and everyone has to adapt to the changes involved. We have discussed the importance of considering the psychological impact of this pandemic in patients with epilepsy [4,5]. It is known that increased psychological stress in patients with epilepsy not only increases the risk of developing psychiatric disorders such as depression but also that stress can trigger and exacerbate seizures. The effects of stress can even kill patients with epilepsy due to the rapid worsening of seizures or suicide caused by the onset of mental illness. Therefore, clinicians need to understand the impact of COVID-19 on the mental stress of patients with epilepsy to maintain appropriate treatment even during the COVID-19 pandemic.
Patients with epilepsy are reported to be more vulnerable to the psychological effects of the COVID-19 pandemic than those without epilepsy [6]. If we know the impact of the COVID-19 pandemic on the mental health of patients with epilepsy, clinicians can consider, prevent, or respond quickly to the psychological comorbidities of patients with epilepsy. [4] It would also allow us to put proper protective/proactive interventions in place for people with epilepsy during the pandemic and other times of crisis. However, the magnitude of its impact is uncertain and varies from study to study [4,6]. Therefore, this study aimed to clarify the impact of the COVID-19 pandemic on the mental health of patients with epilepsy. We investigated the incidence of psychological comorbidities in patients with epilepsy during the COVID-19 pandemic using a systematic review and meta-analysis.

Searching strategy
We conducted a search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [7]. This review protocol has not been registered previously. The following databases were searched systematically up to March 20, 2021

Inclusion and exclusion criteria
Studies were included based on the following criteria: (1) studies that have reported data of at least one psychological comorbidity in patients with epilepsy or reported by their caregivers during the COVID-19 pandemic; (2) studies from which we can calculate the incidence proportion of patients/caregivers with psychological comorbidities during the COVID-19 pandemic. We excluded studies based on the following criteria: (1) studies that were not yet recruiting, currently recruiting, or were withdrawn according to Clinical.Trials.gov; (2) studies that reported patients diagnosed with psychogenic nonepileptic seizures; (3) case reports; and (4) studies written in languages other than English. In addition, we did not include studies focusing on patients with epilepsy during the pandemic, which reported only the number or proportion of patients with epilepsy who had preexisting psychiatric disorders as demographic data and did not examine anxiety, depression, or stress during the pandemic. This is because the existence of preexisting psychiatric disorders before the COVID-19 pandemic does not reflect the influence of COVID-19 on patients with epilepsy.
Psychological comorbidities were defined as anxiety, depression, or sleep disturbance. Anxiety included anxiety/worry in patients with epilepsy or their caregivers' anxiety and worry. Depression included depression/bad mood in patients with epilepsy or their caregivers' depression/bad mood. Sleep disturbances included insomnia, nocturnal awakening, and sleep pattern changes in patients with epilepsy or their caregivers' sleep pattern changes. If studies categorized outcomes into four categories (i.e., less, mild, moderate, and severe) based on scales/scores, then we defined the incidence of psychological comorbidities in the studies as outcomes of moderate or severe. Any type of outcome was measured using a questionnaire, survey, or the presence of psychological consultation. However, we excluded studies that reported only the mean ± standard deviation of psychological scores because we could not calculate the incidence proportion.
To assess the quality of the included articles, we scored the level of risk of bias using the risk of bias instrument for cross-sectional surveys of attitudes and practices contributed by the CLARITY group at McMaster University [8] and Joanna Briggs Institute checklist for cohort studies [9]. Any disagreements or discrepancies between the reviewers regarding outcomes were resolved through discussion.

Data extraction and outcome measurements
Two reviewers (NK and TK) independently screened the titles and abstracts and evaluated the full texts of the selected articles. The risk of bias was independently assessed. Any disagreements were resolved through discussion between the reviewers (NK and TK). The following variables were extracted: author, publication year, study period, country in which the study was conducted, participants, study design, outcome measurement scales, the proportion of anxiety/worry, depression/bad mood, and sleep disturbance. We further extracted independent risk factors for anxiety, depression, and insomnia identified by multivariate analysis and their odds ratios (ORs).

Statistical analysis
In this systematic review and meta-analysis, we used a singlearm analysis. Percentages, means, and standard deviations were calculated for the categorical variables. We used random-effects models with the DerSimonian-Laird estimator to consider the variance between and among the studies. We calculated the pooled proportions using the variance-stabilized Freeman Tukey's double arcsine transformation. Confidence intervals (CIs) for individual studies were computed using the Wilson score CI method, adjusting for continuity. The I 2 statistic and Cochran's Q test were used to indicate heterogeneity between the studies. For the I 2 statistic, 0% I 2 < 25%, 25% I 2 < 50%, 50% I 2 < 75%, and 75% were considered very low, low, moderate, and high heterogeneity, respectively [10]. For Cochran's Q test, P < 0.10 was considered to indicate severe heterogeneity [11,12]. Publication bias was assessed using a funnel plot and Egger's test, which is a quantitative analysis of asymmetry in the funnel plot. For Egger's test, P < 0.10 was considered significant publication bias [12,13]. We did not assess publication bias for outcomes reported in fewer than ten studies. All statistical analyses were conducted using R software (version 3.6.2; R Development Core Team 2019), with meta version 4.15-0 and metaphor version 2.4-0.

Subgroup analysis
Subgroup analyses were conducted to investigate potential explanatory variables of heterogeneity using the following methods: (1) analysis limited to studies reporting only patients with epilepsy, excluding studies that included caregivers of patients with epilepsy; (2) analysis limited to studies that measured outcomes using valid and established measurement scales; (3) analysis based on each valid and established measurement scale; (4) analysis divided into each continent (Asia/Oceania, Africa, Europe, North America, and, South America -Turkey was included in both Asia/Oceania and Europe); (5) analysis was divided into low/ middle-income and high-income countries based on the Develop-N. Kuroda (6) analysis was divided into the early and late phases of the pandemic. Regarding (6), we defined the studies conducted until May 2020 (within three months of the World Health Organization's declaration of the pandemic) as early phase studies and those whose period was from June 2020 as a late phase. Studies that straddled both phases were excluded from the subgroup analysis of (6).

Summary of reviewed articles
The selection process is illustrated in Fig. 1. A total of 802 studies were retrieved (217 papers from MEDLINE, 0 papers from CEN-TRAL, 583 papers from EMBASE, and two studies from ClinicalTrials.gov) up to March 20, 2021. After removing duplicates and screening the titles and abstracts, 88 studies were identified. The full-text screening of these studies led to the exclusion of 60 studies that did not meet the inclusion criteria. Thus, a total of 28 studies with 7,959 patients/caregivers fulfilled the eligibility criteria for inclusion in the meta-analysis . Table 1 summarizes the findings of the included studies. The mean scores for the quality of 23 cross-sectional studies and five cohort studies were 2.7 out of 5 and 5.0 out of 11, respectively (Table 1 and Supplementary Table 1).
We looked for publication bias for anxiety/worry, depression/ bad mood, and sleep disturbance using a funnel plot and Egger's test (Table 2). There was no significant publication bias for each outcome (P = 0.48, P = 0.87, and P = 0.42, respectively) ( Table 2). We have summarized the reported independent risk factors and their ORs for anxiety, depression, or insomnia in Table 3.

Summary
This systematic review and meta-analysis of 28 studies showed that the incidence rates of anxiety, depression, and sleep disturbance were 38.9%, 30.9%, and 36.5%, respectively. However, the heterogeneity in the meta-analysis was very high for every outcome (anxiety: I 2 = 97%; depression: I 2 = 97%; sleep disturbance: I 2 = 97%). We performed subgroup analyses to consider potential heterogeneity due to participants (patients or caregivers), the validity of outcome measurements, and differences among outcome measurement scales, continents, study period, and wealth of countries. However, even after subgroup analysis to consider participants, continents, study period, and wealth of countries, heterogeneity hardly improved. Subgroup analysis of the same outcome measurement scale showed a relatively improved heterogeneity.
These results indicate that the incidence of psychological complications may vary greatly depending on the scale used to measure them. Meanwhile, there was some heterogeneity in the incidence of psychological complications, even among studies using the same measurement scale, within the same continent, similar period, or similar wealth of country.
The reason for the heterogeneity among studies that used the same measurement scale was the difference in cutoff values in each study. Indeed, several studies have reported that different cutoff values are optimal [42][43][44][45][46][47][48][49], depending on the profile of patients and translated language. Another explanation for this heterogeneity is that the mental health effects of COVID-19 may vary greatly depending on the condition of the disease, such as the severity of epilepsy or the presence of complications. Indeed, some measurement scales, such as the HADS, were evaluated as near cutoff values; nevertheless, the heterogeneity was still high.

Comparison with stress in the general population during the COVID-19 pandemic
Some studies have compared stress between patients with epilepsy and the general population [17,31]. A study from Italy reported that patients with epilepsy experienced more severe depressive and anxiety symptoms than those in the control group [17]. As for insomnia, it was reported that there were no differences between patients with epilepsy and the control group. Another study from Iran also reported that the proportion of people with severe anxiety was higher in patients with epilepsy than in the control group [31]. On the other hand, it was also reported that the proportion of people with insomnia was higher in the control group than in the epilepsy group.

Comparison with stress in patients with other diseases during the COVID-19 pandemic
The impact of COVID-19 on mental health has been reported in several studies. A study reported that 16% of patients with diabetes mellitus experienced mental stress, and 24% experienced sleep change [50]. Meta-analysis of mental stress due to the COVID-19 pandemic on healthcare staff reported various incidence proportions of anxiety, depression, and sleep disturbance depending on each study, as well as in our study [51].
Multiple sclerosis, similar to epilepsy, is a chronic neurological disease. A study reported mental stress in patients with multiple sclerosis [52]. According to this study, 22% of the patients reported moderate or severe anxiety/depression.
Our results showed a relatively high incidence of psychological comorbidities compared to studies on patients with diabetes mellitus and multiple sclerosis. People with epilepsy are known to have more psychiatric complications than people without epilepsy, which may be one reason for the high incidence proportion compared to other diseases.

Comparison with stress in patients with epilepsy under other situations
Although COVID-19 is a pandemic like no other in history, it is important to characterize the stress caused by COVID-19 in patients with epilepsy, compared to the stress caused by other major social events, such as disasters and accidents. These data may be important in predicting the impact of the next major social event on patients with epilepsy.
In terms of the impact of major social events (disasters, accidents, etc.) on patients with epilepsy, some studies have been reported in the past. A study reported the impact of the 9/11/2001 terror attacks in the US on patients with epilepsy [53]. According to this study, 15/66 (22.7%) patients experienced moderate or severe stress. Another study reported that 70% of evacuees from an extremely high water level in 1995 in the Netherlands had any type of mental stress [54].
Our study, as well as other studies [53][54], showed that patients with epilepsy are vulnerable to disasters. People with epilepsy are considered to be exposed to psychological stress in many ways. In the event of a disaster, these may include concerns, such as whether they will be able to secure antiepileptic drugs or stress related to the disease, such as when seizures occur. These findings will be important for epileptologists, neurologists, and other physicians, nurses, and healthcare providers to prepare for other disasters, including pandemics, and to protect patients with epilepsy from psychological stress. Specifically, some included studies reported the importance of maintaining access to healthcare providers or obtaining anti-seizure medications for patients/people with epilepsy [24,36]. To keep it, telemedicine is one of the good options during the COVID-19 pandemic.
In addition, the COVID-19 pandemic is unique compared to other disasters in that it is prolonged, global, and has a direct impact on infection risk as well as restrictions on social and work life. During the prolonged COVID-19 pandemic, clinicians need to intervene early in the stress of patients with epilepsy to prevent worsening stress, which can result in seizure worsening. Specifically, a study suggests the effectiveness of early physical consultation with stringent precautionary measures during the COVID-19 pandemic [55].

Conclusion
We investigated the psychological impact of patients with epilepsy during the COVID-19 pandemic by performing a systematic review and meta-analysis of the incidence of anxiety, depression, and sleep disturbances. Although the heterogeneity was high, our results showed a relatively high incidence of psychological comorbidities. Therefore, clinicians need to intervene early in the stress of patients with epilepsy to prevent worsening stress, which can result in seizure worsening.

Financial disclosures
This work did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.