Long-term analysis of the effects of COVID-19 in people with epilepsy: results from a multicenter on-line survey across the pandemic waves
Abstract
Purpose
The worldwide pandemic caused by SARS-CoV-2 virus posed many challenges to the scientific and medical communities, including the protection and management of fragile populations. People with epilepsy (PWE) are a heterogenous group of subjects, with different treatment regimens and severity of symptoms. During the National lockdown, in Italy many patients with chronic conditions lost their regular follow-up program. The aim of this study was to investigate the impact of COVID-19 on their health status, from the start of the pandemic (March 2020) to July 2021 and one year later.
Methods
We proposed an online questionnaire to subjects followed at different epilepsy centers located in Milano, Monza & Lodi, three of Lombardy, Northern Italy, the most affected areas by the pandemic. Survey evaluated age, sex, characteristics of patients, type of epilepsy and therapies, COVID-19 diagnosis, vaccines, sleep quality and anxiety status.
Results
Among 178 analyzed surveys, 37 individuals reported symptoms of COVID-19 in closed contacts, including 9 with molecular diagnosis and 16 PWE performed the nasopharyngeal swab with 3 positive cases. One year later, 35 individuals reported at least one symptom overlapping with those typical of COVID-19, 8 received COVID-19 diagnosis, among which 6 were positive for SARS-CoV-2 infection. According to the sleep quality scale assessment, most PWE (52.3%) had poor sleep quality. Assessing anxiety status, 32 (38.1%) had a pathological score.
Conclusion
In this multicenter study, we observed that PWE do not appear to be at higher risk of severe COVID-19. It will be fundamental monitoring this group to assess possible differences in long-COVID-19 and/or neuro-COVID-19 prevalence. On the other hand, our survey confirmed the impact of the pandemic on anxiety and quality of sleep in PWE. Thus, it is important to promptly recognize and treat psychological distress in PWE, because it could be a risk factor in seizure aggravation and quality of life deterioration. Telemedicine appears to be a useful tool to support patients with chronic diseases, such as epilepsy.
1. Introduction
]. This condition was soon described as coronavirus disease 2019 (COVID-19) [
,
] and it is caused by SARS-CoV-2 virus. From China, SARS-CoV-2 has rapidly expanded to the rest of the world and, in a few months, many countries have been hit by the consequences of this pandemic.
].
].
,
]. A spectrum of neurological manifestations has been reported in the literature associated with SARS-CoV-2 [
,
], and epilepsy is infrequently reported [
,
].
]. On the other hand, it is unclear whether or not people with epilepsy (PWE), characterized by a chronic condition, are at higher risk of a severe COVID-19 [
].
].
]. During COVID-19 pandemic, telemedicine has been an alternative for allowing patients to maintain contact with their physician [
,
].
,
,
]. Although the extent of impact is uncertain, the pandemic has certainly had an impact on the mental health of the general population including patients with epilepsy. Should the effects be understood, psychological comorbidities could be minimized [
].
Hence, the aim of this study – through a protocol consisting of an online questionnaire directed to patients with epilepsy treated with ASMs followed at different tertiary care units in Lombardy – was to investigate if during the first wave peak of SARS-CoV-2 spreading there was a different response in a specific fragile population – PWE- compared to the general population. Specifically, we investigated whether PWE would manifest different symptoms – more severe or milder – in response to the infection caused by SARS-CoV-2 and a possible correlation with the type of concomitant antiseizure therapy, the possible variation of the frequency and of intensity of the seizures. Moreover, we conducted a second survey with the PWE who answered to our first questionnaire one year later, in order to verify whether they have been infected by SARS-CoV-2 in the meantime.
We also evaluated their adherence to the anti-COVID vaccination campaign and whether patients with epilepsy experienced sleep disorders or increased amount of anxiety and whether there is a correlation between the two problems. The intent was to assess also anxiety status and sleep quality in PWE after a year of pandemic that has imposed a long period of stress on people around the world.
2. Materials and methods
2.1 Study population and survey
The study involved the enrollment of adult patients (over 18y.o.) with epilepsy resident in the Lombardy Region, through the involvement of neurologists belonging to the Italian League against Epilepsy – Lombardy Section, who are in charge of medical follow-up (no deaths were recorded in the selected period). For the second phase of the study, participants who had given consent to be re-contacted were contacted. Patients independently completed a questionnaire relating to the presence or absence of symptoms typical of COVID-19, concomitant antiseizures therapy, any variation in the frequency and intensity of the seizures. Patients were grouped according to the type of therapy and the severity of the COVID-19 symptoms (in terms of type and intensity of the symptoms in relation to different degrees of medical interventions, e.g. home-based treatment, hospitalization or intensive care unit), also in relation to the severity of family members / cohabitants. The first questionnaire was sent at the end of the first wave of COVID-19 (May – July 2020) when many of the effects of this virus were not yet known, especially in our population of interest.
With the Decree of March 12, 2021, our Country adopted the new national strategic plan for the prevention of SARS-CoV-2 infections for the execution of the national vaccination campaign (prepared by the Ministry of Health, Extraordinary Commissioner for emergency, Istituto Superiore di Sanità, AGENAS and AIFA). Age and the presence of pathologies represented the main correlation variables with mortality from COVID-19. The order of priority of the categories of people to be vaccinated in the campaign was: category 1 were highly frail people; category 2 were people between 70 and 79 years of age; category 3 were people between 60 and 69 years of age; category 4 were people under the age of 60 with co-morbidities but without the connotation of severity reported for category 1; category 5 represented the rest of the population under the age of 60. In addition, some categories have also been identified as priorities, regardless of age and pathological conditions: school and university staff, armed police and public aid forces, penitentiary services, and other residential communities.
The first vaccines available in Italy were mRNA BNT162b2 (Comirnaty) produced by Pfizer and BioNTech and Spikevax (mRNA-1273), the vaccine developed by Moderna. This was followed by the introduction of the ChAdOx1-S vaccine, developed by the University of Oxford and AstraZeneca and the vaccine developed by the pharmaceutical company Janssen (of the Johnson & Johnson group) – the last two suspended in May 2021.
In the second questionnaire, we added questions related to quality of life, sleep, anxiety and adherence to the anti-COVID vaccination campaign. The second questionnaire was sent exactly one year after the first (June – July 2021) which corresponded to the end of the third wave of the pandemic in Italy.
] is a 19-item self-administered questionnaire used to evaluate sleep disturbances and sleep quality over a period of a month. Each item is rated on a four-point Likert-like scale. The combination of the different items generates seven scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of the 7 scores produces a global score. A global score of 5 or higher provides a sensitive and specific measure of poor sleep quality.
] is a 20-item, self-report questionnaire used to evaluate state anxiety; each item is rated on a four-point Likert scale. STAI S-Anxiety scale is one of the two parts of STAI questionnaire (Spielberg et al. 1970), which is composed of 40 items, 20 for trait anxiety (T-Anxiety) evaluation, and 20 for state anxiety (S-Anxiety) evaluation. Range of scores for each subtest is 20–80, the higher score indicating greater anxiety. A cut off of 39–40 has been suggested to detect clinically significant symptoms for the S-Anxiety scale. In this survey, we asked PWEs how they accessed medical care and whether they used telemedicine. The surveys are available in the supplementary information (Supplementary Table 1 and 2).
2.2 Statistical analysis
For data analysis, chi-square testing was performed to test the difference between the outcomes in our study group and the general population. The analysis of variance test – ANOVA – was used to analyze a possible correlation between the antiseizure therapy and the appearance of symptoms attributable to COVID-19. P-value≤0.05 was considered significant.
3. Results
3.1 First phase of survey
Table 1Characteristics and antiseizures therapy in the PWE.
Figure 1Geographic distribution of the study population. The map represents the distribution of PWE in the different provinces in Lombardy; the color is darker where there is a greater number of patients who participated in the study.
The type of epilepsy appears to be generalized epilepsy in 85 individuals (47.7%), 74 focal epilepsy (41.6%) and the other cases unspecified epilepsy. During the survey period, only 17 subjects (9.5%) changed anti-epileptic therapy but 8 of them (47%) had uncontrolled seizures for at least a year – in 133 PWE (75%) seizures were under control.
Among all the participants, 92 individuals (51.7%) reported at least one symptom overlapping with COVID-19 from January 2020, 65 individuals (36.5%) declared they had at least two symptoms possibly caused by COVID-19 – based on self-report. We show that 25 PWE reported fever (14%), 10 anosmia, ageusia (absence of smell and taste) (5.6%), 25 cough (14%), 35 cold (19.6%), 23 diarrheas, nausea or vomiting (13%), 37 asthenia/fatigue (20.8%) and 13 conjunctivitis (7.3%); 24 PWE (13.5%) underwent a nasopharyngeal swab test for SARS-CoV2, 12% were positive.
Among PWE who reported at least two symptoms, 16 performed the nasopharyngeal swab and among these we found the 3 positive cases plus one negative but with positive serological SARS-CoV2 IgG test in our entire population. Six subjects (3.4%) were hospitalized and, among them, 4 had nasopharyngeal swabs for SARS-CoV2, but only 2 were positive. No correlation was found between treatment and the presence of symptoms (> 2) related to COVID-19. In our study population, we observed a significant difference (p-value=0.01, ≤0.05) between subjects who reported onset of symptoms (> 2) related to COVID-19 (42, 23.6%) and subjects who did not report (88, 49.4%), regardless of medication taken. Out of the total population, the percentage of subjects tested positive for SARS-CoV-2 is 1.7%. Furthermore, 37 PWE family members reported symptoms of COVID-19, including 9 with molecular diagnosis.
In Italy, the general population as per January 2021 presents a positive / cases tested ratio that stands at 29.5% and shows a considerable regional variability – Lombardy stands at 31.5% (Data from Italian National Health Institute, publicly available). Updated reports of the general population show that the number of total positive cases corresponds to 4.2% (2.560.957) in Italy and 5.3% (539.147) in Lombardy. Among hospitalized patients –3.489 in Lombardy – the percentage of access in ICUs corresponds to 10.6% (371). A chi-square test was performed to examine the relation between hospitalized patients in our study population and Lombardy population – the difference between these outcomes was significant (p-value=0.00001, ≤0.05).
No significance difference was found among ICU admission in our study population (none) and those recorded in Lombardy (7.2% of SARS-CoV-2 positive tested).
3.2 Second phase of survey
In the second phase of the study, 155 surveys were sent by e-mail in the period from June 25th to July 30th, 2021. We enrolled all patients answering the questions upon informed consent of data use. A total of 86 subjects (55.5%) accessed the online survey, and 84 of them (54.2%) gave their consent to proceed with the questionnaire and processing of personal data. Among the subjects who gave their consent, the age range went from those born in 1937 to those born in 2002 (age mean 43 years old, SD = 13.6, median 41 years of age) – 61 are females (73.5%) and 23 males (27.5%). The age of diagnosis of epilepsy was in a range from 0 to 64 years, mean 20.4 and median 17 years of age.
In our second study group, the type of epilepsy appears to be generalized epilepsy in 48 individuals (57.1%), 32 focal epilepsy (38.1%) and the other cases unspecified epilepsy. From October 2020, only 18 of them (21.4%) had uncontrolled seizures for at least a year – in 66 PWE (78.6%) seizures were under control. In this second survey, our population a total of 15 (1.9%) patients receiving treatment with VPA: 6 patients were treated with valproic acid (VPA) alone (7.1%), or in combination (9 patients, 10.7%). Three patients (3.5%) received flu vaccination during this period.
Within the study group, 72 subjects (85.7%) received vaccination for SARS-CoV-2 and, among them, 25 (34.7%) received both flu and SARS-CoV-2 vaccination. Among PWE who received SARS-CoV-2 vaccination: 51 Comirnaty (70.8%, Pfizer/BioNTech), 10 Moderna (13.8%, Biotech), 7 Vaxzevria (9.7%, Astrazeneca), 3 heterologous vaccine covid Comirnaty and Vaxzevria (4.2%), and only 1 Johnson & Johnson (1.4%, Janssen). During the first phase there were no vaccines againt COVID-19 and limited diagnostics, hence comparison is not possible.
Among all the participants, 35 of them (41.6%) reported at least one symptom overlapping with COVID-19 from October 2020, 24 individuals (28.5%) declared they had at least two symptoms possibly caused by COVID-19 – based on self-report. We found that, among 35 PWE reported at least one symptom, 27 PWE (32.1%) underwent a nasopharyngeal swab test for SARS-CoV2. Among PWE who reported at least one symptom, 8 (9.5%) received COVID-19 diagnosis (7 females and 1 male). Among 3 PWE not vaccinated, 2 reported several symptoms overlapping with COVID-19 and received flu vaccination. 2 individuals presented other pathologies and only one had seizures not controlled by medications. No subject who received COVID-19 diagnosis were treated with VPA.
Among those subjects who completed the second survey, 6 (7.1%) tested positive to SARS-CoV-2 infection: 1 had controlled seizures, 1 had an improvement on seizures and 1 changed antiseizure therapy during the last period. 4 of them were treated for COVID-19 and 3 performed antibody testing for COVID-19 and resulted positive. All of them had family members who reported symptoms of COVID-19, including 5 with molecular diagnosis. No individuals were hospitalized.
3.3 Access to medical care and psychological side effects
Out of the total population, from October 2020 to July 2021, 82 (97.6%) had access to medical care and most of them (72, 85.7%) had the opportunity to contact the physician epileptologist: 7 by email, 16 by phone, 8 in telemedicine, 41 in presence. The remaining subjects reported no contact with the physician, as some did not have the need for it and others were waiting for their annual visit.
Figure 2(A) Sleep Quality (SQ) scale. Good SQ (in blue) score <5; Poor SQ (in red) score >5; Bordeline SQ = 5. (B) Anxiety status STAI scale. Normal STAI (in blue) score <40; Pathological STAI (in red) score ≥ 45; Bordeline STAI (in yellow) score 40 – 44.
Although not reaching statistical significance, 52.3% of patients reported Poor SQ and 38.1% of patients a pathological anxiety status.
4. Discussion
Since Northern Italy, and specifically Lombardy, has been reached by Coronavirus disease 2019 (COVID-19) pandemic among the first regions worldwide, people with chronic diseases, such as epilepsy, were concerned about the management of their seizures and both about the possible effects of this new infection in PWE. Thus, we delineated an observational survey directly fulfilled by patients or their caregivers, living in Lombardy at the time of the first pandemic spread and a follow-up after one year, in order to capture the impact of COVID-19 on this population of frail subjects. Responder anonymity represents a limitation of the study but, considering the demographic and clinical data, our cohort mirrors PWE who are followed in our centers.
]. Further, because of the mitigation measures during COVID-19 pandemic, chronic patients reported issues in access both to drugs and medical care [
]. To this end, it has been suggested that different types of e-health applications should be used simultaneously – as complementary resources – to improve the outcomes of chronic patients including PWE [
,
]. This fundamental aspect should be considered for SARS-CoV-2 future pandemic waves and/or other emerging pathogens, as modern technologies represent an invaluable tool for guarantying medical support to those in need.
,
]. The regional distribution of the answers to the survey could be explained by both population density and possibly a more habit to research interviews given that in Milan there are 4 Medical Research Universities.
]; however some studies report an increase in seizure frequency in patients with change in sleep, increase in stress and reduced compliance to ASMs [
,
]. This scenario reflects the overall prevalence of drug-resistance in PWE [
], and allows considering our sample representative of population with epilepsy.
We collected information about ASM and found that the most used were Valproic acid, Carbamazepine, Clobazam, Levetiracetam, Lamotrigine, Perampanel in monotherapy or in combination.
] listed HDAC2 among the interactors of the major viral protease SARS-CoV-2-3-chymotrypsin-like protease (3CLpro). Whether this interaction has positive or negative consequences on viral replication is still to be elucidated, but other authors [
] suggested HDACi ability to prevent SARS-CoV-2 entry into target cells. VPA would seem to be a possible candidate for further use in patients at risk of COVID-19 [
].
,
]. Our study reflects the effect of the first wave of COVID-19 pandemic, when the tracking of asymptomatic cases was not performed. For this reason, the incidence of SARS-CoV-2 in our sample was not specifically investigated.
]. Other studies found no association of epilepsy and COVID-19 death rate [
,
,
]. Further analysis on a wider population would be of great importance.
In the second phase, 7.1% individuals in our population tested positive for SARS-CoV-2 infection. An additional 2.3% received diagnosis of SARS-CoV-2 based on clinical symptoms albeit not confirmed by specific test. These numbers are in line with pandemic situation at the time in the Lombardy. This observation appears to support that the PWE population does not present an increased risk of severe COVID-19 compared with the general population.
,
,
].
], while QoL of PWE worsened, and anxiety level increased.
], probably due to concern of possible side effects, but PWE usually have a good safety profile and a low risk of epilepsy worsening. We observed a high adherence to the vaccination campaign (85.7%) from patients responses, in line with the national population response.
,
], we confirmed that COVID-19 pandemic had an impact on sleep quality and anxiety level in our sample. Psychological distress in PWE should be promptly captured and adequately treated because could also result in seizure aggravation and quality of life deterioration [
]. Indeed, telemedicine implementation can support patients with chronic diseases, such as epilepsy, and thus reducing the distance between PWE and their treating physicians [
,
]. The use of telemedicine has grown significantly over the past decade because of the clear advantages: the ability to provide care for people with mobility limitations, people living in rural areas, and costs savings. This tool became essential during the recent pandemic. Unfortunately, this methodology present obvious limitations: for example, blood tests and the most common diagnostic tests require an in-person approach. Further digital data require a secure plan for data management and storage [
,
]. Our data regard only one region, and it is difficult to compare with others given the specific age/socioeconomic status. The impact of ethnicities and socio-economic status may have an additional effect on severe SARS-CoV-2 disease, considering that our study population is high social economic status. Indeed, socioeconomic determinants were strongly associated with COVID-19 outcomes in racial and ethnic minority populations [
]. Moreover, additional environmental risk factors (e.g. air pollution, high mobility, high population density) may be determinant in the spread of SARS-CoV-2 infection in an industrialized region such as Lombardy, but are difficult to rule out [
].
Clearly, using a self-completing questionnaire, this study has limitations – also due to obvious reasons, especially during the first phase of the study – concerning the lack of a control group, the uncertainty about the temporal relationship in vaccinated patients between vaccination and COVID-19 symptoms. Moreover, it should be taken into account that different variants of Sars-Cov2 may have different characteristics, for example in contagiousness and severity of symptomatology, so that the current situation may be different from previous waves.
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