DR. ELENA FONSECA (Orcid ID : 0000-0002-3895-1237) Accepted Article DR. LAURA ABRAIRA (Orcid ID : 0000-0002-5119-7929) PROF. MANUEL TOLEDO (Orcid ID : 0000-0003-1550-3316) Article type : Original Article EPILEPSY IN TIME OF COVID-19. A SURVEY-BASED STUDY RUNNING TITLE: Epilepsy and COVID-19 pandemic. Elena Fonseca1,2, Manuel Quintana1,2, Sofía Lallana1, Juan Luis Restrepo1, Laura Abraira1,2, Estevo Santamarina1,2, Iván Seijo-Raposo1,2, Manuel Toledo1,2 Authors’ affiliations 1Epilepsy Unit Neurology Department, Vall d’Hebron University Hospital. Medicine Department, Universitat Autònoma de Barcelona, Barcelona, Spain 2Epilepsy Research Group, Vall d’Hebron Research Institute (VHIR). Barcelona, Spain. Corresponding author: Dr Estevo Santamarina Epilepsy Unit, Vall d’Hebron University Hospital Passeig Vall d’Hebron 119-129, 08035 Barcelona, Spain Tel: 934894257; e-mail: esantamarina@vhebron.net This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/ANE.13335 This article is protected by copyright. All rights reserved ACKNOWLEDGEMENTS Accepted Article This research did not receive a grant from funding agencies in the public, commercial, or not-for- profit sector. The authors thank Celine Cavallo for English language support. ABSTRACT Objectives: Collateral damage may occur in epilepsy management during the coronavirus (COVID-19) pandemic. We aimed to establish the impact of this pandemic on epilepsy patients in terms of patient-reported seizure control and emerging symptoms. Materials & Methods: Cross-sectional study including consecutive patients assessed by telephone contact in an epilepsy clinic during the first month of confinement. Demographic and clinical characteristics were recorded and a 19-item questionnaire was systematically completed. Data regarding the impact of confinement, economic effects of the pandemic, and subjective perception of telemedicine were recorded. Additional clinical data were obtained in patients with a COVID-19 diagnosis. Results: Two-hundred and fifty-five patients were recruited: mean age 48.2±19.8 years, 121 (47.5%) women. An increase in seizure frequency was reported by 25 (9.8%) patients. Sixty-eight (26.7%) patients reported confinement-related anxiety, 22 (8.6%) depression, 31 (12.2%) both, and 72 (28.2%) insomnia. Seventy-three (28.6%) patients reported a reduction in economic income. Logistic regression analysis showed that tumor-related epilepsy etiology [OR=7.36 (95% CI 2.17-24.96)], drug-resistant epilepsy [OR=3.44 (95% CI 1.19-9.95)], insomnia [OR=3.25 (95% CI 1.18-8.96)], fear of epilepsy [OR=3.26 (95% CI 1.09-9.74)], and income reduction [OR=3.65 (95% CI 1.21-10.95)] were associated with a higher risk of increased seizure frequency. Telemedicine was considered satisfactory by 214 (83.9%) patients. Five patients were diagnosed with COVID-19, with no changes in seizure frequency. This article is protected by copyright. All rights reserved Conclusions: The COVID-19 pandemic has effects in epilepsy patients. Patients with tumor- related, drug-resistant epilepsy, insomnia, and economic difficulties are at a higher risk of increased seizure frequency. Telemedicine represents a suitable tool in this setting. Accepted Article KEYWORDS: Seizures, coronavirus, pandemics, epilepsy, quality of life This article is protected by copyright. All rights reserved INTRODUCTION In late December 2019, the health authorities of Wuhan City (Hubei province, China) reported a series of pneumonia cases of unknown etiology. Shortly thereafter, the novel severe acute Accepted Article respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the etiologic agent causing coronavirus disease (COVID-19).1 This infectious disease rapidly advanced to become a pandemic, as declared by the World Health Organization (WHO) on 11 March, 2020,2 and at the time of writing of this article, there are more than two million cases worldwide.3 Spain is one of the most highly affected countries, with nearly 200,000 total cases and 20,000 deaths.4 The COVID-19 pandemic is a challenge for healthcare systems around the world. It is an exceptional health emergency that is generating an enormous health and socio-economic impact. The pandemic has led governments to impose stringent measures on the population such as mandatory home confinement to contain the spread of the infection. Among European countries, Spain is second only to Italy in terms of extreme pressure on the healthcare system.5 The huge demand for hospital and out-of-hospital resources to treat these patients has led to reorganization of the entire healthcare infrastructure and its workers, and this has inevitably affected healthcare for other conditions, including epilepsy. In epilepsy patients, the pandemic has led to postponement of outpatient visits, cancellation of epilepsy-related tests, such as electroencephalograms (EEG) and magnetic resonance imaging (MRI) studies, and even difficulties in attending emergency situations due to saturation of the healthcare services. In this context, communications technology is undergoing a revolution, with telemedicine being a useful emerging alternative to facilitate medical care in chronic patients.6,7,8 Chronic health conditions such as hypertension, diabetes, and cardiovascular disease have been identified as risk factors for developing severe Covid-19.9,10 However, the relationship between epilepsy and COVID-19, and the effects of the pandemic on epilepsy patients have been scarcely investigated to date. Patients with epilepsy face a unique situation at this time, and some may be at risk of breakthrough seizures not only due to COVID-19 itself, but also to the effects of home confinement and collapse of the healthcare services. This study provides the results of a cross-sectional survey of patients from a specialized Epilepsy Unit at a Spanish tertiary hospital and reference center for patients with COVID-19. The aim of the study was to establish the impact of the pandemic on epilepsy patients in terms of seizure This article is protected by copyright. All rights reserved control and other key indicators, and to determine their subjective perception of telemedicine as a remote resource in this exceptional setting. METHODS Accepted Article Study design and participants This is a cross-sectional study conducted in a specialized Epilepsy Unit including patients assessed by the outpatient clinic between 16 March and 17 April 2020. Following the guidelines described in the Vall d’Hebron Hospital contingency plan, all patients with an outpatient visit scheduled before the Spanish Government’s state of alarm declaration on 13 March 2020 were assessed by telephone visit. The study conforms with World Medical Association Declaration of Helsinki and it was approved by the Vall d’Hebron Research Institute Clinical Research Ethics Committee [PR(AG)2018-2020]. Patients 17 years of age and older with a definite diagnosis of epilepsy according to the International League Against Epilepsy (ILAE) criteria11 were consecutively included in the study. All patients included gave oral consent for participation. The presence of psychogenic non-epileptic seizures only, paroxysmal neurological symptoms of an uncertain or non-epileptic nature, acute symptomatic seizures without a strict epilepsy diagnosis, and inability to complete the questionnaire by patients or their caregivers were considered exclusion criteria. All patients were attended by a trained epileptologist in a telephone visit, in which seizure frequency, treatment-related adverse events and other emerging symptoms were assessed as a routine outpatient evaluation. Information regarding epilepsy syndromes, current antiepileptic drug (AED) treatment, average baseline seizure frequency and drug resistance was obtained from the medical records. All epilepsies were classified according to the current ILAE classification.12 The Modified Rankin scale (mRS) score13, presence of dysphagia, and demographic data, including current living and employment situation, were assessed. The presence of intellectual disability was also recorded, defined as neurodevelopmental disorders involving significant limitations in both intellectual functioning and in adaptive behavior, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).14 Telephone survey description After the routine clinical telephone visit, a neurologist administered a 19-item questionnaire to all participants. The survey was administered directly to patients, or to their caregivers in those with intellectual disability, dementia, or other conditions which, in the neurologist’s opinion, made This article is protected by copyright. All rights reserved them unable to answer the questions. The 19 items included were mainly closed-ended questions for which patients had a choice of answers. The last question was open-ended and patients were able to provide additional comments or suggestions related to the survey, the pandemic, or the Accepted Article confinement measures if they so desired. The questionnaire had five sections related to the following: 1) effects of the isolation measures taken by the patient or their families/caregivers; 2) effects of the government-imposed confinement on seizure frequency, AED treatment, emergency room consultations, delays in testing, and emergence of anxiety/depression symptoms and sleep disturbances, as perceived and self-reported by the patients. Changes in seizure frequency were estimated based on the average baseline seizure frequency and seizure count during the confinement period. Severity and impact of anxiety and depression symptoms were evaluated by the neurologist, and were interpreted as emerging symptoms when considered clinically significant. Patients were also asked what their worst fear was at the moment; 3) economic impact of the pandemic on the patients’ usual income; 4) subjective perception of telephone visits during the pandemic. Finally, 5) patients were questioned about symptoms compatible with COVID-19. Those with a possible or confirmed diagnosis of COVID-19 were then asked about their seizure frequency during the disease, need for hospital or intensive care unit (ICU) admission, treatments received, progress of the disease, and possible changes in AED treatment. If necessary, medical records were reviewed to obtain detailed information regarding the treatments received and clinical outcome. The presence of fever, cough, myalgia or arthralgia and associated fatigue without dyspnea or clinical/radiological signs of pneumonia were considered mild COVID-19- compatible symptoms.15 A self-reported 50% or higher increase with respect to the patient’s baseline seizure frequency, obtained from the medical records, or the development of unprovoked seizures in previously seizure-free patients were considered increased seizure frequency. Statistical analysis Descriptive and frequency statistical analyses were obtained and comparisons were made using the IBM SPSS Statistics 22.0 software. Categorical variables are reported as frequencies (percentages) and continuous variables as the mean ± standard deviation (SD) or median and interquartile range [IQR], as appropriate. Statistical significance in comparisons between the variables studied and increased seizure frequency were assessed using Pearson’s chi-square test for categorical variables (except when at least one expected frequency in the contingency table was less than 5, in which case the Fisher exact test was used), the Student t test in comparisons with age, and the Mann- This article is protected by copyright. All rights reserved Whitney U test in comparisons with the number of antiepileptic drugs and the mRS. Variables associated with a p-value <0.1 in the univariate analysis were entered in a forward stepwise multiple logistic regression model as independent variables to identify factors independently Accepted Article associated with an increase in seizure frequency. Odds ratios (ORs) and 95% confidence intervals (CIs) are shown in the final model. A bar chart was designed to show the probability of a seizure frequency increase according to the cumulative number of independently associated factors. P- values <0.05 were considered statistically significant. RESULTS During the period of study, 335 patients were assessed by telephone contact with the Epilepsy Clinic and 255 of them were included in the analysis. The details of the enrollment process are shown in Figure 1. Mean age of the patients included was 48.2 ± 19.8 years, and 121 (47.5%) were women. Most patients had focal epilepsy (n=223; 87.5%), and 56 (22%) patients had a diagnosis of drug- resistant epilepsy. The most frequent focal epilepsy subtype was temporal lobe epilepsy (n=101; 44.9%), followed by frontal (n=60; 26.7%), parietal (n=9; 4%), and posterior quadrant (n=9; 4%). Forty-six patients (20.4%) had focal epilepsy with undetermined epileptic foci. The demographic and clinical characteristics of the sample are summarized in Table 1. Impact of confinement and isolation measures Twenty-five (9.8%) patients reported an increase in seizure frequency relative to their baseline status since the start of confinement, whereas 11 patients (4.3%) reported a reduction in seizure frequency. Among those with an increase, five patients (20%) consulted in the emergency department because of seizures, three (12%) considered consulting but did not for fear of SARS- CoV-2 contagion, two (8%) contacted the emergency phone line and were advised to stay home, and one patient (4%) tried to contact the emergency line, but found it saturated. A delay in performance of epilepsy-related tests occurred in 37 patients (14.5%). Routine EEG was the test most often delayed (n=11; 29.7%), followed by MRI (n=9; 24.3%), and video-EEG monitoring (n=8; 21.6%). Seven patients (2.7%) reported difficulties obtaining their medication supply in the pharmacy, six (85.7%) because their prescription had expired and one (14.3%) because the medication was not available. This article is protected by copyright. All rights reserved Confinement-related anxiety and depression were reported by 68 (26.7%) and 22 (8.6%) patients, respectively, and 31 patients (12.2%) reported having both anxiety and depression symptoms since the start of confinement. Regarding sleep disturbance, 72 patients (28.2%) reported insomnia and Accepted Article 22 patients (8.6%) reported that their usual sleep schedules had changed. Eighteen patients (7.1%) stated that they were sleeping for a longer period per day than usual due to the confinement measures (Figure 2). Seventy-three patients (28.6%) stated that the usual family income had decreased because of the confinement-related restrictions. When asked about their worst fear at the time of the interview, 90 patients (35.3%) answered that their worst fear was contracting COVID-19 infection and 37 (14.5%) responded that it was epilepsy. Sixty-one patients (23.9%) had no particular fear at the time, and 37 patients (14.5%) were unable or refused to answer. Thirty patients (11.8%) expressed other fears, the most common being duration of confinement (n=6; 2.4%), neoplastic disease (n=6; 2.4%), and their relatives’ health (n=4; 1.6%). Eighteen patients (7.1%) had to remain under isolation inside their homes to protect themselves or their relatives from contagion. In 21 patients (8.2%), at least one relative with whom they usually live had to be under isolation measures, most often their mother (n=8; 3.1%) or husband/wife (n=6; 2.4%). Among these, five (23.8%) were the patient’s principal caregiver. Three patients (1.2%) had to move to a different home because of a suspected case in the family. Several factors were associated with increased seizure frequency during the confinement period. A tumor-related etiology (p=0.011), drug-resistant epilepsy (p=0.001), the presence of anxiety (p=0.028) or insomnia (p=0.001), the fear of epilepsy (p=0.002), and a reduction in economic income (p=0.018) were significantly associated with increased seizure frequency (Table 2). On multivariate analysis, a tumor-related etiology (OR=7.36, 95% CI 2.17-24.96), drug-resistant epilepsy (OR=3.44, 95% CI 1.19-9.95), fear of epilepsy (OR=3.26, 95% CI 1.09-9.74), insomnia (OR=3.25, 95% CI 1.18-8.96), and income reduction (OR=3.65, 95% CI 1.21-10.95) were independently associated with increased seizure frequency. The combinations of these factors provided a cumulative probability estimate of increased seizure frequency (Figure 3). Perception of telemedicine during the pandemic This article is protected by copyright. All rights reserved When asked about their perception of the usefulness of telephone visits during confinement, 124 patients (48.6%) stated they were very satisfied, and 90 (35.3%) were quite satisfied. Seven patients (2.7%) reported that the visits were unsatisfactory, and some refused to answer (n=34; Accepted Article 13.3%). None of the clinical factors were predictive of a better opinion of telemedicine in this setting. For future follow-ups, 97 (38%) patients considered it useful to conduct telephone visits, while 93 (36.5%) preferred face-to-face visits. Fifty-five patients (21.6%) said they did not prefer one of these options over the other, and nine patients (3.5%) refused to answer. Interestingly, five patients (2%) spontaneously mentioned that they would like to try a video call option. In the analysis of clinical factors potentially predictive of a better perception of telemedicine in the future, patients with a greater fear for COVID-19 felt positive about conducting telephone visits (49.2% had expressed this fear vs. 30.1% of patients who preferred face-to-face visits; p=0.037). A non-significantly higher percentage of patients with drug resistant-epilepsy preferred face-to- face visits (28% vs. 18.4% of those preferring telemedicine visits; p=0.081). COVID-19 in epilepsy patients Five patients (2%) had a diagnosis of SARS-CoV-2 infection based on PCR detection in a nasal and/or oropharyngeal smear, and all of them required hospital admission. None received mechanical ventilation, and two patients (0.78% of the total sample) died. All five patients received their usual AED treatment, and no changes in seizure frequency were reported. Details on COVID-19 disease in these patients are provided in Table 3. Twenty-three patients (9%) reported symptoms compatible with mild COVID-19, but had no confirmatory diagnostic test. None of these patients received specific COVID-19 treatment. Nineteen of them (82.6%) reported no changes in seizure frequency, while four patients (17.4%) reported increased frequency. Twenty-one (91.3%) of the possible COVID-19 patients remained under the same AED treatment, and two (8.7%) had treatment changes, one because of a prescription change due to increased seizure frequency and one because of missed AED doses. Patients with confirmed COVID-19 infection had a higher mean mRS score (3, IQR 2.5-4 vs. 1, IQR 1-2; p=0.005) than patients with mild symptoms suggestive of COVID-19 without a confirmed laboratory diagnosis, and there was a higher percentage of men (100% vs. 30.4%; This article is protected by copyright. All rights reserved p=0.008) and ADL-dependent patients (80% vs. 17.4%; p=0.015). In addition, confirmed COVID- 19 patients were older (mean age 62.5±24.5 vs. 46.3±22.8; p=0.165) and had a higher percentage of vascular etiologies (40% vs. 10%; p=0.099), but the differences did not reach statistical Accepted Article significance. DISCUSSION This study assesses the impact of the COVID-19 pandemic on epilepsy patients with regard to seizure control, emerging symptoms, and other key indicators. The results show that nearly 10% of patients experienced an increase in seizure frequency during the confinement measures, almost half of them reported having anxiety and/or depression symptoms, and nearly 30% experienced insomnia in this context. Some information is available on the impact of the pandemic on several medical specialties,16 but there is scarce evidence on how it affects patients with chronic neurological disorders, such as epilepsy. Our results provide an overview of the consequences of the confinement measures and restructuring of the healthcare system. Our sample is a real-life cohort of patients attended in an epilepsy clinic. All patients were assessed by a trained epileptologist, and the epilepsy diagnosis and classification were accurately performed in each case. The percentage of treatment-refractory epilepsy patients was similar to the expected rate in the general epilepsy population,17 and patients with intellectual disability and dependence for daily living activities were included. Hence, the sample is diverse and representative of the usual patient profile assessed in a tertiary hospital epilepsy clinic. We found several collateral effects of the pandemic in this sample of patients. A delay in epilepsy- related tests occurred in 15% of patients. However, this value may be underestimated, as patients with a first unprovoked seizure who were not as yet formally diagnosed with epilepsy were excluded from the analysis. It is likely that examinations were delayed in new-onset seizures during the lockdown. The percentage of patients reporting difficulties with their medication supply was found to be low. The survey was conducted between four and six weeks after the start of confinement measures and no drug supply problems have been reported in Spain to date, although this is a potential problem to keep in mind for the long-term that depends on the particularities of pharmaceutical regulation in each country. Almost 30% of patients experienced a negative economic impact related to the pandemic and confinement measures, and this factor was independently associated with an increase in seizure This article is protected by copyright. All rights reserved frequency. This is an intriguing finding and a cause for concern. Epilepsy patients are known to be at higher risk of employment difficulties and sociodemographic vulnerability,18,19 and the socioeconomic impact of the pandemic could have devastating consequences in the epilepsy Accepted Article population worldwide. A high percentage of epilepsy patients experienced anxiety and depression symptoms, as well as insomnia during the confinement measures. Almost half the patients in our study reported one or more of these symptoms, in line with recent evidence from west China showing that severe psychological distress occurred in epilepsy patients during COVID-19 outbreak20. The magnitude of these manifestations cannot be accurately assessed in a survey analysis, but they provide an approximation of the overall psychological burden of the situation in this population. Anxiety and insomnia were also independently associated with an increase in seizure frequency. This gives an indication of the negative effect these symptoms may have on the overall health state of epilepsy patients, a concept that has been proposed by previous evidence21. Sleep deprivation is a known precipitating factor for seizures, and our results are in the line with those reported in the literature, where psychiatric comorbidities have been identified as risk factors for seizure recurrence and pharmacoresistance.17,22,23 Nearly one in every ten epilepsy patients reported an increase in seizure frequency since the start of confinement measures. This result deserves special attention from clinicians, as a significant number of patients may be at risk of breakthrough seizures during this exceptional situation. Tumor-related and drug-resistant epilepsy, the presence of insomnia, and income reductions were identified as independent risk factors for worsening seizure frequency. The two particular types of epilepsy mentioned represent a more difficult-to-treat patient population24. Also, drug-resistant epilepsy has been associated with severe psychological distress during the pandemic20, and our results highlight the need for special attention to these patients. Moreover, a reduction in economic income, in itself, can be a major source of anxiety, depression and insomnia, and therefore, a stress-precipitating factor. Interestingly, the fear of epilepsy was also associated with an increase in seizures. This can be understood as adequate insight on the patients’ part about their disease and its control, and it should be taken into account when patients seek medical attention. On the other hand, a small proportion of patients reported a reduction in seizure frequency during the confinement period. This is an interesting finding, which could represent a spontaneous fluctuation for some patients, but also indicates that a certain beneficial effect of confinement This article is protected by copyright. All rights reserved measures could exist in some particular cases, in terms of schedule and lifestyle regularity and reduction in work stress. However, this small number of patients does not allow making assumptions in this matter, and the negative impact seems to prevail in the overall population of Accepted Article our study, in line with recent literature25. The presence of three or more of the risk factors identified here elevated the risk of a seizure frequency increase to 40%, and to our knowledge, no further data related to this issue are available. These findings might be useful to identify the most vulnerable patients in this particular setting who could require closer monitoring. The use of communication technology to provide medical information has been investigated in chronic diseases and in epilepsy,26,27 and the unprecedented situation we are currently facing offers a unique scenario in which telemedicine has become an essential tool. According to the recently provided recommendations, telehealth should be prioritized if possible in the current situation,7 and in fact our patients had an overall positive opinion of telephone visits during the pandemic. It is likely that the use of more developed tools (i.e. video call) offers a more profitable use of telehealth, since visual contact can help decrease anxiety and concerns regarding health problems. Regarding COVID-19 itself, five patients in our sample had confirmed SARS-CoV-2 infection. This represents a small proportion of patients included in the cohort. However, there was some bias in COVID-19 detection, as confirmatory diagnostic testing was not indicated in cases with mild symptoms, and many patients with mild symptoms did not consult with the health services. All five confirmed cases required hospitalization, and two patients had a fatal outcome. Epilepsy has not been identified as a risk factor for developing severe COVID-19.9,10 The five confirmed cases in our sample had a higher rate of previous disability and tended to be older than the mild cases, thus suggesting that they had other major risk factors for developing severe COVID-19. Men are also reported to be at higher risk of a poor outcome,28 and all five of our confirmed cases were men. The two deaths reported occurred in patients who were older than 70 years, with previous disability and several comorbidities predisposing to a severe COVID-19. Conclusions cannot be stated with such a small number of confirmed COVID-19 in our sample, but these findings suggest that severe and fatal COVID-19 was probably related to several baseline clinical risk factors other than epilepsy itself in these patients. None of these patients experienced worsening of seizure frequency, in line with a recently published multicenter study in which no This article is protected by copyright. All rights reserved evidence was found to establish a higher risk of acute symptomatic seizures in patients with COVID-19.29 This study has some limitations. The survey design inevitably implies that the data reported are Accepted Article subjective, particularly the presence of emerging symptoms such as anxiety and depression, which could not be quantified by standardized measurement tools. Also, changes in seizure frequency could not be evaluated by an accurate seizure diary given the study design during this period. In addition, the universal application of confinement measures and the diversity of patients and epilepsy types included prevents rigorous comparison with a normal situation, and some outcome measures might represent the natural course of the disease in particular cases. However, the study provides compelling new evidence on early collateral consequences of the COVID-19 pandemic in epilepsy patients. Further longitudinal, and multicenter studies are needed to establish these effects with more precision at the long term. CONCLUSION The COVID-19 pandemic and the confinement measures to control it can have an impact on patients with epilepsy. A significant number of patients experienced an increase in seizure frequency, and a high percentage reported anxiety, depressive symptoms, and insomnia. Tumor- related and drug-resistant epilepsy, the presence of insomnia, and a reduction in economic income were found to be risk factors for increased seizure frequency. Telemedicine emerged as a useful tool that was well accepted by patients to offer clinical assessment and mitigate the effects of physical distancing during confinement. CONFLICT OF INTEREST STATEMENT E. Fonseca declares research funding and speaker fees from UCB Pharma, Esteve laboratorios, Eisai Inc and Sanofi Genzyme. L. Abraira declares research funding and speaker fees from UCB Pharma, BIAL Pharmaceutical, EISAI Inc., Sanofi Genzyme and Esteve laboratorios. E. Santamarina declares research funding and speaker fees from UCB Pharma, BIAL Pharmaceutical, EISAI Inc. Arvelle and Esteve laboratorios. I. Seijo-Raposo declares research funding from UCB Pharma, Neuraxpharm and GW pharmaceuticals. M. Toledo declares research funding and speaker fees from UCB Pharma, BIAL Pharmaceutical, EISAI Inc., Sanofi, Arvelle and Esteve laboratorios. M Quintana, S. Lallana and JL. Restrepo have no conflicts of interest to declare. This article is protected by copyright. All rights reserved DATA AVAILABILITY STATEMENT After publication, anonymized data supporting the findings of this study are available from the corresponding author upon reasonable request from any qualified investigator. Accepted Article ETHICAL PUBLICATION STATEMENT We confirm that we have read the Journal’s position on issues concerning ethical publication and affirm that this report is consistent with those guidelines. REFERENCES 1. WHO-China Joint Mission. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). https://reliefweb.int/sites/reliefweb.int/files/resources/who- china-joint-mission-on-covid-19-final-report.pdf. Accessed April 18, 2020. 2. Coronavirus (COVID-19) events as they happen. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen. Accessed April 18, 2020. 3. WHO COVID-19 Dashboard. https://covid19.who.int/. Accessed April 22, 2020. 4. Situación de COVID-19 o Coronavirus en España. https://covid19.isciii.es/. Accessed April 18, 2020. 5. Verelst F, Kuylen E, Beutels P. Indications for healthcare surge capacity in European countries facing an exponential increase in coronavirus disease (COVID-19) cases, March 2020. Eurosurveillance. 2020;25(13):2000323. doi:10.2807/1560- 7917.es.2020.25.13.2000323 6. Keesara S, Jonas A, Schulman K. Covid-19 and Health Care’s Digital Revolution. N Engl J Med. April 2020. doi:10.1056/nejmp2005835 7. French JA, Brodie MJ, Caraballo R, et al. Keeping people with epilepsy safe during the Covid-19 pandemic. Neurology. April 2020:10.1212/WNL.0000000000009632. doi:10.1212/wnl.0000000000009632 8. Impact of COVID-19 on management of epilepsy - eanpages. This article is protected by copyright. All rights reserved https://www.eanpages.org/2020/04/03/impact-of-covid-19-on-management-of-epilepsy/. Accessed June 3, 2020. 9. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities in the novel Wuhan Accepted Article coronavirus (COVID-19) infection: a systematic review and meta-analysis. Int J Infect Dis. March 2020. doi:10.1016/j.ijid.2020.03.017 10. Hu Y, Sun J, Dai Z, et al. Prevalence and severity of corona virus disease 2019 (COVID- 19): A systematic review and meta-analysis. J Clin Virol. April 2020:104371. doi:10.1016/j.jcv.2020.104371 11. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE Official Report: A practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475-482. doi:10.1111/epi.12550 12. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512-521. doi:10.1111/epi.13709 13. Banks JL, Marotta CA. Outcomes validity and reliability of the modified rankin scale: Implications for stroke clinical trials - A literature review and synthesis. Stroke. 2007;38(3):1091-1096. doi:10.1161/01.STR.0000258355.23810.c6 14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®) - American Psychiatric Association - Google Libros. Fifth.; 213AD. https://books.google.es/books?id=-JivBAAAQBAJ&printsec=frontcover&dq=dsm- 5&hl=es&sa=X&ved=0ahUKEwin5a7OrvfoAhWIDxQKHcj9A54Q6AEINDAB#v=onepa ge&q=dsm-5&f=false. Accessed April 20, 2020. 15. Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. February 2020. doi:10.1056/nejmoa2002032 16. Ammar A, Stock AD, Holland R, Gelfand Y, Altschul D. Managing a Specialty Service During the COVID-19 Crisis. Acad Med. April 2020:1. doi:10.1097/ACM.0000000000003440 17. Kalilani L, Sun X, Pelgrims B, Noack-Rink M, Villanueva V. The epidemiology of drug- resistant epilepsy: A systematic review and meta-analysis. Epilepsia. 2018;59(12):2179- This article is protected by copyright. All rights reserved 2193. doi:10.1111/epi.14596 18. Steer S, Pickrell WO, Kerr MP, Thomas RH. Epilepsy prevalence and socioeconomic deprivation in England. Epilepsia. 2014;55(10):1634-1641. doi:10.1111/epi.12763 Accepted Article 19. Espinosa-Jovel C, Toledano R, Aledo-Serrano Á, García-Morales I, Gil-Nagel A. Epidemiological profile of epilepsy in low income populations. Seizure. 2018;56:67-72. doi:10.1016/j.seizure.2018.02.002 20. Hao X, Zhou D, Li Z, et al. Severe psychological distress among epilepsy patients during the COVID-19 outbreak in southwest China. Epilepsia. 2020. doi:10.1111/epi.16544 21. Novakova B, Harris PR, Ponnusamy A, Reuber M. The role of stress as a trigger for epileptic seizures: A narrative review of evidence from human and animal studies. Epilepsia. 2013;54(11):1866-1876. doi:10.1111/epi.12377 22. Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007;75(2-3):192-196. doi:10.1016/j.eplepsyres.2007.06.003 23. Petrovski S, Szoeke CEI, Jones NC, et al. Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients. Neurology. 2010;75(11):1015-1021. doi:10.1212/WNL.0b013e3181f25b16 24. Moots PL, Maciunas RJ, Eisert DR, Parker RA, Laporte K, Khalil BA. The Course of Seizure Disorders in Patients with Malignant Gliomas. Arch Neurol. 1995;52(7):717-724. doi:10.1001/archneur.1995.00540310091021 25. Miller WR, Von Gaudecker J, Tanner A, Buelow JM. Epilepsy self-management during a pandemic: Experiences of people with epilepsy. Epilepsy Behav. 2020;111. doi:10.1016/j.yebeh.2020.107238 26. Chi NC, Demiris G. A systematic review of telehealth tools and interventions to support family caregivers. J Telemed Telecare. 2015;21(1):37-44. doi:10.1177/1357633X14562734 27. Tschamper MK, Jakobsen R. Parents’ experiences of videoconference as a tool for multidisciplinary information exchange for children with epilepsy and disability. J Clin Nurs. 2019;28(9-10):1506-1516. doi:10.1111/jocn.14755 28. Zhang J, Wang X, Jia X, et al. Risk factors for disease severity, unimprovement, and This article is protected by copyright. All rights reserved mortality of COVID-19 patients in Wuhan, China. Clin Microbiol Infect. April 2020. doi:10.1016/j.cmi.2020.04.012 29. Lu L, Xiong W, Liu D, et al. New‐onset acute symptomatic seizure and risk factors in Accepted Article Corona Virus Disease 2019: A Retrospective Multicenter Study. Epilepsia. April 2020:epi.16524. doi:10.1111/epi.16524 This article is protected by copyright. All rights reserved Table 1. Demographic and clinical characteristics of epilepsy patients included in the study Age, years, mean ± SD (range) 48.2 ± 19.8 (17 – 94) Sex, n (%) Male 134 (52.5) Accepted Article Female 121 (47.5) Type of epilepsy, n (%) Focal 223 (87.5) Generalized 30 (11.8) Unclassifiable 2 (0.8) Etiology, n (%) Unknown 76 (29.8) Genetic† 34 (13.3) Vascular 33 (12.9) Tumor 29 (11.4) Perinatal anoxia 17 (6.7) Mesial temporal sclerosis 15 (5.9) Post-traumatic 13 (5.1) Infectious disease 11 (4.3) Malformations of cortical 10 (3.9) development Inflammatory/Autoimmune 5 (2) Post-anoxic encephalopathy 4 (1.6) Toxic/Metabolic 3 (1.2) Other 5 (2) Intellectual disability, n (%) 47 (18.4) Dysphagia, n (%) 20 (7.8) mRS, n (%) 0 25 (9.8) 1 94 (36.9) 2 67 (26.3) 3 41 (16.1) 4 26 (10.2) 5 2 (0.8) Dependence for ADL, n (%) 70 (27.5) Number of AEDs, n (%) 0 5 (2) 1 126 (49.4) 2 74 (29) 3 36 (14.1) This article is protected by copyright. All rights reserved 4 14 (5.5) Drug-resistant epilepsy, n (%) 56 (22) Usual place of residence, n (%) Own home 162 (63.5) Accepted Article Parents’ or caregiver’s home 82 (32.2) Nursing home 10 (3.9) Other 1 (0.4) Current activity, n (%) Unable to work 88 (34.5) Employed 68 (26.7) Retired 53 (20.8) Unemployed 20 (7.8) Student 20 (7.8) Homemaker 6 (2.4) Person responding to the Patient 160 (62.7) survey, n (%) Family/Caregiver 95 (37.3) †Genetic generalized epilepsy (formerly referred to as idiopathic generalized epilepsy) was considered a genetic etiology. ADL, activity of daily living; AEDs, antiepileptic drugs; mRS, modified Rankin scale; SD, standard deviation This article is protected by copyright. All rights reserved Table 2. Demographic and clinical factors in patients with and without an increase in seizure frequency and significant differences between groups in the univariate analysis. Each clinical variable is represented as the percentage of patients who experienced an increase in seizure Accepted Article frequency (“Yes”) and those who did not (“No”). The clinical factors associated with increased seizures were tumor-related etiology with respect to other etiologies, drug-resistant epilepsy, the presence of anxiety and insomnia during confinement, fear of epilepsy, and an income reduction. *Variables with statistically significant differences. Demographic and clinical factors Increased seizure frequency during p-value confinement No (n=230) Yes (n=25) Age, years, mean ± SD 48.719.9 43.719.2 0.228 Sex, female 105 (45.7%) 16 (64%) 0.081 Type of Generalized 29 (12.6%) 1 (4%) epilepsy Focal 200 (87%) 23 (92%) 0.081 Unclassifiable 1 (0.4%) 1 (4%) Epilepsy Temporal 91 (45.3%) 10 (41.7%) foci Frontal 53 (26.4%) 7 (29.2%) Parietal 9 (4.5%) 0 (0%) 0.903 Posterior quadrant 8 (4%) 1 (4.2%) Unknown 40 (19.9%) 6 (25%) Etiology Unknown 70 (30.6%) 6 (24%) Tumor* 21 (9.1%) 8 (32%) Vascular 33 (14.3%) 0 (0%) Malformations of cortical 8 (3.5%) 2 (8%) development Infectious disease 11 (4.8%) 0 (0%) 0.011 Mesial temporal sclerosis 13 (5.7%) 2 (8%) Inflammatory/Autoimmune 3 (1.3%) 2 (8%) Toxic/Metabolic 2 (0.9%) 1 (4%) Post-traumatic 12 (5.2%) 1 (4%) Genetic 32 (13.9%) 2 (8%) This article is protected by copyright. All rights reserved Other 5 (2.2%) 0 (0%) Perinatal anoxia 16 (7%) 1 (4%) Post-anoxic 4 (1.7%) 0 (0%) Accepted Article encephalopathy Intellectual disability 42 (18.3%) 5 (20%) 0.789 Dysphagia 17 (7.4%) 3 (12%) 0.427 mRS 2 (1-3) 2 (1-2.5) 0.637 Dependence for ADLs 64 (27.8%) 6 (24%) 0.684 Number of AEDs 1 (1-2) 2 (1-3) 0.090 Drug-resistant epilepsy* 44 (19.1%) 12 (48%) 0.001 Anxiety* 84 (37.3%) 15 (60%) 0.028 Depression 46 (20.4%) 7 (28%) 0.381 Insomnia† 58 (25.7%) 14 (56%) 0.001 Worst None 60 (30.8%) 1 (4.3%) fear Epilepsy* 28 (14.4%) 9 (39.1%) 0.002 COVID-19 82 (42.1%) 8 (34.8%) Other 25 (12.8%) 5 (21.7%) Reduced income* 61 (26.9%) 12 (50%) 0.018 ADLs, activity of daily living; AEDs, antiepileptic drugs; mRS, modified Rankin scale. This article is protected by copyright. All rights reserved Table 3. Clinical features of confirmed COVID-19 cases in epilepsy patients Case 1 2 3 4 5 Sex, age Male, 38 Male, 82 Male, 83 Male, 74 Male, 33 Accepted Article (years) Epilepsy Focal, Focal, Focal, Focal, GGE diagnosis vascular vascular vascular infectious Vascular risk factors, atrial Vascular risk RBBB, Vascular risk fibrillation, factors, Comor- recurrent factors, ischemic Neurocysti- pacemaker, bidities nephritic hearth failure, heart disease, cercosis chronic renal colic stroke, COPD stroke, failure, SAH chronic renal failure Dysphagia No Yes Yes No No mRS 3 4 4 3 2 Fever, cough, Cough, Cough, Cough, COVID-19 headache, dyspnea, dyspnea, dyspnea, Cough, fever symptoms cough, fever fever fever odynophagi a Left lung Right basal Bilateral Bilateral X-ray No infiltrates infiltrate infiltrate infiltrates infiltrates No treatment No treatment AZM + COVID-19 AZM + AZM + due to due to DRV/c + treatment LPV/r + HCQ LPV/r + HCQ potential potential HCQ interactions interactions Death No No Yes Yes No AZM, azithromycin; COPD, chronic obstructive pulmonary disease; DRV/c, darunavir/cobicistat; GGE, genetic generalized epilepsy; LPV/r, lopinavir/ritonavir; mRS, modified Rankin scale; RBBB, right bundle branch block; SAH, subarachnoid hemorrhage This article is protected by copyright. All rights reserved FIGURE LEGENDS Figure 1. Flow chart of the patient recruitment process. PNES, psychogenic non-epileptic seizures; TIA, transient ischemic attack. Accepted Article Figure 2. Confinement-related emerging symptoms. A) proportion of patients reporting anxiety and depressive symptoms in the telephone survey. B: proportion of patients reporting sleep disturbances in the telephone survey. N/A: not applicable. Figure 3. Probability of increased seizure frequency depending on the cumulative association of 5 risk factors (tumor-related etiology, drug-resistant epilepsy, fear for epilepsy, insomnia and reduction of economic income). The bars represent groups of patients divided according to their number of accumulated risk factors (0, 1, 2 and ≥ 3 risk factors). Error bars show the 95% CI. None of the patients with no risk factors reported an increase in seizure frequency, whereas the group with 3 or more risk factors showed the highest percentage of increased seizure frequency (40%). This article is protected by copyright. All rights reserved epted Arti pted Ar Accepted Article