Epilepsy mortality in Wales during COVID-19


                  Purpose
                  
                     : The COVID-19 pandemic has increased mortality worldwide and those with chronic conditions may have been disproportionally affected. However, it is unknown whether the pandemic has changed mortality rates for people with epilepsy. We aimed to compare mortality rates in people with epilepsy in Wales during the pandemic with pre-pandemic rates.
               
                  Methods
                  
                     : We performed a retrospective study using individual-level linked population-scale anonymised electronic health records. We identified deaths in people with epilepsy (DPWE), i.e. those with a diagnosis of epilepsy, and deaths associated with epilepsy (DAE), where epilepsy was recorded as a cause of death on death certificates. We compared death rates in 2020 with average rates in 2015–2019 using Poisson models to calculate death rate ratios.
               
                  Results
                  
                     : There were 188 DAE and 628 DPWE in Wales in 2020 (death rates: 7.7/100,000/year and 25.7/100,000/year). The average rates for DAE and DPWE from 2015–2019 were 5.8/100,000/year and 23.8/100,000/year, respectively. Death rate ratios (2020 compared to 2015–2019) for DAE were 1.34 (95%CI 1.14–1.57, p<0.001) and for DPWE were 1.08 (0.99–1.17, p=0.09). The death rate ratios for non-COVID deaths (deaths without COVID mentioned on death certificates) for DAE were 1.17 (0.99–1.39, p=0.06) and for DPWE were 0.96 (0.87–1.05, p=0.37).
               
                  Conclusions
                  
                     : The significant increase in DAE in Wales during 2020 could be explained by the direct effect of COVID-19 infection. Non-COVID-19 deaths have not increased significantly but further work is needed to assess the longer-term impact.
               

In addition to the direct effects of COVID-19, the pandemic has affected people with epilepsy in several ways. These include the impact of COVID-19 on mental health, health services, and healthcare seeking behaviour 3,4 . Non-pharmaceutical interventions to decrease virus transmission may have increased psychological stress, disrupted sleep, and reduced contact with vital social support networks 3 . There has been a significant decrease in consultations with health services for non-COVID-19 illnesses, including epilepsy, particularly at the onset of the pandemic. Specialist epilepsy services in Wales adapted rapidly to restrictions imposed during the pandemic, where virtual (telephone and video) epilepsy clinics became the norm from March 2020 onwards. This very significant restriction on face-to-face contact in specialist and primary care settings will have altered patient experience 4,5 . Each of these factors can potentially increase seizure frequency and, subsequently, the risk of death in people with epilepsy.
People with epilepsy already have an increased mortality risk when compared to the general population 6 . The timely assessment of changes in mortality is therefore important to target resources and potentially save lives. To our knowledge, there have been no population level studies on mortality rates in people with epilepsy during the COVID-19 pandemic. We used individual-level, population-scale routinely collected, electronic health record (EHR) data to compare mortality rates in people with epilepsy during the COVID-19 pandemic with background mortality rates.

METHOD
We used the Secure Anonymised Information Linkage (SAIL) Databank, which contains anonymised individual-level, population-scale routinely collected EHR data sources from multiple different sources. These include hospital admission and demographic data for the complete Welsh population (3.1 million) and primary care records for 80% of the population 7,8 .
Our study population consisted of all individuals living in Wales registered with a Welsh General Practice (GP) contributing data to SAIL during 1/1/2015-31/12/2020. We used primary care, death certificate and demographic data and analysed epilepsy-related deaths in two ways: Deaths associated with epilepsy (DAE) had an International Classification of Diseases version 10 (ICD10) code for epilepsy in any of the ten cause of death positions on death certificate data (see Supplementary information S1 for codes) 9 ; this included people who did not necessarily receive a diagnosis of epilepsy before death.

RESULTS
We analysed 14.9 million patient-years of data. The mean number of people with epilepsy was 24,560 and the mean population was 2,481,516 for each study year (2015-2020) (mean epilepsy prevalence=0.99%). During the study period, there were 904 deaths associated with epilepsy (DAE) and 3,595 deaths in people with epilepsy (DPWE). See Table 1 for deaths per year and Figure 1 and Supplementary   1, S4) also reflect monthly patterns in all-cause mortality with a significant peak occurring in April 2020 during the peak of the "first wave" of COVID-19 in Wales. There were lower rates in DAE and DPWE during summer months when COVID-19 rates were low.

Figure 1 All and non-COVID death rates per month in 2020 for: (A) deaths associated with epilepsy (DAE), (B) deaths in people with epilepsy (DPWE) and (C) all deaths in
Background rates of DPWE are around four times higher than DAE (23.8/100,000/year compared with 5.8/100,000/year). DAE are more likely to be directly related to epilepsy prompting the recording of the diagnosis on the death certificate. For example, deaths due to sudden death in epilepsy (SUDEP), status epilepticus, or injuries directly related to seizures. DPWE likely include more deaths not directly related to epilepsy.
We have been able to rapidly analyse contemporaneous individual-level population-scale healthcare data. We have used a validated method of ascertaining people with an established diagnosis of epilepsy to study deaths in people with epilepsy as well as for people with deaths associated with epilepsy. We have also completed a detailed comparison with background mortality rates in 2015-2019. Our analysis will allow for further, more detailed, assessment of the impact of the second UK wave of Covid-19 infections on people living with epilepsy and the longer-term impact on mortality.
Epilepsy is a heterogeneous disorder with many different causes, affecting people of all ages, with a high proportion of comorbidities. We have not accounted for these differences.
It may be that particular subgroups, for example older people with epilepsy or people with epilepsy and comorbid intellectual disability or dementia, have had differing mortality rates when compared with people with epilepsy as a whole, particularly given the strong association between age and COVID-19 mortality. Our method for identifying people with epilepsy would have included a proportion who have been seizure free at time of death, and this may have biased results. People living in areas of increased socioeconomic deprivation have increased epilepsy prevalence and have been disproportionally affected by COVID-we have not accounted for this in our analysis 11 . We also did not account for the position that epilepsy was recorded on the death certificate, which may influence the strength of association of epilepsy with the death.
There is likely a delay in epilepsy diagnoses recording in primary care and we were not able to record new diagnosis of epilepsy made from October 2020. This means that DPWE may be slightly higher than recorded here although these factors will not have affected our figures for DAE. Sudden and unexpected death in epilepsy (SUDEP) is a rare but devastating cause of death in people with epilepsy. We have not specifically looked at SUDEP as it is poorly coded in routinely collected data 12 .

CONCLUSION
In this population-scale study of epilepsy mortality we have found that deaths associated with epilepsy increased significantly in 2020 when compared with rates from 2015-2019. This is largely explained by COVID-19 related deaths as non-COVID-19 deaths associated with epilepsy and non-COVID-19 deaths in people with epilepsy have not increased significantly. Further research is necessary, such as sub-group analysis by age, epilepsy severity, and co-morbidity, to assess the longer-term impact of COVID on epilepsy, especially in vulnerable groups. This study makes use of anonymised data held in the Secure Anonymised Information Linkage (SAIL) Databank. We would like to acknowledge all the data providers who make anonymised data available for research. Approval for the use of data in this study, within the SAIL Databank, was granted by an independent information governance review panel (project 0696).
The work described here is consistent with the Journal's guidelines for ethical publication.
None of the authors have any conflicts of interest to disclose.