Health care utilization and mortality for people with epilepsy during COVID-19: A population study.

OBJECTIVE: This study was undertaken to characterize changes in health care utilization and mortality for people with epilepsy (PWE) during the COVID-19 pandemic. METHODS: We performed a retrospective study using linked, individual-level, population-scale anonymized health data from the Secure Anonymised Information Linkage databank. We identified PWE living in Wales during the study "pandemic period" (January 1, 2020-June 30, 2021) and during a "prepandemic" period (January 1, 2016-December 31, 2019). We compared prepandemic health care utilization, status epilepticus, and mortality rates with corresponding pandemic rates for PWE and people without epilepsy (PWOE). We performed subgroup analyses on children (<18 years old), older people (>65 years old), those with intellectual disability, and those living in the most deprived areas. We used Poisson models to calculate adjusted rate ratios (RRs). RESULTS: We identified 27 279 PWE who had significantly higher rates of hospital (50.3 visits/1000 patient months), emergency department (55.7), and outpatient attendance (172.4) when compared to PWOE (corresponding figures: 25.7, 25.2, and 87.0) in the prepandemic period. Hospital and epilepsy-related hospital admissions, and emergency department and outpatient attendances all reduced significantly for PWE (and all subgroups) during the pandemic period. RRs [95% confidence intervals (CIs)] for pandemic versus prepandemic periods were .70 [.69-.72], .77 [.73-.81], .78 [.77-.79], and .80 [.79-.81]. The corresponding rates also reduced for PWOE. New epilepsy diagnosis rates decreased during the pandemic compared with the prepandemic period (2.3/100 000/month cf. 3.1/100 000/month, RR = .73, 95% CI = .68-.78). Both all-cause deaths and deaths with epilepsy recorded on the death certificate increased for PWE during the pandemic (RR = 1.07, 95% CI = .997-1.145 and RR = 2.44, 95% CI = 2.12-2.81). When removing COVID deaths, RRs were .88 (95% CI = .81-.95) and 1.29 (95% CI = 1.08-1.53). Status epilepticus rates did not change significantly during the pandemic (RR = .95, 95% CI = .78-1.15). SIGNIFICANCE: All-cause non-COVID deaths did not increase but non-COVID deaths associated with epilepsy did increase for PWE during the COVID-19 pandemic. The longer term effects of the decrease in new epilepsy diagnoses and health care utilization and increase in deaths associated with epilepsy need further research.

Epilepsy and the risk of COVID-19-related hospitalization and death: A population study.

OBJECTIVE: People with epilepsy (PWE) may be at an increased risk of severe COVID-19. It is important to characterize this risk to inform PWE and for future health and care planning. We assessed whether PWE were at higher risk of being hospitalized with, or dying from, COVID-19. METHODS: We performed a retrospective cohort study using linked, population-scale, anonymized electronic health records from the SAIL (Secure Anonymised Information Linkage) databank. This includes hospital admission and demographic data for the complete Welsh population (3.1 million) and primary care records for 86% of the population. We identified 27 279 PWE living in Wales during the study period (March 1, 2020 to June 30, 2021). Controls were identified using exact 5:1 matching (sex, age, and socioeconomic status). We defined COVID-19 deaths as having International Classification of Diseases, 10th Revision (ICD-10) codes for COVID-19 on death certificates or occurring within 28 days of a positive SARS-CoV-2 polymerase chain reaction (PCR) test. COVID-19 hospitalizations were defined as having a COVID-19 ICD-10 code for the reason for admission or occurring within 28 days of a positive SARS-CoV-2 PCR test. We recorded COVID-19 vaccinations and comorbidities known to increase the risk of COVID-19 hospitalization and death. We used Cox proportional hazard models to calculate hazard ratios. RESULTS: There were 158 (.58%) COVID-19 deaths and 933 (3.4%) COVID-19 hospitalizations in PWE, and 370 (.27%) deaths and 1871 (1.4%) hospitalizations in controls. Hazard ratios for COVID-19 death and hospitalization in PWE compared to controls were 2.15 (95% confidence interval [CI] = 1.78-2.59) and 2.15 (95% CI = 1.94-2.37), respectively. Adjusted hazard ratios (adjusted for comorbidities) for death and hospitalization were 1.32 (95% CI = 1.08-1.62) and 1.60 (95% CI = 1.44-1.78). SIGNIFICANCE: PWE are at increased risk of being hospitalized with, and dying from, COVID-19 when compared to age-, sex-, and deprivation-matched controls, even when adjusting for comorbidities. This may have implications for prioritizing future COVID-19 treatments and vaccinations for PWE.

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 to 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.

Epilepsy and seizures in young people with 22q11.2 deletion syndrome: Prevalence and links with other neurodevelopmental disorders.

OBJECTIVE: The true prevalence of epileptic seizures and epilepsy in 22q11.2 deletion syndrome (22q11.2DS) is unknown, because previous studies have relied on historical medical record review. Associations of epilepsy with other neurodevelopmental manifestations (eg, specific psychiatric diagnoses) remain unexplored. METHODS: The primary caregivers of 108 deletion carriers (mean age 13.6 years) and 60 control siblings (mean age 13.1 years) completed a validated epilepsy screening questionnaire. A subsample (n = 44) underwent a second assessment with interview, prolonged electroencephalography (EEG), and medical record and epileptologist review. Intelligence quotient (IQ), psychopathology, and other neurodevelopmental problems were examined using neurocognitive assessment and questionnaire/interview. RESULTS: Eleven percent (12/108) of deletion carriers had an epilepsy diagnosis (controls 0%, P = 0.004). Fifty-seven of the remaining 96 deletion carriers (59.4%) had seizures or seizurelike symptoms (controls 13.3%, 8/60, P < 0.001). A febrile seizure was reported for 24.1% (26/107) of cases (controls 0%, P < 0.001). One deletion carrier with a clinical history of epilepsy was diagnosed with an additional type of unprovoked seizure during the second assessment. One deletion carrier was newly diagnosed with epilepsy, and two more with possible nonmotor absence seizures. A positive screen on the epilepsy questionnaire was more likely in deletion carriers with lower performance IQ (odds ratio [OR] 0.96, P = 0.018), attention-deficit/hyperactivity disorder (ADHD) (OR 3.28, P = 0.021), autism symptoms (OR 3.86, P = 0.004), and indicative motor coordination disorder (OR 4.56, P = 0.021). SIGNIFICANCE: Even when accounting for deletion carriers diagnosed with epilepsy, reports of seizures and seizurelike symptoms are common. These may be "true" epileptic seizures in some cases, which are not recognized during routine clinical care. Febrile seizures were far more common in deletion carriers compared to known population risk. A propensity for seizures in 22q11.2DS was associated with cognitive impairment, psychopathology, and motor coordination problems. Future research is required to determine whether this reflects common neurobiologic risk pathways or is a consequence of recurrent seizures.

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.

Change over a 16-month period in the psychological well-being of mothers of girls and women with Rett syndrome.

PURPOSE: There is an emerging research literature on the experiences of family members of girls and women with Rett syndrome (RTT), but a lack of longitudinal data. METHODS: Fifty mothers whose daughters had RTT were surveyed 16-17 months after an earlier cross-sectional study. Measures completed at both time points focused on maternal positive and negative psychological well-being and their daughters' behavioral and emotional problems and RTT behavioral phenotype severity. RESULTS: Maternal stress, anxiety, and depression demonstrated at least moderate levels of stability. Maternal positive perceptions were also moderately stable over 16-17 months. Longitudinal analyses suggested that their daughters' behavioral and emotional problems rather than RTT behavioral phenotype severity predicted later maternal well-being. CONCLUSION: Mothers with RTT daughters experience chronic stress (persisting over time) but also ongoing positive perceptions. Practitioners should recognize positive perceptions and also consider targeted behavioral parent training to reduce behavior problems in individuals with RTT.

Discrimination, domestic violence, abuse, and other adverse life events in people with epilepsy: Population-based study to assess the burden of these events and their contribution to psychopathology.

OBJECTIVE: To quantify the experience of discrimination, domestic violence, abuse, and other stressful life events in people with epilepsy in comparison with the general population and people with other chronic conditions. To assess whether any excess relative burden of these adversities could explain the higher rates of depression in people with epilepsy. METHODS: The Adult Psychiatric Morbidity Survey 2007 used comprehensive interviews with 7,403 individuals living in private residences in England. Doctor-diagnosed epilepsy and other chronic conditions were established by self-report. Discrimination, domestic violence, physical and sexual abuse, and other stressful life events were assessed using computerized self-completion and a face-to-face interview, respectively. RESULTS: People with epilepsy were sevenfold more likely to have reported experiencing discrimination due to health problems (adjusted odds ratio [OR] 7.1; 95% confidence interval [CI] 3.1-16.3), than the general population without epilepsy. This estimate was substantially greater in people with epilepsy than for people with other chronic conditions. People with epilepsy also had greater odds of experiencing domestic violence and sexual abuse than the general population, although these associations were also found in people with other chronic conditions. There was less evidence of an association between epilepsy and a history of physical abuse or having a greater burden of other stressful life events. In exploratory analyses, assuming they lie on the causal pathway, discrimination, domestic violence, and sexual abuse explained 42.7% of the total effect of the relationship between epilepsy and depression or anxiety disorders. SIGNIFICANCE: People with epilepsy can face a range of psychosocial adversities and extensively report feeling discriminated against as compared to the general population. In addition, if confirmed in longitudinal studies, the results suggest that these psychosocial adversities may have a significant role in the development of psychiatric comorbidity and may be targets for future interventions.

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy.

BACKGROUND: Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. METHODS: We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. RESULTS: 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. CONCLUSIONS: We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults.

Psychological Well-Being of Mothers and Siblings in Families of Girls and Women with Rett Syndrome.

Few published studies have reported on the psychological well-being of family members of individuals with Rett syndrome (RTT). Eighty-seven mothers of girls and women with RTT completed a questionnaire survey about their daughters' behavioral phenotype, current health, and behavior problems, and their own and a sibling's well-being. Mothers reported increased anxiety but similar levels of depression when compared to a normative sample. Across all problem domains on the Strengths and Difficulties Questionnaire, child and adolescent siblings (n = 39) were reported by mothers to have fewer difficulties than a normative sample. The severity of their daughters' RTT behavioral phenotype predicted increased anxiety and stress for mothers. Increased RTT daughters' current health problems predicted more maternal perceptions of positive gain.

Epilepsy prevalence and socioeconomic deprivation in England.

OBJECTIVE: Epilepsy is more prevalent in areas of greater socioeconomic deprivation; however, the factors that comprise this deprivation are not understood. We aimed to investigate the association between epilepsy, individual elements of deprivation, and geographic region in order to identify modifiable elements. METHODS: Epilepsy prevalence was calculated via retrospective analysis of data recorded by general practitioners via the Quality and Outcomes Framework. The Index of Multiple Deprivation scores at Local Authority level for the entire population of England was employed. Epilepsy prevalence was evaluated for correlation against all seven indicators within the Indices of Multiple Deprivation. Data were analyzed including and excluding the city of London. RESULTS: Of the 37,699,503 patients in this study, 304,331 were registered as having epilepsy (prevalence 8 per 1,000; range 4.3-11.6). Positive correlation was seen with total Index of Multiple Deprivation score (r = 0.468, p < 0.01); education skills and training (r = 0.665, p < 0.01); employment deprivation (r = 0.629, p < 0.01); health deprivation and disability (r = 0.617, p < 0.01); income deprivation (r = 0.358, p < 0.01); crime (r = 0.232, p < 0.01); but not living environment (r = 0.079, p = 0.08). Negative correlation was seen between epilepsy prevalence and barriers to housing and services (r = -0.415, p < 0.01). When the data were analyzed excluding London, all correlations were strengthened. Epilepsy prevalence in adults varies by 2.5-fold across England, from 4.3 per 1,000 in Kensington and Chelsea to 11.6 per 1,000 in Blackpool. SIGNIFICANCE: This study shows a strong correlation between epilepsy prevalence and specific measures of socioeconomic deprivation. Many of these deprivation factors are potentially remediable. We hypothesize that people with epilepsy may move into urban areas and toward their general practitioner. This predominantly means an urban location but avoiding areas where the cost of living-particularly housing-is prohibitive, such as central London. The existing negative impact of epilepsy on employment and higher education may be exacerbated when people with epilepsy live in areas of greater socioeconomic deprivation.

Neuropsychiatric disease in patients with periventricular heterotopia.

Periventricular heterotopia (PH) is a disorder of neuronal migration. Previous clinical reports of PH have largely focused on the seizure-related and neurodevelopmental consequences of this condition. The authors report four unrelated individuals with PH, with particular emphasis on their behavioral and psychiatric morbidity. A review of the literature suggests that neuropsychiatric presentations are an underrecognized consequence of PH. Clinicians need to be alert to psychiatric complications associated with PH and related disorders of neuronal migration.

Translation of genetic findings to clinical practice in juvenile myoclonic epilepsy.

It has been estimated that JME (juvenile myoclonic epilepsy), when compared to other adult epilepsy syndromes, is most likely to have a genetic cause. However, decades of research have not brought us closer to finding a single 'JME gene' that is important on a population basis. Is this due in part to the genetic complexity of the syndrome, the cryptic nature of the genes of effect, or perhaps because JME is not one condition at all but many? Before we can begin to harness the power of next-generation sequencing techniques, we must first reduce JME down to lacunae of homogeneity--using increasingly more sophisticated phenotyping tools. The current technological advances in gene sequencing have been used to dramatic effect to identify single gene causes in rare syndromes and identify risk variants in malignancies. Filtering the variety of the human exome or genome down into a handful of biologically plausible candidates now relies on a pipeline of biostatistics, software, and functional analyses. It is simply unacceptable to return uncertain findings to the clinical domain and, therefore, it is crucial that pathogenicity is fully determined before families receive genetic counseling and test results.

Epilepsy and psychiatric comorbidity: a nationally representative population-based study.

PURPOSE: In a nationally representative population-based study in England, we estimated the burden of psychiatric and neurodevelopmental comorbidities in people with epilepsy. We investigated whether any overrepresentation of comorbidities could be explained by epilepsy being a chronic medical or neurologic condition, or by the confounding effect of demographic and socioeconomic factors or other health conditions. METHODS: The Adult Psychiatric Morbidity Survey 2007 comprised detailed interviews with 7,403 individuals living in private households in England. Doctor-diagnosed epilepsy (and asthma, diabetes, and migraine, chronic conditions for comparison) was ascertained by self-report, and extensive diagnostic and screening interviews were used to assess psychiatric and neurodevelopmental conditions. KEY FINDINGS: The estimated lifetime prevalence of epilepsy in the adult (≥ 16 years old) population of England was 1.2% (95% confidence interval [CI] 1.0-1.5). Almost one-third of the people with epilepsy had an International Classification of Diseases, Tenth Revision (ICD-10) anxiety or depressive disorder (compared with one in six people without epilepsy). Among these, social phobia and agoraphobia, generalized anxiety disorder, depression, and measures of suicidality had strong associations with epilepsy, which remained robust after accounting for potential confounders. These associations were consistently stronger than those in people with asthma or diabetes, and similar to those in people reporting migraine or chronic headaches. Epilepsy was also strongly associated with autism spectrum disorders (odds ratio [OR] 7.4, 95% CI 1.5-35.5) and possible eating disorders, and these associations were not evident in people with asthma, diabetes, or migraine. SIGNIFICANCE: Psychiatric and neurodevelopmental conditions were overrepresented in people with epilepsy. These associations were stronger than with other nonneurologic chronic conditions, and not explained by confounding. Some overlap in the psychopathology observed in epilepsy and migraine cannot rule out the presence of common pathways of psychiatric comorbidity in neurologic conditions. However, associations of epilepsy with conditions such as autism spectrum disorders point to comorbidities specific to epilepsy that may not be shared by other neurologic conditions.

Help-seeking and treatment preferences for depression in epilepsy.

Depression among people with a diagnosis of epilepsy is common, underrecognized, and undertreated, yet the reasons for this are unclear. In this study people with a diagnosis of epilepsy recruited from primary care were mailed a questionnaire covering help seeking for psychological distress, treatment preferences for depression, and current symptoms of depression using the Patient Health Questionnaire-2 (PHQ2). Eighty-six people with epilepsy responded to the survey and 44% of the sample reported they would not seek help if they were feeling stressed, worried, or low and it was affecting their daily lives. Almost 40% of the participants screened positive for current depression and PHQ2 scores were statistically unchanged over an average of 8.6 months. The most popular treatment for depression was advice from a general practitioner or from family and friends. The majority of respondents felt speed of treatment should take priority over receiving preferred treatment for depression care.

The psychosocial impact of epilepsy in adults with an intellectual disability.

Epilepsy has a pervasive impact on the quality of life, and thus the psychosocial well-being, of adults with an intellectual disability. Social and economical well-being appears to be affected by an increase in restrictions on activities and thus social contact. The population has very high rates of challenging behaviors and of mental illness. It is likely that these have a significant impact on epilepsy management. When populations with and without epilepsy are controlled for level of ability, no difference in prevalence of behavior or mental illness is seen between the populations. Current knowledge is limited on crucial issues such as the long-term effect of seizure disorder on mental health, quality of life, and cognition.

A randomized, double-blind, placebo-controlled trial of topiramate in adults with epilepsy and intellectual disability: impact on seizures, severity, and quality of life.

This randomized, double-blind, placebo-controlled UK trial evaluated the effect of topiramate as add-on therapy on seizure frequency, seizure severity, and quality of life in patients with epilepsy and intellectual disability. There were three phases: 4 weeks baseline, 18 weeks titration to 200-400 mg topiramate/day (adults) or 5-9 mg/kg/day (children), 12 weeks maintenance. Recruitment was low (88/120); analyses were underpowered. Seizure frequency varied enormously (median 17.7, maximum 1706.2). There was no significant difference in reduction in mean total seizure frequency or number of responders between the groups. Topiramate reduced seizure frequency by >30% from baseline (placebo 1%); post hoc analyses showed a trend toward significance (R ratio, P=0.052). There were no significant differences between the groups with respect to mean seizure severity or other outcome measures. Topiramate was generally well tolerated; body weight (P=0.015) and systolic blood pressure (P=0.043) were reduced. The study suggests that topiramate reduces seizure frequency in patients with epilepsy and intellectual disability without the added burden of behavior effects, and was potentially advantageous to physical well-being.

The outcome of initiation of antiepileptic drug monotherapy in primary care: a UK database survey.

We describe the incidence of newly treated epilepsy in primary care and patterns of antiepileptic drug prescription, numbers of patients who remain on initial therapy and health service utilisation. Data was collected from 100 general practices that subscribed to the Doctors Independent Network (DIN-LINK) project. Over the study period 1531 patients were identified, equating to an annual incidence rate of 36.3 per 100 000 (95% confidence interval [CI] = 32.1 to 40.8). Of these patients, 1465 (95.7%) were started on antiepileptic drugs. Overall, 1154 (78.8%) patients remained on the original monotherapy at the 12-month stage. Primary care consultations, secondary care referrals and emergency admissions were all increased for those whose treatment was changed either to polytherapy or an alternative monotherapy.