The impact of COVID-19 on people with epilepsy: Global results from the coronavirus and epilepsy study.

OBJECTIVE: To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID-19 pandemic and compare experiences in high-income countries (HICs) with non-HICs. METHODS: Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID-19 infections, the effect of COVID-related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non-HICs and HICs were compared using non-parametric Chi-square tests. RESULTS: Two thousand one hundred and  five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non-HICs and HICs reported COVID-19 infection (7%). Those in HICs were more likely to report that COVID-19 measures had affected their health (32% vs. 23%; p < 0.001). There was no difference between non-HICs and HICs in the proportion who reported difficulty in obtaining help for epilepsy. HCWs in non-HICs were more likely to report COVID-19 infection than those in HICs (18% vs 6%; p = 0.001) and that their clinical work had been affected by concerns about contracting COVID-19, lack of personal protective equipment, and the impact of the pandemic on mental health (all p < 0.001). Compared to pre-pandemic practices, there was a significant shift to remote consultations in both non-HICs and HICs (p < 0.001). SIGNIFICANCE: While the frequency of COVID-19 infection was relatively low in these data from early in the pandemic, our findings suggest broader health consequences and an increased psychosocial burden, particularly among HCWs in non-HICs. Planning for future pandemics should prioritize mental healthcare alongside ensuring access to essential epilepsy services and expanding and enhancing access to remote consultations. PLAIN LANGUAGE SUMMARY: We asked people with epilepsy about the effects of COVID-19 on their health and healthcare. We wanted to compare responses from people in high-income countries and other countries. We found that people in high-income countries and other countries had similar levels of difficulty in getting help for their epilepsy. People in high-income countries were more likely to say that their general health had been affected. Healthcare workers in non-high-income settings were more likely to have contracted COVID-19 and have the care they deliver affected by the pandemic. Across all settings, COVID-19 associated with a large shift to remote consultations.

Do germline genetic variants influence surgical outcomes in drug-resistant epilepsy?

OBJECTIVE: We retrospectively explored patients with drug-resistant epilepsy (DRE) who previously underwent presurgical evaluation to identify correlations between surgical outcomes and pathogenic variants in epilepsy genes. METHODS: Through an international collaboration, we evaluated adult DRE patients who were screened for surgical candidacy. Patients with pathogenic (P) or likely pathogenic (LP) germline variants in genes relevant to their epilepsy were included, regardless of whether the genetic diagnosis was made before or after the presurgical evaluation. Patients were divided into two groups: resective surgery (RS) and non-resective surgery candidates (NRSC), with the latter group further divided into: palliative surgery (vagus nerve stimulation, deep brain stimulation, responsive neurostimulation or corpus callosotomy) and no surgery. We compared surgical candidacy evaluations and postsurgical outcomes in patients with different genetic abnormalities. RESULTS: We identified 142 patients with P/LP variants. After presurgical evaluation, 36 patients underwent RS, while 106 patients were NRSC. Patients with variants in ion channel and synaptic transmission genes were more common in the NRSC group (48 %), compared with the RS group (14 %) (p<0.001). Most patients in the RS group had tuberous sclerosis complex. Almost half (17/36, 47 %) in the RS group had Engel class I or II outcomes. Patients with channelopathies were less likely to undergo a surgical procedure than patients with mTORopathies, but when deemed suitable for resection had better surgical outcomes (71 % versus 41 % with Engel I/II). Within the NRSC group, 40 underwent palliative surgery, with 26/40 (65 %) having ≥50 % seizure reduction after mean follow-up of 11 years. Favourable palliative surgery outcomes were observed across a diverse range of genetic epilepsies. SIGNIFICANCE: Genomic findings, including a channelopathy diagnosis, should not preclude presurgical evaluation or epilepsy surgery, and appropriately selected cases may have good surgical outcomes. Prospective registries of patients with monogenic epilepsies who undergo epilepsy surgery can provide additional insights on outcomes.

Translation to Portuguese and cross-cultural adaptation of the epilepsy transition readiness checklist for use in Brazil.

OBJECTIVES: Planning for the child and adolescent to have a safe handling in the epilepsy transition process is essential. In this work, the authors translated the "Readiness Checklists" and applied them to a group of patients and their respective caregivers in the transition process to assess the possibility of using them as a monitoring and instructional instrument. METHODS: The "Readiness Checklists" were applied to thirty adolescents with epilepsy and their caregivers. The original English version of this instrument underwent a process of translation and cultural adaptation by a translator with knowledge of English and epilepsy. Subsequently, it was carried out the back-translation and the Portuguese version was compared to the original, analyzing discrepancies, thus obtaining the final version for the Brazilian population. RESULTS: Participants were able to answer the questions. In four questions there was an association between the teenagers' educational level and the response pattern to the questionnaires. The authors found a strong positive correlation between the responses of adolescents and caregivers (RhoSpearman = 0.837; p < 0.001). The application of the questionnaire by the health team was feasible for all interviewed patients and their respective caregivers. CONCLUSION: The translation and application of the "Readiness Checklists" is feasible in Portuguese. Patients with lower educational levels felt less prepared for the transition than patients with higher educational levels, independently of age. Adolescents and caregivers showed similar perceptions regarding patients' abilities. The lists can be very useful tools to assess and plan the follow-up of the population of patients with epilepsy in the process of transition.

Evaluating the Current State of Epilepsy Care in the Province of Ontario.

There are numerous challenges pertaining to epilepsy care across Ontario, including Epilepsy Monitoring Unit (EMU) bed pressures, surgical access and community supports. We sampled the current clinical, community and operational state of Ontario epilepsy centres and community epilepsy agencies post COVID-19 pandemic. A 44-item survey was distributed to all 11 district and regional adult and paediatric Ontario epilepsy centres. Qualitative responses were collected from community epilepsy agencies. Results revealed ongoing gaps in epilepsy care across Ontario, with EMU bed pressures and labour shortages being limiting factors. A clinical network advising the Ontario Ministry of Health will improve access to epilepsy care.

Transition in epilepsy - A pilot study with patients in and outside of academic centers.

RATIONALE: Epilepsy is a complex condition and seizures are only one part of this disease. The move from pediatric to adult healthcare system proves difficult for many adolescents with epilepsy and their families. The challenges increase when patients have epilepsies associated with intellectual and/or developmental disabilities, autism spectrum disorder, and motor disorders. Knowledge and system gaps may exist between the two systems, adding to the challenges. The main goal of this study is to understand the perception of patients with epilepsy and their families who were preparing to move from pediatric to adult healthcare system or had already moved. METHODS: A survey was distributed to patients/caregivers of patients with epilepsy through patient support groups in North America and in-person through the 2019 Epilepsy Awareness Day at Disneyland. Patients were required to be 12 years or older at the time of the survey and were divided into two groups: those between 12 and 17 years and those 18 years or older. Caregivers answered on behalf of patients who were unable to respond (e.g., intellectual disability). Major components of the survey included demographics, epilepsy details, quality and access to care received in pediatric and adult years, and questions regarding transition and readiness. RESULTS: Responses were received from 58 patients/caregivers of patients with epilepsy from Canada and the United States. In group A (patients between 12 and 17 years), none of the 17-year-old patients were spoken to about transition. Patients (caregivers) with epilepsy and intellectual and/or developmental disabilities (IDD) had less time to discuss important things during the transition/transfer phase than patients with normal intelligence. Finally, there was a statistically significant difference observed in access to specialty care reported in the adult years, compared to the years in the pediatric system. In the group B (patients 18 years and older) a) 35 % still visit their family doctor for epilepsy related treatment despite the majority being on 2 or more antiseizure medications (ASMs); b) 27 % of patients in this group were still being followed by their pediatric neurologist; c) one patient received care only through visits to the emergency department; d) only 4 % felt that they received clear instructions during transfer of care such as knowing the name of the adult healthcare practitioner and/or the name of the care institution they were being transferred to. CONCLUSIONS: This study highlights the lack of appropriate transition to adult healthcare system (AHCS) amongst an unselected group of patients with epilepsy in Canada and United States. An overwhelming majority of patients followed in the community and in academy centers were simply "transferred" to an adult health practitioner, or they remained under the care of pediatricians. Finally, most patients lack access to significant social and medical support after moving to the AHCS.

Touch-screen automatisms in the digital age.

OBJECTIVE: To describe a novel set of gestural automatisms related to the use of digital screens on smartphones and tablets in patients with epilepsy. METHODS: Representative patients were selected from among those admitted to the Epilepsy Monitoring Unit at the Toronto Western Hospital between April 2016 and January 2020, and included if they exhibited automatisms clearly related to or mimicking digital device use. RESULTS: In total 5 patients were included, 4 female. All had temporal lobe epilepsy: 2 had left mesial temporal sclerosis and 3 had normal imaging. Nearly equal numbers of seizures began with right (5/9) and left (4/9) temporal onsets, with most automatisms occurring after seizure propagation to bilateral temporal involvement (6/9). Left-handed automatisms were most common (8/9). The majority of the automatisms (7/9) were perseverative on device usage prior to the seizure. CONCLUSION: Gestural automatisms appear related to the contemporary lived experience, culture, and habitual behaviour of patients with epilepsy. In the modern era, the use of smartphones and tablets are both common and habitual for many, and this case series shows that touch-screen automatisms may be added to the semiological panoply of temporal lobe seizures.

Translation to Portuguese and cross-cultural adaptation of the epilepsy transition readiness checklist for use in Brazil

Abstract Objectives: Planning for the child and adolescent to have a safe handling in the epilepsy transition process is essential. In this work, the authors translated the "Readiness Checklists" and applied them to a group of patients and their respective caregivers in the transition process to assess the possibility of using them as a monitoring and instructional instrument. Methods: The "Readiness Checklists" were applied to thirty adolescents with epilepsy and their caregivers. The original English version of this instrument underwent a process of translation and cultural adaptation by a translator with knowledge of English and epilepsy. Subsequently, it was carried out the back-translation and the Portuguese version was compared to the original, analyzing discrepancies, thus obtaining the final version for the Brazilian population. Results: Participants were able to answer the questions. In four questions there was an association between the teenagers' educational level and the response pattern to the questionnaires. The authors found a strong positive correlation between the responses of adolescents and caregivers (RhoSpearman = 0.837; p < 0.001). The application of the questionnaire by the health team was feasible for all interviewed patients and their respective caregivers. Conclusion: The translation and application of the "Readiness Checklists" is feasible in Portuguese. Patients with lower educational levels felt less prepared for the transition than patients with higher educational levels, independently of age. Adolescents and caregivers showed similar perceptions regarding patients' abilities. The lists can be very useful tools to assess and plan the follow-up of the population of patients with epilepsy in the process of transition.

Adult Phenotype of SYNGAP1-DEE.

Background and Objectives: SYNGAP1 variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although SYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults with SYNGAP1 variants and epilepsy. Methods: Patients 18 years or older with DEE carrying likely pathogenic and pathogenic (LP/P) SYNGAP1 variants were recruited through physicians' practices and patient organization groups. We used standardized questionnaires to evaluate current seizures, medication use, sleep, gastrointestinal symptoms, pain response, gait, social communication disorder and adaptive skills of patients. We also assessed caregiver burden. Results: Fourteen unrelated adult patients (median: 21 years, range: 18-65 years) with SYNGAP1-DEE were identified, 11 with novel and 3 with known LP/P SYNGAP1 de novo variants. One patient with a partial exon 3 deletion had greater daily living skills and social skills than others with single-nucleotide variants. Ten of 14 (71%) patients had drug-resistant seizures, treated with a median of 2 antiseizure medications. All patients (100%) had abnormal pain processing. Sleep disturbances, social communication disorders, and aggressive/self-injurious behaviors were each reported in 86% of patients. Only half of adults could walk with minimal or no assistance. Toileting was normal in 29%, and 71% had constipation. No adult patients could read or understand verbal material at a sixth-grade level or higher. Aggressive/self-injurious behaviors were leading cause of caregiver burden. The oldest patient was aged 65 years; although nonambulant, she had walked independently when younger. Discussion: Seventy-one percent of patients with SYNGAP1-DEEs continue to have seizures when adults. Nonseizure comorbidities, especially aggression and self-injurious behaviors, are major management challenges in adults with SYNGAP1-DEE. Only 50% of adults can ambulate with minimal or no assistance. Almost all adult patients depend on caregivers for many activities of daily living. Prompt diagnostic genetic testing of adults with DEE can inform clinical care and guide outcomes of precision therapies.

Building the Bridge From Pediatric to Adult Neurological Care.

In this brief communication, we discuss the current landscape and unmet needs of pediatric to adult transition care in neurology. Optimizing transition care is a priority for patients, families, and providers with growing discussion in neurology. We also introduce the activities of the University of Toronto Pediatric-Adult Transition Working Group - a collaborative interdivisional and inter-subspeciality group of faculty, advanced-practice providers, trainees, and patient-family advisors pursuing collaboration with patients, families, and universities from across Canada. We envision that these efforts will result in a national neurology transition strategy that will inform designation of health authority attention and funding.

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Management of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: There are limited data about the treatment and management of epilepsy with eyelid myoclonia (EEM). The objective of this study was to determine areas of consensus among an international panel of experts for the management of EEM (formerly known as Jeavons syndrome). METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the treatment, other areas of management, and prognosis for EEM. RESULTS: There was a strong consensus for valproic acid as the first-line treatment, with levetiracetam or lamotrigine as preferable alternatives for women of childbearing age. There was a moderate consensus that ethosuximide and clobazam are also efficacious. There was a strong consensus to avoid sodium channel-blocking medications, except for lamotrigine, as they may worsen seizure control. There was consensus that seizures typically persist into adulthood, with remission occurring in <50% of patients. There was less agreement about other areas of management, including dietary therapy, lens therapy, candidacy for driving, and outcome. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the optimal management of EEM. These areas of consensus may inform clinical practice to improve the management of EEM. In addition, multiple areas with less agreement were identified, which highlight topics for further research.

Variation in prognosis and treatment outcome in juvenile myoclonic epilepsy: a Biology of Juvenile Myoclonic Epilepsy Consortium proposal for a practical definition and stratified medicine classifications.

Reliable definitions, classifications and prognostic models are the cornerstones of stratified medicine, but none of the current classifications systems in epilepsy address prognostic or outcome issues. Although heterogeneity is widely acknowledged within epilepsy syndromes, the significance of variation in electroclinical features, comorbidities and treatment response, as they relate to diagnostic and prognostic purposes, has not been explored. In this paper, we aim to provide an evidence-based definition of juvenile myoclonic epilepsy showing that with a predefined and limited set of mandatory features, variation in juvenile myoclonic epilepsy phenotype can be exploited for prognostic purposes. Our study is based on clinical data collected by the Biology of Juvenile Myoclonic Epilepsy Consortium augmented by literature data. We review prognosis research on mortality and seizure remission, predictors of antiseizure medication resistance and selected adverse drug events to valproate, levetiracetam and lamotrigine. Based on our analysis, a simplified set of diagnostic criteria for juvenile myoclonic epilepsy includes the following: (i) myoclonic jerks as mandatory seizure type; (ii) a circadian timing for myoclonia not mandatory for the diagnosis of juvenile myoclonic epilepsy; (iii) age of onset ranging from 6 to 40 years; (iv) generalized EEG abnormalities; and (v) intelligence conforming to population distribution. We find sufficient evidence to propose a predictive model of antiseizure medication resistance that emphasises (i) absence seizures as the strongest stratifying factor with regard to antiseizure medication resistance or seizure freedom for both sexes and (ii) sex as a major stratifying factor, revealing elevated odds of antiseizure medication resistance that correlates to self-report of catamenial and stress-related factors including sleep deprivation. In women, there are reduced odds of antiseizure medication resistance associated with EEG-measured or self-reported photosensitivity. In conclusion, by applying a simplified set of criteria to define phenotypic variations of juvenile myoclonic epilepsy, our paper proposes an evidence-based definition and prognostic stratification of juvenile myoclonic epilepsy. Further studies in existing data sets of individual patient data would be helpful to replicate our findings, and prospective studies in inception cohorts will contribute to validate them in real-world practice for juvenile myoclonic epilepsy management.

Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: The objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis. METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM. RESULTS: There was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic-clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug-resistant epilepsy. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.

A comprehensive narrative review of epilepsy with eyelid myoclonia.

Epilepsy with eyelid myoclonia (EEM) is a generalized epilepsy syndrome with childhood-onset and 2:1 female predominance that consists of: 1. eyelid myoclonia with or without absence seizures, 2. eye closure induced seizures or EEG paroxysms, 3. clinical or EEG photosensitivity. While eyelid myoclonia is the disease hallmark, other seizure types, including absence seizures and generalized tonic-clonic seizures, may be present. It is thought to have a genetic etiology, and around one-third of patients may have a positive family history of epilepsy. Recently, specific genetic mutations have been recognized in a minority patients, including in SYNGAP1, NEXMIF, RORB, and CHD2 genes. There are no randomized controlled trials in EEM, and the management literature is largely restricted to small retrospective studies. Broad-spectrum antiseizure medications such as valproate, levetiracetam, lamotrigine, and benzodiazepines are typically used. Seizures typically persist into adulthood, and drug-resistant epilepsy is reported in over 50%.

Hydrogel Based on Nanoclay and Gelatin Methacrylate Polymeric Matrix as a Potential Osteogenic Application.

A nanocomposite hydrogel has potentially applicability in the induction of osteogenesis. The hydrogel was synthesized using 1% gelatin methacrylate (GelMA), a biodegradable and bioactive polymer containing the structure of gelatin, denatured collagen derived from the extracellular bone matrix, and 6% laponite (Lap), a synthetic phyllosilicate of nanosized particles. Initially, 0.6 g of Lap was added to deionized water, and then a solution of GelMA/Igarcure was added under stirring and UV light for crosslinking. The spectra in the Fourier-transform infrared region showed bands that indicate the interaction between gelatin and methacrylate anhydride. X-ray diffraction patterns confirmed the presence of Lap and GelMA in the hydrogel. The thermogravimetric analysis suggested an increase in the thermal stability of the hydrogel with the presence of clay mineral. Rheological analysis showed that the hydrogel had a viscosity that allowed its injectability. The hydrogel did not show acute toxicity at any of the concentrations tested according to the Artemia salina lethality test. It showed cell viability more significant than 80% in the MTT test, which makes it suitable for in vivo osteogenic induction tests. The cell differentiation test showed the differentiation of stem cells into osteogenic cells. It indicates a material with the potential for osteogenic induction and possible application in bone tissue engineering.

Excluding Digenic Inheritance of PGAP2 and PGAP3 Variants in Mabry Syndrome (OMIM 239300) Patient: Phenotypic Spectrum Associated with PGAP2 Gene Variants in Hyperphosphatasia with Mental Retardation Syndrome-3 (HPMRS3).

We present a case report of a child with features of hyperphosphatasia with neurologic deficit (HPMRS) or Mabry syndrome (MIM 239300) with variants of unknown significance in two post-GPI attachments to proteins genes, PGAP2 and PGAP3, that underlie HPMRS 3 and 4. BACKGROUND: In addition to HPMRS 3 and 4, disruption of four phosphatidylinositol glycan (PIG) biosynthesis genes, PIGV, PIGO, PIGW and PIGY, result in HPMRS 1, 2, 5 and 6, respectively. METHODS: Targeted exome panel sequencing identified homozygous variants of unknown significance (VUS) in PGAP2 c:284A>G and PGAP3 c:259G>A. To assay the pathogenicity of these variants, we conducted a rescue assay in PGAP2 and PGAP3 deficient CHO cell lines. RESULTS: Using a strong (pME) promoter, the PGAP2 variant did not rescue activity in CHO cells and the protein was not detected. Flow cytometric analysis showed that CD59 and CD55 expression on the PGAP2 deficient cell line was not restored by variant PGAP2. By contrast, activity of the PGAP3 variant was similar to wild-type. CONCLUSIONS: For this patient with Mabry syndrome, the phenotype is likely to be predominantly HPMRS3: resulting from autosomal recessive inheritance of NM_001256240.2 PGAP2 c:284A>G, p.Tyr95Cys. We discuss strategies for establishing evidence for putative digenic inheritance in GPI deficiency disorders.