Tadeu A. Fantaneanu

Objective: GRIN‐related disorders due to pathogenic variants in GRIN1 , GRIN2A , GRIN2B , or GRIN2D genes are associated with altered N‐methyl‐D‐aspartate receptor (NMDAR) function. Functional changes include gain (GoF) and loss of receptor function (LoF). Clinical reports describing the use of the NMDAR blocker memantine in GRIN‐related disorders show a diverse and inconsistent spectrum of treatment responses. Methods: To evaluate clinical responses to memantine, we collected retrospective data on 34 individuals with GRIN variants, including 20 unpublished and 14 published cases. Variants were reclassified following American College of Medical Genetics and Genomics guidelines, and six in vitro functional assays were used to assess receptor function. We compared individuals with pathogenic GoF versus LoF in terms of associated clinical improvements, memantine sensitivity, and variant localization within the gene. Results: In 19 of the 34 variants, a pathogenic likely or possible GoF of the receptor was detected. Fourteen of 19 individuals (74%) benefited from memantine, comprising improvements in behavior (71%), development (50%), and seizure frequency (39%). Individuals with either LoF or a functionally indeterminate or no effect GRIN variant (15/34 individuals) showed significantly less benefit from memantine treatment but nevertheless rare adverse events (3/15). An increased distance of the variant from the memantine binding site was associated with a clinical benefit. Significance: Our retrospective observational study outlines the importance of correct classification of GRIN variants with regard to pathogenicity and functional consequence prior to applying memantine or other precision medicine approaches in clinical trials. Furthermore, the distance from a GoF variant to the memantine binding site correlated with a positive treatment response and may, at least in part, explain different degrees of therapeutic benefit.

Continuous EEG (cEEG) is the gold standard for diagnosing nonconvulsive seizures (NCSs) and nonconvulsive status epilepticus (NCSE) in critically ill patients, with NCSE occurring in 8%-10% of patients with unexplained coma. Untreated NCSs are associated with secondary brain injury, as well as increased mortality and morbidity. cEEG monitoring allows clinicians to identify more than twice the number of seizures compared with a 30-min routine EEG recording. However, there are limited data on cEEG practices in Canadian hospitals. The aim of this study was to evaluate the availability, indications, and barriers to cEEG access in Canada. A national cross-sectional survey was distributed to EEG laboratory directors and physicians who interpret cEEGs to assess cEEG monitoring practices in Canadian adult hospitals. The survey evaluated institutional cEEG availability, clinical applications, and technical infrastructure. Among 1,267 adult hospitals in Canada, only 92 hospital networks (9%) were identified as having an EEG laboratory. Twenty-four were identified as potentially offering cEEG monitoring, and a survey was sent to a physician at these institutions. Responses were received from 22 institutions (92% response rate), with 19 hospital networks reporting cEEG availability-representing just 2% of Canadian hospitals. Geographic disparities were significant, with 3 provinces and all 3 territories lacking cEEG access. Among tertiary care hospitals, only 68% reported cEEG availability. Barriers included insufficient EEG technologist coverage and prolonged processing periods for 24-hour EEG recordings. Most institutions lacked standardized guidelines, were unable to perform new cEEG hookups after regular work hours, and did not have access to abbreviated montages when cEEG was unavailable. cEEG availability in Canada is highly limited, including at tertiary care centers, with significant geographic inequities and operational barriers. Most Canadian hospitals do not meet guideline standards for cEEG use. These findings highlight the need for systemic changes to improve cEEG access and align Canadian cEEG practices with international standards.

Objective: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency in the majority of cases. Caregivers of adults with DS often complain about the loss of previously acquired skills. We set out to explore these perceptions and determine whether abnormalities reported were detectable in validated tests. We also investigated possible correlations between symptoms, age, and exposure to sodium channel blockers (SCBs). Methods: This cross‐sectional, multicenter study used the Vineland Adaptive Behavior Scales, 3rd edition (raw scores) for behavior analyses and Moss–Psychiatric Assessment Schedules checklist to screen for psychiatric symptoms. The Social Communication Questionnaire screened for social communication deficits. Parkinsonian features were evaluated with the modified Unified Parkinson's Disease Rating Scale. For gait evaluation, we validated the use of home videos, using instrumental gait analysis in a subgroup of patients, and then used the home videos for the remainder. Results: A total of 92 patients were enrolled (age range = 18–51 years, mean = 27.93 ± 8.59 years). Sixty percent of caregivers observed a decline in previously acquired skills, including intelligence, speech, interaction with others, ability to climb stairs and walk without support, and hand coordination. Adaptive skills, parkinsonian symptoms, and gait were worse in older patients and those exposed to SCBs for longer periods of time. Fourteen percent of patients screened positive for affective disorders, 11.6% for dementia, and 10.5% for a psychotic disorder. Fifty‐three percent screened positive for social communication deficits. Significance: This is the largest group of adults with DS to be systematically evaluated. They had severe nonseizure symptoms. Older age and longer use of SCBs were associated with worse adaptive skills, gait, and parkinsonism. Some older adults screened positive for depression and dementia. Caregivers identified functional decline in activities of daily living (ADLs). Taken together, the risk of dementia, parkinsonian gait, and decline in ability to perform previously mastered ADLs support that some adults with DS may be developing a neurodegenerative disorder.

The Canadian League Against Epilepsy initiated a virtual epilepsy education program, conducting 29 webinars from March 2021 to September 2023. We report our experience, with the goal to inspire other groups to develop inclusive, equitable, and free educational spaces with a worldwide reach. Monthly sessions drew a median attendance of 118 participants, predominantly Canadian but also international, including physicians (58.9%) and trainees (22.8%). Post-webinar surveys (average 40% response rate) noted high satisfaction, a strong inclination to recommend the sessions, and an interest in clinical case-based topics. We plan to consider integrating a self-assessment section evaluating knowledge gained after each seminar.

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.