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Pathogenic variants in KCNT1 have been associated with severe forms of epilepsy, typically sleep-related hypermotor epilepsy or epilepsy of infancy with migrating focal seizures. To show that pathogenic variants in KCNT1 can be associated with mild extra-frontal epilepsy, we report a KCNT1 family with a wide spectrum of phenotypes ranging from developmental and epileptic encephalopathy to mild focal epilepsy without cognitive regression and not consistent with sleep-related hypermotor epilepsy. A large Canadian family of Caucasian descent including 9 affected family members was recruited. Family members were phenotyped by direct interview and review of existing medical records. Clinical epilepsy gene panel analysis and exome sequencing were performed. Phenotypic information was available for five family members of which two had developmental and epileptic encephalopathy and three had normal development and focal epilepsy with presumed extra-frontal onset. All three had predominantly nocturnal seizures that did not show hyperkinetic features. All three reported clusters of seizures at night with a feeling of being unable to breathe associated with gasping for air, choking and/or repetitive swallowing possibly suggesting insular or opercular involvement. Genetic analysis identified a heterozygous KCNT1 c.2882G > A, p.Arg961His variant that was predicted to be deleterious. This family demonstrates that the phenotypic spectrum associated with KCNT1 pathogenic variants is broader than previously assumed. Our findings indicate that variants in KCNT1 can be associated with mild focal epilepsy and should not be excluded during variant interpretation in such patients based solely on gene–disease validity.

CDKL5 Deficiency Disorder (CDD) or CDKL5-associated epileptic encephalopathy (CAEE) is a distinct X-linked dominant epileptic encephalopathy that shares many features with Rett syndrome. In the past decade, mutations in CDKL5 gene were identified as part of the molecular heterogeneity of MECP2- negative Rett syndrome. CDD has increasingly gained recognition as a distinct molecular and clinical phenotype. Here we present four new patients with CDD: one with a clinical presentation of reflex seizures previously reported as a case report by the same group, and three cases with novel disease-causing mutations. The emerging distinct phenotype of CDD should allow the clinician to suspect the diagnosis early and avoid a lengthy diagnostic odyssey.

Key points Children with chronic debilitating illness and pain are increasingly using cannabis for medical purposes, particularly when conventional treatment options have limited benefit or substantial adverse effects. Caregivers are becoming aware of evidence that suggests medical cannabis provides

Objective To characterize the molecular and clinical phenotypic basis of developmental and epileptic encephalopathies caused by rare biallelic variants in CACNA2D2. Methods Two affected individuals from a family with clinical features of early onset epileptic encephalopathy were recruited for exome sequencing at the Centers for Mendelian Genomics to identify their molecular diagnosis. GeneMatcher facilitated identification of a second family with a shared candidate disease gene identified through clinical gene panel‐based testing. Results Rare biallelic CACNA2D2 variants have been previously reported in three families with developmental and epileptic encephalopathy, and one family with congenital ataxia. We identified three individuals in two unrelated families with novel homozygous rare variants in CACNA2D2 with clinical features of developmental and epileptic encephalopathy and cerebellar atrophy. Family 1 includes two affected siblings with a likely damaging homozygous rare missense variant c.1778G>C; p.(Arg593Pro) in CACNA2D2. Family 2 includes a proband with a homozygous rare nonsense variant c.485_486del; p.(Tyr162Ter) in CACNA2D2. We compared clinical and molecular findings from all nine individuals reported to date and note that cerebellar atrophy is shared among all. Interpretation Our study supports the candidacy of CACNA2D2 as a disease gene associated with a phenotypic spectrum of neurological disease that include features of developmental and epileptic encephalopathy, ataxia, and cerebellar atrophy. Age at presentation may affect apparent penetrance of neurogenetic trait manifestations and of a particular clinical neurological endophenotype, for example, seizures or ataxia.

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Objectives: The use of telemedicine has grown exponentially as an alternative to providing care to patients with epilepsy during the pandemic. We investigated the impact of the current pandemic among children with epilepsy from two distinct pediatric epilepsy centers. We also compared perceptions among those who received telemedicine against those who did not.Methods: We developed a questionnaire and invited families followed in Freiburg, Germany, and Calgary, Alberta, Canada, to participate during the initial 9 months of the pandemic. The survey contained 32 questions, 10 of which were stratified according to telemedicine exposure.Results: One hundred twenty-six families (80 in Freiburg, 46 in Calgary) participated, and 40.3% received telemedicine care. Most children (mean age 10.4 years, SD 5.1) had chronic epilepsy but poorly controlled seizures. Negative impacts were reported by 36 and 65% of families who had to reschedule appointments for visits and diagnostics, respectively. Nearly two-thirds of families reported no change in seizure frequency, while 18.2% reported either worsening or improvement of seizures. Although most families did not note behavioral changes, 28.2% reported behavior worsening. Families who received telemedicine care had a statistically significant reduction of parental self-reported anxiety level after virtual visits compared to those who did not experience telemedicine. Families with telemedicine consultations were more likely to consider future virtual care (84 vs. 65.2% of those without), even after the pandemic. Patient data safety, easy access to specialized services, and consistency with the same healthcare provider were graded as important in both centers, while a shorter waiting time was most relevant in Calgary.Conclusion: In our cohort, some children with epilepsy experienced increased seizures and worsening behavior during the first 9 months of the current pandemic. In addition, our data suggest that telemedicine might reduce parental anxiety symptoms, and families who experienced telehealth were more positive and open to similar appointments in the future.

The COVID-19 pandemic has had a major impact on clinical practice. Safe standards of practice are essential to protect health care workers while still allowing them to provide good care. The Canadian Society of Clinical Neurophysiologists, the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists have combined to review current published literature about safe practices for neurophysiology laboratories. Herein, we present the results of our review and provide our expert opinion regarding the safe practice of neurophysiology during the COVID-19 pandemic in Canada.

Anti-muscle specific tyrosine kinase antibody-associated myasthenia gravis (MuSK-MG) is a rare subtype of MG characterized by more frequent relapses and a clinical course that is refractory to standard treatments. Rituximab, a monoclonal antibody targeting CD20+ B cells, has been used effectively in the adult population to achieve stable remission. We describe a pediatric patient with MuSK-MG who demonstrated an excellent response to rituximab after failing standard therapy.

Objective Continuous spike and wave in slow-wave sleep (CSWS), an epileptic encephalopathy, occurs after perinatal stroke where it is associated with cognitive decline. CSWS features a distinct EEG pattern, electrical status epilepticus in sleep (ESES). Biomarkers for the prediction of ESES have not been identified but will facilitate earlier diagnosis and treatment. We hypothesized that spike-frequency and differences in power spectra would be predictive of subsequent ESES. Methods A cross-sectional study comparing EEG spike-frequency and Power before the development of ESES in patients with perinatal stroke, patients with focal epilepsy, and appropriate controls. Results 43 patients met the inclusion criteria; 11 stroke-ESES, 10 stroke controls, 14 epilepsy-ESES, 8 epilepsy controls. ESES patients had higher pre-diagnosis mean spike-frequency (24.0 ± 24 versus 6.6 ± 9.1 SW/min, p = 0.002) than patients that did not develop ESES; these differences present ~ 3 years before ESES diagnosis. Pre-diagnosis, normalized delta power (1–4 Hz) was higher in the stroke-ESES group (105.7 ± 58 dB/Hz) compared to stroke controls (57.4 ± 45 dB/Hz, p = 0.036). Conclusion Spike-frequency and delta power may represent EEG biomarkers of the risk of developing ESES in children with perinatal stroke. Significance EEG biomarkers may be used by clinicians to assess which patients are more at-risk for ESES. Using spike-frequency, clinicians may be able to identify patients at risk of developing ESES.

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) that presents with childhood developmental delay (especially speech delay), occasionally associated with epileptic encephalopathy, autism, or Rett-like syndrome. The majority of children described to date have been severely affected, with little to no expressive speech function, severe developmental delay, and cognitive impairment. Herein, five additional patients with BPAN identified in the same center in Canada are described, four with the typical severe phenotype and one with a milder phenotype. Our findings provide further evidence that a spectrum of severity exists for this rare and newly described condition. Challenges in identifying iron accumulation on brain MRI are also addressed. Additionally, the importance of including the WDR45 gene on epilepsy and Rett-like syndrome genetic panels is highlighted. Keywords: Iron accumulation, Neurodegeneration, Brain, BPAN, WDR45, Rett

Despite the introduction of therapeutic hypothermia, infants with moderate-to-severe hypoxic-ischemic encephalopathy remain at risk of mortality and morbidity. A dedicated service with standardized management protocols and improved communication may help improve care. We aimed to evaluate the impact of a dedicated neonatal neurocritical care service on short-term outcomes in infants with hypoxic-ischemic encephalopathy.We performed a retrospective cohort study (July 2008 to December 2017) on term and near-term infants admitted to two tertiary neonatal intensive care units with moderate-to-severe hypoxic-ischemic encephalopathy, before and after neonatal neurocritical care service implementation. The primary outcome was brain magnetic resonance imaging findings consistent with those of hypoxic-ischemic encephalopathy. Secondary outcomes included the cooling initiation rate, hospital stay duration, antiseizure medication use, and inotrope use. Regression analysis and interrupted time series analysis were performed after adjusting for confounding factors.In total, 216 infants with moderate-to-severe hypoxic-ischemic encephalopathy were analyzed-109 before and 107 after neonatal neurocritical care implementation. After adjusting for confounding factors, there was a significant reduction in primary outcomes (adjusted odds ratio: 0.3, confidence interval: 0.15 to 0.57, P 0.001) after neonatal neurocritical care implementation. Average hospital stay duration reduced by 5.2 days per infant (P = 0.03), identification of eligible infants for cooling improved (P 0.001), antiseizure medication use reduced (P = 0.001), and early inotropes use reduced (P = 0.04).Implementation of a neonatal neurocritical care service associated with decreased brain injury shortened the hospital stay duration and improved the care of infants with moderate-to-severe hypoxic-ischemic encephalopathy.

Surface electroencephalogram (EEG) recording remains the gold standard for noninvasive assessment of electrical brain activity. It is the most efficient way to diagnose and classify epilepsy syndromes as well as define the localization of the epileptogenic zone. The EEG is useful for management decisions and for establishing prognosis in some types of epilepsy. Electroencephalography is an evolving field in which new methods are being introduced. The Canadian Society of Clinical Neurophysiologists convened an expert panel to develop new national minimal guidelines. A comprehensive evidence review was conducted. This document is organized into 10 sections, including indications, recommendations for trained personnel, EEG yield, paediatric and neonatal EEGs, laboratory minimal standards, requisitions, reports, storage, safety measures, and quality assurance.

We present the case of an 8-month-old boy who presented with apparent life-threatening events later characterized as seizures in clusters. A total of 14 apneic episodes were observed within 24 hours before loading the patient with phenobarbital at which point the seizures stopped. There was no obvious explanation for his seizures. EEG revealed midline interictal discharges; MRI-head was normal; and all other investigations were normal. The patient’s stool was sent for virology with the clinical suspicion of benign infantile seizures associated with mild gastroenteritis (BISMG) despite lack of gastrointestinal symptoms. A small round virus was found. His clinical course followed the same progression as typical BISMG. This begs the question whether it is possible for virus in the stool to cause an asymptomatic gastrointestinal infection with its only clinical manifestation as seizures. We conclude that it may be possible for BISMG to present without gastrointestinal symptoms. As well, BISMG may be an unrecognized cause of apparent life-threatening events and should be considered in the differential diagnosis.

We report a teenager with childhood onset focal seizures associated with the chapeau de gendarme sign or ictal pouting of anterior insular lobe origin. The chapeau de gendarme sign has been associated with frontal lobe seizures in patients with focal epilepsy. However, in this case, stereo-electroencephalography (SEEG) localized seizures to the anterior insular cortex prior to her typical clinical manifestations. Surgical resection of the insular and frontal-lobe network resulted in seizure freedom. We propose that the anterior insular cortex should be a site of investigation during pre-surgical phase 2 evaluation in patients exhibiting the chapeau de gendarme sign during focal seizures., Highlights • Chapeau de gendarme seizures or ictal pouting could have insular lobe involvement at electrical seizure onset. • Phase 2 investigation should include insular monitoring when assessing for this kind of seizures. • Pediatric population could also have chapeau de gendarme or ictal pouting seizures. • Ripples were associated with epileptogenicity in insular cortex requiring resection.

Background: Despite advances in neonatal care, neonates with moderate to severe HIE are at high risk of mortality and morbidity. we report the impact of a dedicated NNCC team on short term mortality and morbidities. Methods: A retrospective cohort study on neonates with moderate to serve HIE between July 1st 2008 and December 31st 2017. primary outcome : a composite of death and/or brain injury on MRI. Secondary outcomes: rate of cooling, length of hospital stay, anti-seizure medication burden, and use of inotropes. A regression analysis was done adjusting for gestational age, birth weight, gender, out-born status, Apgar score at 10 minutes, cord blood pH, and HIE clinical staging Results: 216 neonates were included, 109 before NNCC implementation, and 107 thereafter. NNCC program resulted in reduction in the primary outcome (AOR: 0.28, CI: 0.14-0.54, pConclusions: NNCC program decreased mortality and brain injury , shortened the length of hospital stay and improved care of neonates with significant HIE.

Background: Therapeutic hypothermia (TH) improves the outcome in HIE but cvEEG is vital to detect any seizures that occur. Unfortunately, the costs associated with cvEEG can make it impractical. We studied outcomes in TH with the objective of optimizing the length of cvEEG required. Methods: Term infants with HIE were treated with 72 h of TH followed by 6 h of rewarming. cvEEG reports were quantified (background, sharp transients, seizures) and compared with pre and post-cooling variables to determine whether risk stratification was possible. Results: 25/78 infants had seizures during the TH, however, most seizures occurred early, with 7 infants seizing prior to cooling and 15 having their first seizure within 24h. Only 3 infants had their first seizure between 24-48h and none were recorded after. Novel seizures after 24h were brief and did not require treatment. EEG variables such as frequent sharp transients and first seizures within 24h were correlated with MRI abnormalities. Conclusions: For the majority of infants undergoing TH, 24h of cvEEG may be sufficient with few infants requiring longer than 48h. A combination of clinical variables (abnormal neurological exam) and EEG traits (frequency of discharges, seizures) can help to decide on the likelihood of seizures and length of EEG recording needed.

Objective: To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels. Methods: Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay. Results: Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13–75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances [8], ataxia [7], dysphagia [6], dysarthria [4], respiratory failure [3]). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea [6], gastroparesis, and constipation [3]), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndrome patients. Conclusions: DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems.

Objective:To examine how the introduction of amplitude-integrated electroencephalography (aEEG) to our neonatal intensive care unit (NICU) influenced clinical practice.Methods:This was a retrospective study examining clinical practice three years before and three years after the introduction of aEEG monitors to our NICU. A time series analysis was performed to explore whether aEEG introduction was associated with changes in the rates of conventional EEGs performed, neurology consultations and neonates diagnosed with seizures.Results:Following aEEG introduction, the total number of conventional EEGs performed remained constant; however, there was significant shift in conventional EEG utilization towards neonates receiving fewer multiple EEGs and more single EEGs. There was no change in the rate of neurology consultations or the number of neonates diagnosed with seizures.Conclusions:Introduction of aEEG monitors to our NICU has led to less reliance on conventional EEG as a tool for the serial evaluation of brain function. Since the number of neonates diagnosed with seizures did not increase, aEEG monitoring did not appear to uncover a significant subgroup of patients with subclinical seizures that would previously have gone undetected. Conventional EEG and aEEG are complementary tools for the assessment of newborn cerebral function.