Elective inpatient video-EEG monitoring during the COVID-19 pandemic.

To evaluate the safety and feasibility of admission for elective video-EEG monitoring during the SARS-CoV-2 pandemic. We performed a retrospective review of elective inpatient epilepsy monitoring unit admissions at our institution from May 3rd, 2020 to August 12th, 2020. All patients were screened by telephone for symptoms concerning infection or recent diagnosis of SARS-CoV-2 or excess medical risk prior to admission. Patients deemed eligible for admission underwent testing via a nasopharyngeal swab for SARS-CoV-2 within three days of admission, and were directed to self-quarantine between testing and admission. The community seven-day case rate for SARS-CoV-2 (new cases per 100,000 population) ranged from 2.8 to 28.9 during the study period in our region. A total of 95 patients (63 adults and 32 children) were admitted. One adult patient developed mild SARS-CoV-2 infection and one adult patient tested positive for asymptomatic SARS-CoV-2 infection. These findings illustrate that inpatient epilepsy monitoring can be safely performed in carefully selected patients when appropriate processes are in place, even in the setting of the SARS-CoV-2 pandemic. There is a risk of nosocomial spread, and the potential benefits of admission should be balanced against the risks of infection.

Cannabis for Pediatric Epilepsy.

Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. Up to 30% of children with epilepsy will be refractory to standard anticonvulsant therapy, and those with epileptic encephalopathy can be particularly challenging to treat. The endocannabinoid system can modulate the physiologic processes underlying epileptogenesis. The anticonvulsant properties of several cannabinoids, namely Δ-tetrahydrocannabinol and cannabidiol (CBD), have been demonstrated in both in vitro and in vivo studies. Cannabis-based therapies have been used for millennia to treat a variety of diseases including epilepsy. Several studies have shown that CBD, both in isolation as a pharmaceutical-grade preparation or as part of a CBD-enriched cannabis herbal extract, is beneficial in decreasing seizure frequency in children with treatment-resistant epilepsy. Overall, cannabis herbal extracts appear to provide greater efficacy in decreasing seizure frequency, but the studies assessing cannabis herbal extract are either retrospective or small-scale observational studies. The two large randomized controlled studies assessing the efficacy of pharmaceutical-grade CBD in children with Dravet and Lennox-Gastaut syndromes showed similar efficacy to other anticonvulsants. Lack of data regarding appropriate dosing and pediatric pharmacokinetics continues to make authorization of cannabis-based therapies to children with treatment-resistant epilepsy challenging.

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study.

Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians.

The plant Cannabis sativa produces over 140 known cannabinoids. These chemicals generate considerable interest in the medical research community for their possible application to several intractable disease conditions. Recent reports have prompted parents to strongly consider Cannabis products to treat their children with drug resistant epilepsy. Physicians, though, are reluctant to prescribe Cannabis products due to confusion about their regulatory status and limited clinical data supporting their use. We provide the general paediatrician with a brief review of cannabinoid biology, the literature regarding their use in children with drug resistant epilepsy, the current Health Canada and Canadian Paediatric Society recommendations and also the regulations from the physician regulatory bodies for each province and territory. Given the complexities of conducting research on Cannabis products for children with epilepsy, we also discuss outstanding research objectives that must be addressed to support Cannabis products as an accepted treatment option for children with refractory epilepsy.

The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life. METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects. DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827.

Breaking the cycle: A comparison between intravenous immunoglobulins and high dosage prednisone in the treatment of medically intractable epilepsy in children.

PURPOSE: Because immune mediated mechanisms are suspected in epileptogenesis, IVIg and corticosteroids have been used as alternatives to treat refractory seizures. We present our experience treating intractable epileptic children with IVIg and prednisone. METHODS: Children with intractable epilepsy treated with prednisone or IVIg between 2005-2016 were reviewed retrospectively. Children with infantile spasms and autoimmune epilepsy were excluded. Data analyzed include epilepsy type and etiology, duration of epilepsy prior to treatment, seizure outcome, time to best seizure outcome, and adverse effects. RESULTS: Fifty-one patients were included: 26 received IVIg; 25 received prednisone. Etiologies were similar between cohorts: genetic (13 IVIg; 10 prednisone), lesional (8 IVIg; 7 prednisone), and unknown (5 IVIg; 8 prednisone). In the prednisone cohort, 92.0% had generalized epilepsy compared to 61.5% for IVIg. Among the IVIg treated, 84.6% responded (10 genetic, 4 unknown, and 8 lesional) with mean seizure reduction of 77.3% and mean time to best response of 9.8 weeks. With prednisone, 24.0% responded (2 genetic, 3 unknown, and 1 lesional) with a mean seizure reduction of 95.0% and mean time to best response of 2.7 weeks. Adverse effects occurred in 2 and 16 patients treated with IVIg and prednisone, respectively. The difference in responders and seizure reduction was statistically significant (p<0.0001 and p=0.001, respectively). CONCLUSION: IVIg had greater responders and lower adverse effects and honeymoon effect. This response was independent of epilepsy type, etiology, and duration suggesting different mechanisms of action between prednisone and IVIg and a common, reversible, immune-mediated pathway to intractability.

Quantitative phenotypic and network analysis of 1q44 microdeletion for microcephaly.

As genome wide techniques become more common, an increasing proportion of patients with intellectual disability (ID) are found to have genetic defects allowing genotype-phenotype correlations. Previously, AKT3 deletion was suggested to be responsible for microcephaly in patients with 1q43-q44 deletion syndrome, but this does not correspond to all cases. We report a case of a de novo 1q44 deletion in an 8-year-old boy with microcephaly in whom AKT3 is not deleted. We used a systematic review of the literature, our patient, and network analysis to gain a better understanding of the genetic basis of microcephaly in 1q deletion patients. Our analysis showed that while AKT3 deletion is associated with more severe (≤3 SD) microcephaly in 1q43-q44 deletion patients, other genes may contribute to microcephaly in AKT3 intact patients with microcephaly and 1q43-44 deletion syndrome. We identified a potential role for HNRNPU, SMYD3, NLRP3, and KIF26B in microcephaly. Overall, our study highlights the need for network analysis and quantitative measures reporting in the phenotypic analysis of a complex genetic syndrome related to copy number variation.

Canadian Paediatric Neurology Workforce Survey and Consensus Statement.

BACKGROUND: Little knowledge exists on the availability of academic and community paediatric neurology positions. This knowledge is crucial for making workforce decisions. Our study aimed to: 1) obtain information regarding the availability of positions for paediatric neurologists in academic centres; 2) survey paediatric neurology trainees regarding their perceptions of employment issues and career plans; 3) survey practicing community paediatric neurologists 4) convene a group of paediatric neurologists to develop consensus regarding how to address these workforce issues. METHODS: Surveys addressing workforce issues regarding paediatric neurology in Canada were sent to: 1) all paediatric neurology program directors in Canada (n=9) who then solicited information from division heads and from paediatric neurologists in surrounding areas; 2) paediatric neurology trainees in Canada (n=57) and; 3) community paediatric neurologists (n=27). A meeting was held with relevant stakeholders to develop a consensus on how to approach employment issues. RESULTS: The response rate was 100% from program directors, 57.9% from residents and 44% from community paediatric neurologists. We found that the number of projected positions in academic paediatric neurology is fewer than the number of paediatric neurologists that are being trained over the next five to ten years, despite a clinical need for paediatric neurologists. Paediatric neurology residents are concerned about job availability and desire more career counselling. CONCLUSIONS: There is a current and projected clinical demand for paediatric neurologists despite a lack of academic positions. Training programs should focus on community neurology as a viable career option.

Insight into the precuneus: a novel seizure semiology in a child with epilepsy arising from the right posterior precuneus.

To date, there is limited understanding of the role of the precuneus. fMRI studies have suggested its involvement in a wide spectrum of highly integrated tasks, including spatially-guided behaviour, visuo-spatial imagery, and consciousness. We present a patient with intractable parietal lobe epilepsy arising from a lesion localized to the right precuneus. Two seizure types with distinct semiologies were captured on video-EEG monitoring. The first type consisted of an urge described as a "feeling of wanting to move". On video analysis, the patient is seen to turn his head and body to his left. He remains conscious, he is able to answer questions and when asked, he can look to his right. This seizure was associated with an ictal pattern localized to the right parieto-occipital region. The second seizure type consisted of reading-induced visual distortion with macropsia and micropsia. Interictally, intermittent rhythmic slowing and spikes were seen and localized to the parietal midline and the right parieto-occipital regions. Our patient's seizures are positive phenomena of the right precuneus and its related processing network. They represent unique seizure semiologies that offer further insight into the role of the precuneus in spatial awareness, visuo-spatial processing and consciousness.

Gelastic seizures with dancing arising from the anterior prefrontal cortex.

AIM: This case report provides insight into the function of the anterior prefrontal cortex (aPFC), specifically Brodmann Area 10 (BA10), and its interconnectivity. METHOD: We present a 10-year-old patient with lesional epilepsy and ictal onset, localised to BA10 in the aPFC. RESULTS: Thirty-four seizures were recorded. All seizures involved a demonstration of elation with laughter that was associated with a variety of different patterns of complex motor behaviour that included performing specific celebratory movements and acting out a Michael Jackson dance move. Electrographically, the seizures were all stereotyped and arose from the right frontal region, followed by a distinct left temporal ictal rhythm that corresponded with the onset of the behaviours. The lesion in the right aPFC was identified as a mixed lesion with both dysembryoplastic neuroepithelial tumour cells and type II cortical dysplasia. CONCLUSION: The electrographic analysis and unique seizure semiology suggest a connection between the aPFC and the contralateral temporal lobe. This neural pathway appears to be involved in the activation of previously formed procedural memories, creating an intensely positive emotional experience.

Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.

BACKGROUND: Rasmussen's encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain. METHODS: Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. RESULTS: Four patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3ϵ, HLA-DRA, and TNFα together with several inflammasome-associated genes (IL-1ß, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n = 6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1ß, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1ß, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits. CONCLUSION: Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions.

Oral automatisms induced by stimulation of the mesial frontal cortex.

Extraoperative electrical stimulation is frequently used to identify eloquent areas in patients with pharmacoresistant epilepsy who undergo subdural grid evaluation for epilepsy surgery. Oral automatisms elicited by cortical stimulation have been described in the mesial temporal lobe, but also in the mesial frontal lobe, particularly the cingulate gyrus. However oral automatisms attributed to stimulation in the superior frontal gyrus without afterdischarges have never been reported. Herein we present two patients with right frontal lobe epilepsy with oral automatisms induced by electrical stimulation of the right mesial superior frontal gyrus.

A clinical and etiologic profile of spastic diplegia.

To identify the clinical and etiologic profile of children with spastic diplegia, the medical records of patients with spastic diplegia in a single practice over a 12-year period were systematically and retrospectively reviewed. Clinical factors and possible etiology based on investigations were identified. Univariate and binomial logistical regression analyses were undertaken to identify factors correlating with an etiologic determination. Chart review identified 54 children with spastic diplegia. There were 31 (57.4%) preterm children and 23 (42.6%) term children. Periventricular leukomalacia was diagnosed in 24 (44.4%) children (26.1% of term children, 58.1% of preterm children). An etiology was not identified in 25 (46.3%) children: 14 (60.9%) term children and 11 (35.5%) preterm children. Periventricular leukomalacia among all children correlated with a birth weight less than 2000 gm (P = 0.037), history of neonatal resuscitation (P = 0.004), and gestation less than 33 weeks (P = 0.001). Factors specifically associated with periventricular leukomalacia in term children were a problematic perinatal history (P = 0.011), a history of neonatal resuscitation (P = 0.011), and a history of neonatal respiratory distress (P = 0.046). Regression analysis revealed a correlation between an abnormal perinatal history and an etiology of periventricular leukomalacia among term children (odds ratio 8.67, 95% confidence interval 2.51-29.97, P = 0.001). Approximately half of all children with spastic diplegia encountered in clinical practice will have an etiology identified.

Outcomes in pediatric epilepsy: seeing through the fog.

To identify clinical and predictive features of outcome in cryptogenic epilepsy in pediatric neurology practice, the medical records of all patients with cryptogenic epilepsy (as defined by the International League Against Epilepsy) in a single pediatric neurology practice over a 12-year interval with at least 2 years of follow-up were systematically and retrospectively reviewed. Review revealed 60 children with cryptogenic epilepsy: 32 (53.3%) males, 11 (18.3%) prior febrile seizure, 9 (15.0%) developmental delay at onset, and 38 (63.3%) placement in regular classes. Twenty-two (35.7%) had generalized seizures. Mean follow-up after initiating antiepileptic medication was 53 months (range 24-128 months). Four (6.7%) were intractable; 4 (6.7%) had very poor outcomes; 8 (13.3%) had poor outcomes; 44 (73.3%) were well controlled. Sixteen (26.7%) and 31 (51.7%) had seizure recurrence within the last 12 and 24 months, respectively. Twenty-nine (48.3%) were seizure-free for at least 24 months. Factors associated with a poor outcome include seizure recurrence in the 6- to 12-month interval after therapy initiation (P = 0.006) and developmental delay at onset (P = 0.023). This case series suggests that children with cryptogenic epilepsy tend to have a favorable outcome. Seizure recurrence in the first months after therapy initiation and developmental delay apparent at onset are predictive of poor outcome.