Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6.

OBJECTIVE: To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo-controlled, phase 3 trial in patients with drug-resistant epilepsy associated with tuberous sclerosis complex (TSC). METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4-week titration, 12-week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC-associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1-56.8) years. Patients had discontinued a median (range) of 4 (0-15) antiseizure medications and were currently taking 3 (0-5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in ≥50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients. SIGNIFICANCE: Onset of treatment effect occurred within 6-10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16-week trial in most patients.

Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy.

BACKGROUND: Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy. METHODS: In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). RESULTS: Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). CONCLUSIONS: Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02324673).

Focal cortical dysplasia is more common in boys than in girls.

Genetics and environment likely contribute to the development of medically intractable epilepsy; however, in most patients the specific combination of etiologies remains unknown. Here, we undertook a multicenter retrospective cohort study of sex distribution in pediatric patients undergoing epilepsy surgery and carried out a secondary analysis of the same population subdivided by histopathologic diagnosis. In the multicenter cohort of patients with intractable epilepsy undergoing surgery regardless of etiology (n=206), 63% were boys, which is significantly more boys than expected for the general population (Fisher exact two-tailed p=0.017). Subgroup analysis found that of the 90 patients with a histopathologic diagnosis of focal cortical dysplasia, 72% were boys, giving an odds ratio (OR) of 2.5 (95% CI, 1.34 to 4.62) for male sex. None of the other etiologies had a male sex predominance. Future studies could examine the biological relevance and potential genetic and pathophysiological mechanisms of this observation.

Vagus nerve stimulation for partial and generalized epilepsy from infancy to adolescence.

OBJECT: Vagus nerve stimulation (VNS) is approved by the FDA for the treatment of partial epilepsy in patients older than 12 years. Authors of the current study performed a large retrospective analysis and comparison of VNS outcomes in children with an age ≥ and < 12 years, including those with partial and generalized epilepsy. METHODS: A retrospective review of the records of pediatric patients (age < 18 years) who had undergone primary VNS system implantation between 2001 and 2010 by a single pediatric neurosurgeon was undertaken. Considered data included demographics, epilepsy type (partial vs generalized), seizure frequency, seizure duration, postictal period duration, and antiepileptic medication use. RESULTS: One hundred forty-six patients (49% female) were followed up for a mean of 41 months after VNS implantation. Thirty-two percent of patients had partial epilepsy and 68% had generalized epilepsy. After VNS system implantation, seizure frequency was reduced in 91% of patients, seizure duration in 50%, postictal period in 49%, and antiepileptic medication use in 75%. There was no significant difference in age, sex, or duration of follow-up according to epilepsy type. Neither was there any significant difference in seizure frequency reduction, seizure duration, postictal period, medication use, overall clinical improvement, or improvement in quality of life based on an age ≥ or < 12 years or epilepsy type. CONCLUSIONS: Vagus nerve stimulation reduced both seizure frequency and antiepileptic medication use in the majority of pediatric patients regardless of sex, age cohort, or epilepsy type. Vagus nerve stimulation also reduced seizure duration and postictal period in approximately half of the pediatric patients. Contrary to expectation, children with partial epilepsy do not benefit from VNS at higher rates than those with generalized epilepsy.

Transendoscopic intraoperative recording of gelastic seizures from a hypothalamic hamartoma.

OBJECT: The differential diagnosis of hypothalamic masses in children includes hamartomas, which are associated with gelastic seizures and endocrine dysfunction. The purpose of this study was to utilize transendoscopic electroencephalography (EEG) recording at the time of tissue biopsy to further assist in diagnosis, determination of prognosis, and treatment planning. METHODS: We present the case of an infant with gelastic seizures and a large hypothalamic mass lesion. Despite a clinical and radiographic presentation typical of hypothalamic hamartoma (HH), slight growth on serial imaging raised concern for a diagnosis of intrinsic neoplasm. Biopsy of the lesion was recommended. RESULTS: Transventricular, endoscopic biopsy, was undertaken, with concurrent intraoperative, transendoscopic EEG recording using a standard epilepsy depth recording macroelectrode. Numerous electrographic seizures were recorded. Histopathology revealed a HH. CONCLUSION: This is the first report of intraoperative macroelectrode recording of electrographic seizures transendoscopically from a HH. This technique may prove useful for diagnosis, prognosis and treatment planning, as well as to guide transendoscopic therapeutic interventions for HH.

Skull-fixated fiducial markers improve accuracy in staged frameless stereotactic epilepsy surgery in children.

OBJECT: Surgery to monitor and resect epileptogenic foci may be undertaken in 2 stages, providing an opportunity to use skull-fixated fiducials implanted during the first stage to improve the accuracy of cortical resection during the second stage. This study compared the intrinsic accuracy of skin-based and skull-fixated fiducial markers in registering frameless stereotaxy during pediatric epilepsy surgery. To the authors' knowledge, these modalities of registration have not previously been directly compared in this population. METHODS: The authors undertook a retrospective review of pediatric patients who underwent resection of epileptogenic foci in 2 stages with frameless stereotactic assistance, performed by a single surgeon at Oregon Health & Science University. For the first stage (subdural grid implantation), 9 skin fiducial markers were used to register anatomical data in a frameless stereotactic station. Intraoperatively, four 3-mm screws were placed circumferentially around the craniotomy. Postoperatively, thin-slice brain MR and CT images were obtained and fused. For the second stage, the 4 screws were used as fiducial markers to register the stereotactic anatomical data. For both stages, accuracy (difference in millimeters from zero of the manual fiducial registration compared with the computer model) was determined using navigation software. The intrinsic accuracy of these 2 methods of fiducial registration was compared using a paired Student t-test. RESULTS: Between 2004 and 2009, 40 pediatric patients with epilepsy underwent frameless stereotactic surgical procedures. Fourteen patients who had 2-stage procedures using skin-based and skull-fixated registration with complete accuracy data were included in this retrospective review. Mean registration error was significantly lower using skull-fixated fiducials (1.35 mm, 95% CI 1.09-1.60 mm) than using skin-based fiducials (1.85 mm, 95% CI 1.56-2.13 mm; p = 0.0016). CONCLUSIONS: A significantly higher degree of accuracy was achieved using 4 skull-fixated fiducials compared with using 9 skin-based fiducials. This simple and accurate method for registering frameless stereotactic anatomical data does not involve the potential time, expense, discomfort, and morbidity of extraoperative skull-fixated fiducial placement. The method described in this paper could also be extrapolated to other planned 2-stage cranial surgical procedures such as combined skull base approaches.

Focal seizure propagation in the intracranial EEG.

INTRODUCTION: intracranial EEG offers a unique opportunity to study epileptic seizures in humans. Seizure propagation has not been extensively studied. We aimed to compare the propagation of focal seizures with onset in different brain regions. METHODS: seven zones were defined as medial frontal (MF), dorsolateral frontal (DLF), orbitofrontal (OF), medial temporal (MF), lateral temporal (LT), parietal (P) and occipital (O). Routes and times of ipsilateral (IPT) and contralateral (CPT) propagation as well as ictal frequency in onset zone and propagation zone were compared. RESULTS: forty patients had 112 seizures. (Mean and median number of seizures per zone was 16 and 15). Preferred routes of propagation, based on ictal onset, were: MF to contralateral MF; DLF to ispilateral temporal lobe; OF to contralateral OF and ispilateral temporal lobe; MT to contralateral MT; LT to ispilateral MT and OF and contralateral LT and MT; P to ispilateral temporal lobe, DLF and O; O to ipsilateral MT. IPT and CPT varied markedly between zones. Ictal onset frequency was faster than propagated frequency. CONCLUSION: seizure propagation varies according to onset zone possibly following major pathways. This needs confirmation. The findings could aid in the interpretation of symptoms and EEG and may result useful for future treatment using brain stimulation or disconnective surgery. The limitations are clearly stated.