SUMMARYPurpose: High-frequency oscillations (HFOs), termed ripples at 80-200 Hz and fast ripples (FRs) at >200/250 Hz, recorded by intracranial electroencephalography (EEG), may be a valuable surrogate marker for the localization of the epileptogenic zone. We evaluated the relationship of the resection of focal brain regions containing high-rate interictal HFOs and the seizure-onset zone (SOZ) determined by visual EEG analysis with the postsurgical seizure outcome, using extraoperative intracranial EEG monitoring in pediatric patients and automated HFO detection. Methods: We retrospectively analyzed 28 pediatric epilepsy patients who underwent extraoperative intracranial video-EEG monitoring prior to focal resection. Utilizing the automated analysis, we identified interictal HFOs during 20 min of sleep EEG and determined the brain regions containing high-rate HFOs. We investigated spatial relationships between regions with high-rate HFOs and SOZs. We compared the size of these regions, the surgical resection, and the amount of the regions with high-rate HFOs/ SOZs within the resection area with seizure outcome.Key Findings: Ten patients were completely seizure-free and 18 were not at 2 years after surgery. The brain regions with high-rate ripples were larger than those with high-rate FRs (p = 0.0011) with partial overlap. More complete resection of the regions with high-rate FRs significantly correlated with a better seizure outcome (p = 0.046). More complete resection of the regions with high-rate ripples tended to improve seizure outcome (p = 0.091); however, the resection of SOZ did not influence seizure outcome (p = 0.18). The size of surgical resection was not associated with seizure outcome (p = 0.22-0.39). Significance: The interictal high-rate FRs are a possible surrogate marker of the epileptogenic zone. Interictal ripples are not as specific a marker of the epileptogenic zone as interictal FRs. Resection of the brain regions with high-rate interictal FRs in addition to the SOZ may achieve a better seizure outcome.
Summary Purpose To examine patterns of use, efficacy and safety of intravenous ketamine for the treatment of refractory status epilepticus (RSE). Methods Multicenter retrospective review of medical records and EEG reports in ten academic medical centers in North America and Europe, including 58 subjects, representing 60 episodes of RSE were identified between 1999 and 2012. Seven episodes occurred after anoxic brain injury. Key findings Permanent control of RSE was achieved in 57% (34/60) of episodes. Ketamine was felt to have contributed to permanent control (“possible” or “likely” responses) in 32% (19/60) including seven (12%) in which ketamine was the last drug added (likely responses). Four of the seven likely responses, but none of the 12 possible ones, occurred in patients with post-anoxic brain injury. No likely responses were observed when infusion rates were lower than 0.9mg/kg/h; when ketamine was introduced at least eight days after SE onset; or after failure of seven or more drugs. Ketamine was discontinued due to possible adverse events in five patients. Complications were mostly attributed to concurrent drugs, especially other anesthetics. Mortality rate was 43% (26/60), but was lower when SE was controlled within 24h of ketamine initiation (16% vs. 56%, p=0.0047). Significance Ketamine appears to be a relatively effective and safe drug for the treatment of RSE. This retrospective series provides preliminary data on effective dose and appropriate time of intervention to aid in the design of a prospective trial to further define the role of ketamine in the treatment of RSE.
Summary Purpose: Continuous electroencephalography (EEG) monitoring is a valuable tool for the detection of seizures among critically ill children, in particular when these seizures occur without clinical signs: termed nonconvulsive seizures. Continuous EEG monitoring is a limited resource in many centers. We sought to identify which critically ill children most frequently experience nonconvulsive seizures, and thus may particularly benefit from continuous EEG monitoring. Methods: Single‐center review was undertaken of consecutive diagnostic continuous EEG (cEEG) recordings performed in our pediatric and neonatal intensive care units (ICUs). We examined the indications for monitoring, the clinical characteristics of monitored patients, the occurrence and timing of seizures, and clinical and EEG characteristics associated with nonconvulsive seizures. Key Findings: One hundred twenty‐one patients underwent diagnostic continuous EEG monitoring, for a mean duration of 26 h. Seizures were detected in 32% of these patients, of which 90% experienced some nonconvulsive seizures, and 72% experienced exclusively nonconvulsive seizures. Patients with nonconvulsive seizures had significantly greater odds of having acute epilepsy, acute structural brain injury, prior in‐hospital convulsive seizures, and the presence of interictal epileptiform abnormalities on EEG. Significance: Seizures are common among critically ill children undergoing diagnostic cEEG monitoring. The great majority of these seizures are nonconvulsive, requiring EEG for their detection. Predictors of nonconvulsive seizures include acute epilepsy, acute structural brain injury, prior in‐hospital convulsive seizures, and interictal epileptiform abnormalities on EEG. These findings can help inform future allocation of limited cEEG monitoring resources to those patients at greatest risk for nonconvulsive seizures.
IntroductionBoth Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug‐resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL‐TC150 ‐ a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC‐ in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.MethodsTwenty children received add‐on therapy with TIL‐TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives.ResultsNineteen participants completed the 20‐week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7–16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14–0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.Conclusions TIL‐TC150 was safe and well tolerated in our subjects. TIL‐TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC‐containing cannabinoid preparations.
Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca 2 þ protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca 2 þ control within neuronal cells highlights its potential for a role in this form of EA.
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Objective: To assess the benefits and harms of cannabis-based products for pediatric epilepsy. Methods: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, Psy-cINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by randomeffects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. Results: Four RCTs and 19 NRSs were included, primarily involving cannabidiol.All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = −2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = −0.3, 95% CI = −0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (−19.8%, 95% CI = −27.0% to −12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. Significance: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products. K E Y W O R D S cannabidiol, cannabis, efficacy, pediatric drug-resistant epilepsy, safety, seizure, systematic review PROSPERO: CRD42018084755
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