Search

Several retrospective studies on pediatric epilepsy reported positive effects of cannabidiol-enriched artisanal cannabis oil and pure cannabidiol oil on seizure reduction.This is a retrospective study of children and adolescents with refractory epilepsy caused by various etiologies who were treated with artisanal cannabis oil during January 2014 to June 2019, with at least one year follow-up.Of 114 patients, 84 (73.3%) reported some improvement in seizure frequency at some point during treatment. Fifty-one (59%) of the 86 patients who continued treatment for at least one year showed50% improvement in seizure frequency. Seizure etiology, seizure type, and patients' age and sex were not found to be associated with the response to cannabidiol-enriched cannabis oil. Side effects were minor, and positive effects beyond seizure reduction were noted.Artisanal cannabidiol-enriched cannabis may be an effective and safe long-term treatment for refractory epilepsy.

Common titration strategies for vagus nerve stimulation (VNS) prioritize monitoring of tolerability during small increases in stimulation intensity over several months. Prioritization of tolerability is partially based on how quickly side effects can be perceived and reported by patients, and the delayed onset of clinical benefits from VNS. However, many practices assess the clinical benefit of VNS at one year after implantation, and excessive caution during the titration phase can significantly delay target dosing or prevent a patient from reaching a therapeutic dose entirely. This study aimed to characterize the relationship between titration speed and the onset of clinical response to VNS. To assess differences between more aggressive titration strategies and more conservative ones, we analyzed the relationship between time-to-dose and time-to-response using a weighted Cox regression. The target dose was empirically defined as 1.625 mA output current delivered at 250 microsecond pulse widths at 20 Hz. Patient-level outcomes and dosing data were segregated into fast (6 months) cohorts based on their titration speed. The statistical model revealed a significant relationship between titration speed and onset of clinical response, defined as a 50% reduction from baseline in seizure frequency. Frequency of adverse events reported between each cohort trended toward higher rates of adverse events in adults who were titrated quickly; however, the pediatric population appeared to be more tolerant of titration at any speed. This analysis indicates that faster titration yields faster onset of clinical benefit and is especially practical in the pediatric population, though attempts to accelerate adult titration may still be warranted.

To assess whether white matter (WM) diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) derived measures correlate with tuberous sclerosis complex (TSC) disease severity.A multi-shell diffusion protocol was added to the clinical MRI brain scans of thirteen patients including 6 males and 7 females with a mean ± std age of 17.2 ± 5.8 years. Fractional anisotropy (FA) and mean diffusivity (MD) were generated from DTI and neurite density index (NDI), orientation dispersion index (ODI) and free water index (fiso) were generated from NODDI. A clinical score was determined for each patient according to the existence of epilepsy, developmental delay, autism or psychiatric disorders. Whole-brain segmented WM was averaged for each parametric map and 3 group k-means clustering was performed on the NDI and FA maps. MRI quantitative parameters were correlated with the clinical scores.Segmented whole brain WM averages of MD and NDI values showed significant negative (p = 0.0058) and positive (p = 0.0092) correlations with the clinical scores, respectively. Additionally, the contribution of the low and high NDI-based clusters to the whole brain WM significantly correlated with the clinical scores (p = 0.03 and p = 0.00047, respectively). No correlation was found when the clusters were based on the FA maps.Advanced diffusion MRI of TSC patients revealed widespread WM alterations. Neurite density showed significant correlations with disease severity and is therefore suggested to reflect an underlying biological process in TSC WM. The quantification of WM alterations by advanced diffusion MRI may be an additional biomarker for TSC and may be advantageous as a complementary MR protocol for the evaluation of TSC patients.

Background Benign childhood epilepsy with centrotemporal spikes is benign childhood epilepsy, presenting between 4 and 10 years of age, characterized by typical clinical and EEG findings. Despite excellent prognosis, there are reports of mild cognitive, language, fine motor and behavioral difficulties. In its atypical form – electrical status epilepticus during slow wave sleep, continuous epileptiform activity during sleep lead to severe neurocognitive deterioration. Our objective was to investigate the influence of abundant sleep epileptiform activity, not fulfilling the criteria for electrical status epilepticus during Slow Wave Sleep, discovered randomly in children without overt intellectual impairment. Methods We retrospectively reviewed the charts and EEG's of 34 children with benign childhood epilepsy with centrotemporal spikes, who underwent neurocognitive evaluation. The neurocognitive battery included items in the following domains: attention span, memory, language, fine motor and behavior. Patients were divided into two groups according to the spike wave index on sleep EEG, with a cut-off point of 50%. The groups were compared regarding to neurocognitive performance. Outcomes Children with epileptiform activity of more than 50%, were diagnosed at a significantly younger age (5.13 ± 1.94 years vs. 7.17 ± 2.45, p = 0.014 T test), had less controlled seizures and received more antiepileptic drugs. However, there was no difference in neurocognitive performance, except in fine motor tasks (Pegboard), where children with more abundant activity were scored lower (−0.79 ± 0.96 vs. 0.20 ± 1.05, p = 0.011, T test). Conclusion Our study did not show negative cognitive effect of abundant epileptiform activity discovered randomly in children with benign childhood epilepsy with centrotemporal spikes, warranting aggressive treatment.

Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo , mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA . PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10 −8 ) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285∗), c.247_250del (p.Asn83Hisfs∗4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

X-linked cerebral creatine deficiency (MIM 300036) is caused by deficiency of the creatine transporter encoded by the SLC6A8 gene. Here we report three patients with this condition from Israel. These unrelated patients were evaluated for global developmental delays and language apraxia. Borderline microcephaly was noted in one of them. Diagnosis was prompted by brain magnetic resonance imaging and spectroscopy which revealed normal white matter distribution, but absence of the creatine peak in all three patients. Biochemical testing indicated normal plasma levels of creatine and guanidinoacetate, but an increased urine creatine/creatinine ratio. The diagnosis was confirmed by demonstrating absent [14]C-creatine transport in fibroblasts. Molecular studies indicated that the first patient is hemizygous for a single nucleotide change substituting a single amino acid (c.619 C > T, p.R207W). Expression studies in HeLa cells confirmed the causative role of the R207W substitution. The second patient had a three base pair deletion in the SLC6A8 gene (c.1222_1224delTTC, p.F408del) as well as a single base change (c.1254 + 1G > A) at a splicing site in the intron-exon junction of exon 8, the latter occurring de novo. The third patient, had a three base pair deletion (c.1006_1008delAAC, p.N336del) previously reported in other patients with creatine transporter deficiency. These three patients are the first reported cases of creatine transporter deficiency in Israel.

Purpose To describe the experience of five Israeli pediatric epilepsy clinics treating children and adolescents diagnosed as having intractable epilepsy with a regimen of medical cannabis oil. Methods A retrospective study describing the effect of cannabidiol (CBD)-enriched medical cannabis on children with epilepsy. The cohort included 74 patients (age range 1–18 years) with intractable epilepsy resistant to >7 antiepileptic drugs. Forty-nine (66%) also failed a ketogenic diet, vagal nerve stimulator implantation, or both. They all started medical cannabis oil treatment between 2–11/2014 and were treated for at least 3 months (average 6 months). The selected formula contained CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20mg/kg/d. Seizure frequency was assessed by parental report during clinical visits. Results CBD treatment yielded a significant positive effect on seizure load. Most of the children (66/74, 89%) reported reduction in seizure frequency: 13 (18%) reported 75–100% reduction, 25 (34%) reported 50–75% reduction, 9 (12%) reported 25–50% reduction, and 19 (26%) reported Conclusions The results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising. Further prospective, well-designed clinical trials using enriched CBD medical cannabis are warranted.

Introduction The new anticonvulsant brivaracetam is a levetiracetam analog which binds to the synaptic vesicle protein 2A, and inhibits excitatory neurotransmitters' release. Brivaracetam was Food and Drug Administration (FDA) and European Medicine Agency (EMA) approved in 2016 as adjunctive treatment for focal onset seizures in patients over 16 years of age, and in 2018 for children over four years of age. Our aim was to describe effectiveness and tolerability in real-life pediatric epilepsy clinic. Methods Cross-sectional retrospective chart review of patients under 20 years of age, treated with brivaracetam. Positive response to treatment was considered when 50% decrease in seizure frequency was noted. In responders to levetiracetam, positive effect was regarded if switching to brivaracetam maintained at least the same seizure control. Results Thirty-one patients (67.7% males), aged 13.8 ± 4.07 (6.9–20 years), were treated with brivaracetam 3.8 mg/kg ± 1.8. Age of onset of epilepsy was 5.7 ± 3.7 years; 20 patients had focal epilepsies; and 11 had epileptic syndromes (5 – Lennox–Gastaut, 3 – myoclonic absence, 3 – myoclonic–atonic). Responder rate was 45.2%, with no statistical difference under and over 16 years of age (40% vs. 54.5%, Fisher's exact test). Eight patients had better response to seizures compared to levetiracetam. Gender, duration of epilepsy, and dosage did not affect epilepsy control. Six patients had seizure aggravation. Adverse effects were rare: mild somnolence (6.4%), psychosis (3.2%), and nausea (3.2%). Conclusion Brivaracetam is an effective add-on treatment in focal, as well as generalized seizures in children, with negligible side effects, including children who failed previously on levetiracetam. Seizure exacerbation may occur, but it's reason is unclear.