Objectives
Stiripentol, fenfluramine, and cannabidiol are licensed add‐on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full ...licensed dose regimens, across different jurisdictions, as first‐line add‐on therapies in DS.
Methods
We conducted a systematic review and frequentist network meta‐analysis (NMA) of randomized controlled trial (RCT) data for licensed add‐on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure‐free); serious adverse events (SAEs); discontinuations due to AEs.
Results
We identified relevant data from two placebo‐controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference RD for stiripentol versus fenfluramine 1% 95% confidence interval: −20% to 22%; p = 0.93 and 6% −15% to 27%; p = 0.59, respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure‐free intervals compared to fenfluramine (RD = 26% CI: 8% to 44%; p < 0.01) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter.
Significance
This NMA of RCT data indicates stiripentol, as a first‐line add‐on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add‐on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision‐making and the continued development of guidelines for the treatment of people with DS.
Plain Language Summary
This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS.
Summary
The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood–brain barrier, were associated with severe epileptic encephalopathy. Recently, ...dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.
Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic ...risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.
Objective
To formulate a classification system for foetal cortical formation abnormalities (CFAs) based on in utero magnetic resonance (iuMR) appearances and trial it in 356 cases.
Methods
This ...retrospective study included all cases of foetal CFA diagnosed between 2000 and 2017 from seven centres in Italy and UK. All of the studies were reviewed by a panel of paediatric neuroradiologists experienced in iuMR with the aid of an algorithm designed to categorise the abnormalities.
Results
Consensus expert review confirmed 356 foetuses with CFA and the first level of classification distinguished bilateral CFA (229/356–64%) from unilateral CFA (127/356–36%) cases with sub-classification of the bilateral cases into asymmetric (65/356–18%) and symmetric (164/356–46%) involvement. There was a statistically significant excess of foetuses with small head size, e.g. 17% of the cohort had a bi-parietal diameter < 3rd centile. There was a small but statistically significant excess of males in the cohort. Further categorisation was made on fine anatomical structure.
Conclusions
It is often not possible to classify foetal CFA using the principles and nomenclature used in paediatric neuroradiology. We have created a classification system for foetal CFA based on the analysis of 356 cases and believe that this will assist future research designed to correlate ante-natal and post-natal imaging features and understand the clinical sequelae of CFA described in utero.
Key Points
• We describe a morphological classification system of foetal brain cortical formation abnormalities that can be used in clinical practice.
• This classification system can be used in future research studies to evaluate the long-term imaging and clinical outcomes of foetal brain cortical formation abnormalities in 17- to 38-week gestational age range.
• The practical value of the work is in providing a framework and language to look for imaging clues that may differentiate between different CFA in further studies.
The Commission on Neurosurgery of the International League Against Epilepsy (ILAE) formed the Pediatric Epilepsy Surgery Subcommission in 1998 and charged it with formulating guidelines and ...recommendations for epilepsy surgery in childhood. Also endorsed by the Commission on Paediatrics, the following document is the consensus agreement after a meeting of 32 individuals from 12 countries in 2003. The panel agreed that insufficient class 1 evidence exists to recommend practice guidelines at this time. Instead, the panel generated criteria concerning the unique features of pediatric epilepsy patients to justify dedicated resources for specialty pediatric surgical centers, suggested guidelines for physicians for when to refer children with refractory epilepsy, and recommendations on presurgical evaluation and postoperative assessments. The panel also outlined areas of agreement and disagreement on which future research and consensus meetings should focus attention to generate practice guidelines and criteria for pediatric epilepsy surgery centers.
Psychogenic nonepileptic seizures (PNES) are episodes of paroxysmal impairment associated with a range of motor, sensory, and mental manifestations, which perfectly mimic epileptic seizures. Several ...patterns of neural abnormalities have been described without identifying a definite neurobiological substrate. In this multicenter cross-sectional study, we applied a multivariate classification algorithm on morphological brain imaging metrics to extract reliable biomarkers useful to distinguish patients from controls at an individual level.
Twenty-three patients with PNES and 21 demographically matched healthy controls (HC) underwent an extensive neuropsychiatric/neuropsychological and neuroimaging assessment. One hundred and fifty morphological brain metrics were used for training a random forest (RF) machine-learning (ML) algorithm.
A typical complex psychopathological construct was observed in PNES. Similarly, univariate neuroimaging analysis revealed widespread neuroanatomical changes affecting patients with PNES. Machine-learning approach, after feature selection, was able to perform an individual classification of PNES from controls with a mean accuracy of 74.5%, revealing that brain regions influencing classification accuracy were mainly localized within the limbic (posterior cingulate and insula) and motor inhibition systems (the right inferior frontal cortex (IFC)).
This study provides Class II evidence that the considerable clinical and neurobiological heterogeneity observed in individuals with PNES might be overcome by ML algorithms trained on surface-based magnetic resonance imaging (MRI) data.
•Systematic reviews have failed to identify biotypes of PNES.•Machine learning might represent an essential step to improve clinical diagnosis.•Multivariate approach detected changes in limbic and motor inhibition pathways.•Classification algorithm discriminates PNES with around 75% accuracy.
Abstract The inwardly-rectifying potassium channel Kir4.1 is a major player in the astrocyte-mediated regulation of K+ o in the brain, which is essential for normal neuronal activity and synaptic ...functioning. KCNJ10 , encoding Kir4.1, has been recently linked to seizure susceptibility in humans and mice, and is a possible candidate gene for Autism Spectrum Disorders (ASD). In this study, we performed a mutational screening of KCNJ10 in 52 patients with epilepsy of “unknown cause” associated with impairment of either cognitive or communicative abilities, or both. Among them, 14 patients fitted the diagnostic criteria for ASD. We identified two heterozygous KCNJ10 mutations (p.R18Q and p.V84M) in three children (two unrelated families) with seizures, ASD, and intellectual disability. The mutations replaced amino acid residues that are highly conserved throughout evolution and were undetected in about 500 healthy chromosomes. The effects of mutations on channel activity were functionally assayed using a heterologous expression system. These studies indicated that the molecular mechanism contributing to the disorder relates to an increase in either surface-expression or conductance of the Kir4.1 channel. Unlike previous syndromic associations of genetic variants in KCNJ10 , the pure neuropsychiatric phenotype in our patients suggests that the new mutations affect K+ homeostasis mainly in the brain, by acting through gain-of-function defects. Dysfunction in astrocytic-dependent K+ buffering may contribute to autism/epilepsy phenotype, by altering neuronal excitability and synaptic function, and may represent a new target for novel therapeutic approaches.
Summary
Objective
To analyze the attitude and results of Italian epilepsy surgery centers in the surgical management of “low grade epilepsy associated neuroepithelial tumors” (LEATs).
Methods
We ...conducted a retrospective study enrolling 339 consecutive patients with LEATs who underwent surgery between January 2009 and June 2015 at eight Italian epilepsy surgery centers. We compared demographic, clinical, pathologic, and surgical features of patients with favorable (Engel class I) and unfavorable (Engel class II, III, and IV) seizure outcome. In addition, we compared patients with tumor‐associated focal cortical dysplasia (FCD) and patients with solitary tumors to identify factors correlated with FCD diagnosis.
Results
Fifty‐five (98.2%) of 56 patients with medically controlled epilepsy were seizure‐free after surgery, compared to 249 (88.0%) of 283 patients with refractory epilepsy. At multivariate analysis, three variables independently predict unfavorable seizure outcome in the drug‐resistant group. Age at surgery is largely the most significant (p = 0.001), with an odds ratio (OR) of 1.04. This means that the probability of seizure recurrence grows by 4% for every waited year. The resection site is also significant (p = 0.039), with a relative risk (RR) of 1.99 for extratemporal tumors. Finally, the completeness of tumor resection has a trend toward significance (p = 0.092), with an RR of 1.82 for incomplete resection. Among pediatric patients, a longer duration of epilepsy was significantly associated with preoperative neuropsychological deficits (p < 0.001). A statistically significant association was observed between FCD diagnosis and the following variables: tailored surgery (p < 0.001), temporal resection (p = 0.001), and surgical center (p = 0.012).
Significance
Our nationwide LEATs study gives important insights on factors predicting seizure outcome in refractory epilepsy and determining variability in FCD detection. Timely surgery, regardless of pharmacoresistance and oriented to optimize epileptologic, neuropsychological, and oncologic outcomes should be warranted.
The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain ...neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novo coding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6 demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6 isoform is an example of a primate-specific genomic element supporting brain development.
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•Excess variants within basal radial glia transcriptomic signatures in cases of PH•PLEKHG6 primate-specific isoform mutated in a case of PH functions via RhoA•PLEKHG6 isoforms regulate features of neurogenesis•Modulation of the PLEKHG6 primate isoform reproduces features of PH in organoids
O’Neill et al. show that variants in patients with PH are enriched within genes that define basal radial glia transcriptomic signatures and provide mechanistic evidence that a primate-specific isoform of one gene, mutated in a patient with PH, regulates neurogenesis.
Objectives
We describe 64 foetuses with cortical formation abnormalities (CFA) who had two in utero magnetic resonance (iuMR) exams, paying particular detail to those in which the original ...classification of CFA category changed between the two studies. The goal was to attempt to quantify the value of third-trimester follow-up studies in CFA foetuses on second-trimester iuMR imaging.
Methods
The 64 foetuses reviewed came from a CFA cohort of 374 foetuses reported in an earlier publication, which detailed a classification for foetal CFA. A consensus panel of senior paediatric neuroradiologists reviewed both studies, described any change in the category of CFA between them, and attempted to predict the possible clinical significance of any differences based on the combined clinical experience of the panel.
Results
In 40/64 (62%) foetuses, the CFA description was the same on both studies. In 24/64 (38%) cases, there was a category change which included three foetuses without CFA on first examination, six foetuses where the difference involved change in laterality/symmetry, and in 15 cases the re-classification involved categorical change within the same group. Brain abnormalities other than CFA were present in 30/64 (47%) foetuses on the first study and in 33/64 (52%) on the second. We predicted that prognosis would have changed on the basis of the second study in 8% of cases, all indicating worse prognosis.
Conclusions
We have shown that the extra diagnostic and predicted prognostic yield justifies follow-up studies in the third trimester if a CFA is shown on the second-trimester iuMR imaging.
Key Points
• Sixty-four foetuses with cortical formation abnormalities had two iuMR studies, for the vast majority the baseline in the second trimester and the sequential in the third.
• In three foetuses, the cortical formation abnormality (CFA) was not visible on the first study. In a further 21 foetuses, the categorical description of the CFA changed between the two studies. Prognosis changed in 8% of the cases following the second iuMR study, and in all cases, the prognosis was worse.
• Multiple iuMR studies provide information about the natural history of CFA; the extra diagnostic and predicted prognostic yield justifies follow-up studies.
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