Atonic Seizures Research Articles

Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies.

Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient’s lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%–68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%–78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat–OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a ‘one size fits all’ approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.

Prevalence and classification of childhood epilepsy in Alexandria

Background Approximately 75% of epilepsy begins during childhood. Aim The aim of this work was to study the prevalence of epilepsy and its types and classifications among children with neurological disorders attending the Outpatient Neurology Clinic, Alexandria University Children’s Hospital. Patients and methods This is a retrospective study. All children with a diagnosis of epilepsy attending the clinic between January 1, 2018 and December 31, 2018 were included. Patients’ data were collected from records. Results The prevalence of epilepsy among neurological disorders was 16.4% (88 cases from a total of 537 cases with neurological disorders). The age of the patients ranged between 1 and 14 years; 52.3% were females. 77.3% had genetic epilepsy, 15.9% had structural epilepsy, 3.4% had infectious epilepsy, 2.3% had metabolic epilepsy and 1.1% had mixed epilepsy. 52% had generalized tonic–clonic seizures, 29.5% had focal seizures, 9.1% had focal to bilateral seizures, 4.5% had absence seizures, 3.4% had atonic seizures and 1.1% had myoclonic seizures. 60.2% underwent interictal electroencephalography (EEG); 75.5% of them had abnormal EEG findings. 87.5% of the patients were on antiepileptic drugs: 60.2% of them were on monotherapy and 27.2% were on polytherapy. 52.8% of patients on monotherapy were treated by Na Valproate, 53% by Carbamazpine, and 11.3% by Levetiracetam. Seizure control was achieved in 28.4% of treated patients. Correlations between the etiology of epilepsy and computed tomography, MRI, and EEG findings were statistically significant. Conclusion The prevalence of epilepsy among patients with neurological disorders is considered to be mild to moderate. Generalized tonic–clonic seizures, genetic etiology, and monotherapy control of the attacks are considered the most prevalent characteristics of the disease.

A partial <i>ARID1B</i> deletion in a female child with intractable epilepsy

Although epilepsy is a known complication in Coffin-Siris syndrome, its clinical symptoms and effective treatment methods have not been thoroughly investigated so far. Here, we present the case of a female with a 594-kb interstitial deletion at 6q25.3, involving partially ARID1B, with developmental delay, short stature, and intractable epilepsy. At 4 years of age, she developed epilepsy with clonic seizures in the right half of her body. Treatment with carbamazepine, levetiracetam, or topiramate was ineffective. The frequency of epileptic seizures gradually worsened. At the peak of her seizures, she had focal onset clonic seizures 3-4 times a month, and neck atonic seizures lasting for several seconds more than 10 times a day. After administration of sodium valproate, her epileptic seizures decreased to 0-1 times a year. In conclusion, gathering genetic information in Coffin-Siris syndrome allows improvement of epilepsy treatment and outcomes in these patients.

Cannabidiol en los síndromes de Dravet y Lennox-Gastaut: un nuevo abordaje terapéutico

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are two serious epileptic syndromes with paediatric onset which are refractory to therapy and are associated with an important increase in mortality rates and comorbidities compared to the general population. These pathologies have a strong impact on the lives of patients and their families, because they undergo multiple pharmacological therapies (many of them without specific indication), with frequent changes due to poor efficacy and associated adverse effects. The specialists who care for these patients highlight unmet needs and the lack of specific, safe and effective treatments for better management of the syndrome. A group of four neurologists specializing in epilepsy has met to review the scientific literature and evaluate the efficacy and safety of oral solution cannabidiol in the treatment of these syndromes, both in randomized clinical trials (CT) and in some observational studies. Cannabidiol is positioned as an innovative therapy that allows better control of epileptic seizures and comorbidities of DS and LGS, furthermore its efficacy and safety have been evaluated in more than 700 patients. In CTs, cannabidiol significantly reduced the percentage of convulsive seizures and drop seizures compared to placebo in patients with DS and LGS respectively, which could improve their quality of life and that of their family members. The most frequent adverse effects reported were somnolence and decreased appetite. Elevated liver aminotransferase levels were also reported, especially in patients given concomitant sodium valproate. This therapy may allow better control of the epileptic seizures associated with these syndromes.

Results of an international Delphi consensus in epilepsy with myoclonic atonic seizures/ Doose syndrome

ObjectiveTo establish a standard framework for early phenotypic diagnosis, investigations, expected findings from investigations, evolution, effective therapies and prognosis in the syndrome of Epilepsy with myoclonic atonic seizures (EMAS) / Doose syndrome. MethodsA core study group (CSG) interested in EMAS was convened. CSG then identified and nominated 15 experts in the field of EMAS. This expert panel (EP) from English speaking nations was invited to participate in anonymous questionnaires. A literature review was provided to them (supplement 1). Three rounds of questionnaires were sent to identify areas of consensus, strength of consensus and areas of contention. ResultsStrong consensus was obtained regarding the clinical phenotype of EMAS: myoclonic atonic seizure was identified among others as a mandatory seizure type with typical onset of afebrile seizures between one and six years. A new term “stormy phase” (SP) was designated to delineate a characteristic phenotypic evolution in EMAS patients associated with seizure worsening. Strong consensus regarding the existence and time of onset of the SP, mandatory investigations to be performed early and later in the clinical course of EMAS, first and second tier treatment and prognostic factors for poor outcome were identified. Areas of lack of consensus included some seizure types that are necessary to diagnose EMAS, interictal EEG findings that prognosticate the course of EMAS, overall duration of SP, time to complete remission, and best approach to treat drug resistant EMAS. SignificanceExpert consensus on core diagnostic criteria of EMAS necessary for natural history studies, phenotype-genotype correlations, and clinical trials including comparative studies was demonstrated. Areas of disagreements (especially prognostic features; treatment options) need further research.

Metreleptin for the treatment of progressive encephalopathy with/without lipodystrophy (PELD) in a child with progressive myoclonic epilepsy: a case report

BackgroundA number of genetic syndromes associated with variants in the BSCL2/seipin gene have been identified. Variants that cause skipping of exon 7 are associated with progressive encephalopathy with/without lipodystrophy (PELD), which is characterized by the development of progressive myoclonic epilepsy at a young age, severe progressive neurological impairment, and early death, often in childhood. Because the genetic basis of PELD is similar to that of congenital lipodystrophy type 2, we hypothesized that a patient with PELD may respond to treatments approved for other congenital lipodystrophic syndromes.Case presentationWe describe a 5-year-old boy with an extremely rare phenotype involving severe progressive myoclonic epilepsy who received metreleptin (a recombinant analogue of leptin) to control metabolic abnormalities. At the age of two, he had no subcutaneous adipose tissue, with hypertriglyceridemia, hypertransaminasemia and hepatic steatosis. He also had a moderate psychomotor delay and generalized tonic seizures. At 4 years, he had insulin resistance, hypercholesterolemia, hypertriglyceridemia, mild hepatosplenomegaly and mild hepatic steatosis; he began a hypolipidemic diet. Severe psychomotor delay and myoclonic/myoclonic atonic seizures with absences was evident. At 5 years of age, metreleptin 0.06 mg/kg/day was initiated; after 2 months, the patient’s lipid profile improved and insulin resistance resolved. After 1 year of treatment, hepatic steatosis improved and abdominal ultrasound showed only mild hepatomegaly. Seizure frequency decreased but was not eliminated during metreleptin therapy.ConclusionsMetreleptin may be used to control metabolic disturbances and may lead to better seizure control in children with PELD.

Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant

Developmental and epileptic encephalopathies (DEE) are a group of severe epilepsies that usually present with intractable seizures, developmental delay, and often have elevated risk for premature mortality. Numerous genes have been identified as a monogenic cause of DEE, including KCNB1. The voltage-gated potassium channel KV2.1, encoded by KCNB1, is primarily responsible for delayed rectifier potassium currents that are important regulators of excitability in electrically excitable cells, including neurons. In addition to its canonical role as a voltage-gated potassium conductance, KV2.1 also serves a highly conserved structural function organizing endoplasmic reticulum-plasma membrane junctions clustered in the soma and proximal dendrites of neurons. The de novo pathogenic variant KCNB1-p.G379R was identified in an infant with epileptic spasms, and atonic, focal and tonic-clonic seizures that were refractory to treatment with standard antiepileptic drugs. Previous work demonstrated deficits in potassium conductance, but did not assess non-conducting functions. To determine if the G379R variant affected KV2.1 clustering at endoplasmic reticulum-plasma membrane junctions, KV2.1-G379R was expressed in HEK293T cells. KV2.1-G379R expression did not induce formation of endoplasmic reticulum-plasma membrane junctions, and co-expression of KV2.1-G379R with KV2.1-wild-type lowered induction of these structures relative to KV2.1-WT alone, consistent with a dominant negative effect. To model this variant in vivo, we introduced Kcnb1G379R into mice using CRISPR/Cas9 genome editing. We characterized neuronal expression, neurological and neurobehavioral phenotypes of Kcnb1G379R/+ (Kcnb1R/+) and Kcnb1G379R/G379R (Kcnb1R/R) mice. Immunohistochemistry studies on brains from Kcnb1+/+, Kcnb1R/+ and Kcnb1R/R mice revealed genotype-dependent differences in the expression levels of KV2.1 protein, as well as associated KV2.2 and AMIGO-1 proteins. Kcnb1R/+ and Kcnb1R/R mice displayed profound hyperactivity, repetitive behaviors, impulsivity and reduced anxiety. Spontaneous seizures were observed in Kcnb1R/R mice, as well as seizures induced by exposure to novel environments and/or handling. Both Kcnb1R/+ and Kcnb1R/R mutants were more susceptible to proconvulsant-induced seizures. In addition, both Kcnb1R/+ and Kcnb1R/R mice exhibited abnormal interictal EEG activity, including isolated spike and slow waves. Overall, the Kcnb1G379R mice recapitulate many features observed in individuals with DEE due to pathogenic variants in KCNB1. This new mouse model of KCNB1-associated DEE will be valuable for improving the understanding of the underlying pathophysiology and will provide a valuable tool for the development of therapies to treat this pharmacoresistant DEE.

Clinical profile of children with epilepsy: a cross-sectional study

Introduction: One of the most common chronic neurological disorders is epilepsy, affecting as many as 45 million individuals worldwide. The occurrence is higher in children below the age of three. Around 60 percent to 70 percent of epilepsy patients have an effective response to treatment with antiepileptic medications. This cross-sectional study aimed to explore the clinical profile of children with epilepsy.Methods: Total of 100 children with different types of epilepsy was included in this study. After getting informed consent from the parents, all the demographic data, family history, clinical and laboratory investigations were recorded, and the results were statistically analyzed and discussed.Results: 69 patients had tonic-clonic seizures, 15 patients had a complete partial seizure, 7 patients had absence seizures, 4 patients had unclassified seizures, 3 patients had simple partial seizures, 1 patient had myoclonic seizures, atonic seizures and multiple seizures. Aetiology, 72 patients had an idiopathic cause, 10 patients had hypoxic ischemia, 8 patients had Central nervous system (CNS) infection, 4 patients had cerebral palsy and space-occupying lesion, 2 patients had trauma. Comorbidity, 84 patients had none, 4 patients had mental retardation, 3 patients had eye diseases, cerebral palsy, protein-energy malnutrition, mental retardation with cerebral palsy, 1 patient had a hearing impairment. Drug therapy, 63 patients had sodium valproate, 11 patients had carbamazepine, 2 patients had multidrug treatment, and 1 patient had sodium phenytoin.Conclusion: A significant amount of the aetiology of the condition is expressed among preventable causes of epilepsy. For generalized tonic clonic seizure, sodium valproate was observed to have more positive effects in paediatric patients.

Telephone-based follow-up of children with epilepsy: Comparison of accuracy between a specialty nurse and a pediatric neurology fellow

BackgroundChildhood epilepsy forms a significant burden on the health-care delivery system. Only a few pediatric neurologists available in most of the developing countries and caregivers face a lot of financial and logistic hardships, apart from a long waiting period for initial and follow up visits. Telemedicine is a proposed effective alternative in overcoming this burden. MethodsTelephonic consultation by a pediatric neurology fellow was compared with that of a specialty nurse; both against face-to-face consultation (gold standard). Care-givers of children 4 months-18 years with epilepsy were telephonically consulted 24−48 hours before their scheduled hospital appointment by one specialty nurse and one pediatric neurology fellow at least 24 h apart in a random sequence. During the hospital visit, another pediatric neurology fellow blinded to the telephonic consultation, documented the same after Face-to-Face interview. ResultsIn 141 children with epilepsy, 504 critical clinical events were identified. Telephonic consultation by pediatric neurology fellow had a sensitivity of 99 %, 97 %, and 100 % and specificity of 100 % each in detecting whether the child had any breakthrough seizure, any adverse event and whether the drug compliance was adequate or poor respectively, as compared to face-to-face consultation. Telephonic consultation by specialty nurse had a sensitivity of 91 %, 84 %, and 98 % and specificity of 97 %, 99 %, and 81 % in detecting whether the child had any breakthrough seizure, adverse event and whether the drug compliance was adequate or poor respectively. But the specialty nurses fared poorly in identifying atypical seizure semiologies like atonic and myoclonic seizures and documenting an exact number of breakthrough seizures, as well as few subjective adverse effects like behavioral abnormality and scholastic worsening, which was performed excellently by the pediatric neurology fellow. ConclusionsTelephonic consultation in childhood epilepsy by pediatric neurology fellow has excellent sensitivity and specificity. A specialty nurse has also acceptable sensitivity and specificity in comparison with a face-to-face consultation.

Sleep Paralysis and the Structure of Waking

Sleep dysfunction may be a state, throughout arousal or falling asleep, within which an individual is aware however una ble to manoeuvre or speak. throughout associate degree episode, one could perceive (hear, feel, or see things that don't seem to be there), which regularly leads to worry. Episodes usually last but one or two of minutes. It’s going to occur as one episode or be perennial. The condition could occur in those that are otherwise healthy or those with hypersomnia, or it's going to run in families as a results of specific genetic changes. The condition is triggered by sleep deprivation, psychological stress, or abnormal sleep cycles. The underlying mechanism is believed to involve a dysfunction in rapid eye movement. identification is predicated on a human description. different conditions which will gift equally embody hypersomnia, atonic seizure, and hypokalae mia periodic dysfunction. Treatment choices for sleep dysfunction are poorly studied. It’s suggested that folks be confident that the condition is common and usually not serious. Different efforts that will be tried embody sleep hygiene, psychological feat ure activity medical aid, and antidepressants. Between 8 May 1945 and five hundred of individual’s expertise sleep dysfunction at some purpose in their life. concerning five hitter of individuals have regular episodes. Males and females are affected equall y. Sleep dysfunction has been delineated throughout history. it's believed to own vie a task within the creation of stories concerning alien abduction and different paranormal events.

Seizure outcome during bilateral, continuous, thalamic centromedian nuclei deep brain stimulation in patients with generalized epilepsy: a prospective, open-label study

ObjectiveWe report on the seizure frequency and attention outcome during thalamic centromedian stimulation (CM-DBS) in patients with refractory generalized epilepsy (GE). MethodsTwenty consecutive patients with GE who were submitted to CM-DBS and had at least one year of follow-up were prospectively studied. The CM was targeted bilaterally. Stimulation intensity was ramped up (bipolar, continuous, 130 Hz; 300μsec) until 4.5 V or until side effects developed. Contacts` position was determined on postoperative volumetric MRI scans. Attention was qualitatively evaluated using the SNAP-IV (Swanson, Nolan, and Pelham) questionnaire. Patients were considered responders during CM-DBS if an at least 50% seizure frequency reduction was obtained compared to baseline. ResultsMedian age was 15.5 years (13 males). Median follow-up time was 2.55 years. EEG disclosed generalized spike-and wave discharges in all patients. MRI was normal in 10 patients, showed diffuse atrophy in 6 patients, and showed abnormalities in 4 patients (3 patients had bilateral cortical development abnormalities and one had unilateral hemispheric atrophy). Patients presented with daily multiple seizure types (8 to 66 per day; median: 37), including tonic, atonic, myoclonic, atypical absence and generalized tonic-clonic seizures. Mean DBS intensity was 4.3 V. An insertional effect was noted in 14 patients. CM-DBS was able to significantly reduce the frequency of tonic (p < 0.001), atypical absence seizures (p < 0.001), atonic seizures (p = 0.001) and bilateral generalized tonic-clonic seizures (p = 0.004). One patient became seizure-free. Ninety percent of the patients were considered responders (>50% seizure frequency reduction). All patients showed some improvement in attention. The mean number of items in which improvement was noted in the SNAP-IV questionnaire was 4.8. There was a significant relationship between overall seizure frequency reduction and improvement of attention (p = 0.033). DiscussionThis prospective, open label study included a large, homogeneous cohort and provided evidence on the efficacy of CM-DBS in reducing the seizure burden and increasing attention in patients with refractory generalized epilepsy.

Clinical phenotype features and genetic etiologies of 38 children with progressive myoclonic epilepsy

BackgroundProgressive myoclonic epilepsy (PME) is a group of neurodegenerative diseases with genetic heterogeneity and phenotypic similarities, and many cases remain unknown of the genetic causes. This study is aim to summarize the clinical features and study the genetic causes of PME patients.MethodsSanger sequencing of the target gene, Next Generation Sequencing (NGS) panels of epilepsy, trio-based Whole Exome Sequencing (WES) and detection of cytosine-adenine-guanine (CAG) repeat number were used to investigate the genetic causes of PME patients.ResultsThirty-eight children with PME whose seizure onset age ranged from 3 months to 12 years were collected from February 2012 to November 2019 in three hospitals in Beijing, China. The seizure types included myoclonic seizures (n = 38), focal seizures (n = 19), generalized tonic-clonie seizure (GTCS) (n = 13), absence seizures (n = 4), atonic seizures (n = 3), epileptic spasms (n = 2) and tonic seizures (n = 1). Twenty-seven cases were sporadic and 11 had family members affected. Established PME-related genes were identified in 30 out of 38 (78.9%) patients who had either recessively inherited or de novo heterozygous mutations. Among these 30 cases, there were 12 cases (31.6%) of neuronal ceroid lipofuscinoses (the causing gene contains TPP1, PPT1, CLN5, CLN6 and MFSD8), two cases of sialidosis (the causing gene is NEU1), two cases of neuronopathic Gaucher disease (the causing gene is GBA), one case of spinal muscular atrophy-progressive myoclonic epilepsy (the causing gene is ASAH1), four cases of KCNC1 mutation-related PME, four cases of KCTD7 mutation-related PME, two cases of TBC1D24 mutation-related PME, one case of GOSR2 related PME, and two of dentatorubral-pallidoluysian atrophy (the causing gene is ATN1). In total, 13 PME genes were identified in our cohort. The etiology was not clear in eight patients.ConclusionPME is a group of clinically and genetically heterogeneous diseases. Genetic diagnosis was clear in 78.9% of PME patients. Various of genetic testing methods could increase the rate of genetic diagnosis. Neuronal ceroid lipofuscinoses (NCL) is the most common etiology of PME in children. Nearly one third PME children were diagnosed with NCL. GOSR2 related PME was in our cohort in Asia for the first time.

Epilepsy With Myoclonic Atonic Seizures: Why Is the Yield of Genetic Testing for a “Presumed Genetic” Epilepsy Low?

Phenotypic and Genetic Spectrum of Epilepsy With Myoclonic Atonic Seizures Tang S, Addis L, Smith A, Topp SD, Pendziwiat M, Mei D, Parker A, Agrawal S, Hughes E, Lascelles K, Williams RE, Fallon P, Robinson R, Cross HJ, Hedderly T, Eltze C, Kerr T, Desurkar A, Hussain N, Kinali M, Bagnasco I, Vassallo G, Whitehouse W, Goyal S, Absoud M, EuroEPINOMICS-RES Consortium, Møller RS, Helbig I, Weber, YG, Marini C, Guerrini R, Simpson MA, Pal DK. Epilepsia. 2020;61(5):995-1007. doi: 10.1111/epi.16508Objective:We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAEs).Methods:We deeply phenotyped patients with MAE for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies.Results:We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including 5 previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified 3 new candidate genes, ASH1L, CHD4, and SMARCA2 in 1 patient each.Significance:MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.

Cost-Effectiveness of Cannabidiol Adjunct Therapy versus Usual Care for the Treatment of Seizures in Lennox-Gastaut Syndrome.

Cannabidiol (CBD) is a novel therapy for the treatment of Lennox-Gastaut Syndrome (LGS), a rare, treatment-refractory epileptic encephalopathy. Two pivotal trials found CBD 20mg/kg/day conferred a reduction from baseline in median drop seizure frequency of 44% and 42%, respectively, compared with 22% and 17%, respectively, in the usual care arms. No economic evaluations have been published to date. This analysis assessed the cost effectiveness of CBD adjunct therapy compared with usual care alone in LGS from the US payer perspective. We developed a lifetime horizon Markov decision analytic model. Efficacy, healthcare costs (2020 US$), and health state utilities were ascertained from published clinical trials, retrospective analyses, and time trade-off interviews conducted in the UK, respectively. Fifteen-year-old patients entering the model transitioned to states representing a percentage reduction in drop seizure frequency from baseline, where they remained until reverting back to baseline drop seizure frequency, or death. One-way and probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty, and scenario analyses investigated the impact of various assumptions. Costs and outcomes were discounted at 3%. Compared with usual care alone, CBD yielded 0.7 additional quality-adjusted life-years (QALYs) and $314,900 additional healthcare expenditure, resulting in $451,800 per QALY. Uncertainty in health state utilities were the largest contributor to uncertainty in the results. Results from the 5000-simulation probabilistic sensitivity analysis indicated a 0% chance of CBD being cost effective at a $150,000 per QALY willingness-to-pay threshold, with a 95% credible range for the incremental cost-effectiveness ratio of $325,300-$690,000 per QALY. CBD does not appear to be a cost-effective therapeutic option in LGS patients at a willingness-to-pay threshold of $150,000/QALY.

Phenotypic spectrum of patients with GABRB2 variants: from mild febrile seizures to severe epileptic encephalopathy.

To characterize the different phenotypes of GABRB2-related epilepsy and to establish a genotype-phenotype correlation. We used next-generation sequencing to identify GABRB2 variants in 15 patients. Eleven GABRB2 variants were novel and 12 were de novo. The age at the onset of seizures ranged from 1day to 26months. Nine patients had multiple seizure types, including focal seizures, generalized tonic-clonic seizures, myoclonic seizures, epileptic spasms, and atonic seizures. Seizures were fever-sensitive in 13 out of the 15 patients. Eleven patients displayed developmental delay, while 11 had abnormal video electroencephalography. Abnormalities in the brain images included dysplasia of the frontal and temporal cortex, dysplasia of the corpus callosum, and delayed myelination in four patients. One patient was diagnosed with febrile seizures, three with febrile seizures plus, three with Dravet syndrome, three with West syndrome, one with Ohtahara syndrome, three with developmental delays and epilepsy, and one with non-specific early-onset epileptic encephalopathy. The most common phenotypes of patients with GABRB2 variants include early onset of seizure and fever sensitivity. Febrile seizures and febrile seizures plus are new phenotypes of GABRB2 variants. The phenotypic spectrum of GABRB2 variants ranges from mild febrile seizures to severe epileptic encephalopathy.

Etiology and Types of Seizures in Patients Presenting to a Tertiary Care Hospital in Karachi: A Cross-Sectional Study.

IntroductionEpilepsy is a burdensome disorder for affected individuals and community. There is limited data available on the epidemiological aspects of seizures in Pakistan and further research is necessary. We aimed to fill this gap by studying this information in epilepsy patients presenting to our neurology department. The purpose of this study is to evaluate the causes and types of seizures among the target population.MethodThis is a cross-sectional study conducted at the Department of Neurology, Dr. Ruth K.M. Pfau Civil Hospital Karachi. In this study we evaluated the causes and types of seizures among patients presenting to our department during the two-year study duration (January 2018-December 2019). Informed consent was taken. Detailed history was taken including features of seizure episodes, age at first seizure, family history and comorbid conditions. Relevant investigations were carried out. The data was compiled to deduce the relevant information using SPSS v20.0. T-test and Chi-square were used for analyzing the data.ResultsA total of 996 patients presented during the study duration. Primary seizures were found in 58% cases while secondary seizures were found in 42% cases. This distribution was more equal in children with 49.6% primary seizures and 50.4% secondary seizures; the gap widened in adults with 64.3% primary seizures and 35.7% secondary seizures. The most common cause of secondary seizures was neonatal encephalopathy which was present in 18.7% patients, followed by traumatic head injury in 18.2% patients. Central nervous system (CNS) infection was the cause in 17.9% patients, cerebral tumors in 14.1% patients, stroke in 11.5%, metabolic encephalopathy in 7.4%, febrile seizures in 6.5% and CNS malformations in 5.7% patients. The top three causes in children were neonatal encephalopathy (28.3%), CNS infections (19.3%) and febrile seizures (12.7%). Adults with secondary seizures were diagnosed most often with head trauma (25.2%), cerebral tumors (19.9%) and stroke (18.4%) as causative factors. The most common type of seizures was generalized onset tonic-clonic seizures which was found in 73.0% patients followed by focal to bilateral tonic-clonic seizures in 8.9% patients. Other types of seizures included focal aware seizures in 5.0%, mixed seizure types in 4.2%, focal impaired awareness seizures in 3.1%, absence seizures in 2.7%, myoclonic seizures in 2.0% and atonic seizures in 1.0% patients. Seizures in children were mostly generalized onset tonic-clonic seizures (75.4%), mixed seizure types (5.7%) and focal to bilateral tonic-clonic seizures (5.2%). In adults the three most common types corresponded to the overall result: generalized onset tonic-clonic seizures (71.2%), focal to bilateral tonic-clonic seizures (11.6%) and focal aware seizures (6.6%).ConclusionWe found that the most common cause of seizures overall in our study population was primary seizures, though primary and secondary seizures were more evenly present in children. Among secondary causes neonatal encephalopathy stood out as the most common cause in children; head trauma was the predominant cause in adults. Most common type of seizures overall and in adults was generalized onset tonic-clonic seizures, followed by focal to bilateral tonic-clonic and focal aware seizure types. Pediatric patients presented most often with generalized onset tonic-clonic seizures, followed by mixed seizure types and focal to bilateral tonic-clonic seizures.

Lamotrigine add-on therapy for drug-resistant generalised tonic-clonic seizures.

This is an update of the Cochrane Review first published in 2010; it includes one additional study. Primary generalised tonic-clonic seizures are a type of generalised seizure. Other types of seizures include: absence, myoclonic, and atonic seizures. Effective control of tonic-clonic seizures reduces the risk of injury and death, and improves quality of life. While most people achieve seizure control with one antiepileptic drug, around 30% do not, and require a combination of antiepileptic drugs. To assess the effectiveness and tolerability of add-on lamotrigine for drug-resistant primary generalised tonic-clonic seizures. For the latest update, we searched these databases on 19 March 2019: Cochrane Register of Studies (CRS) Web, MEDLINE Ovid, and the WHO International Clinical Trials Registry Platform (ICTRP). The CRS includes records from the Cochrane Epilepsy Group Specialized Register, CENTRAL, Embase, and ClinicalTrials.gov. We imposed no language restrictions. We also contacted GlaxoSmithKline, manufacturers of lamotrigine. Randomised controlled parallel or cross-over trials of add-on lamotrigine for people of any age with drug-resistant primary generalised tonic-clonic seizures. We followed standard Cochrane methodology; two review authors independently assessed trials for inclusion, evaluated risk of bias, extracted relevant data, and GRADE-assessed evidence. We investigated these outcomes: (1) 50% or greater reduction in primary generalised tonic-clonic seizure frequency; (2) seizure freedom; (3) treatment withdrawal; (4) adverse effects; (5) cognitive effects; and (6) quality of life. We used an intention-to-treat (ITT) population for all analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs); for adverse effects, we used 99% CIs to compensate for multiple hypothesis testing. We included three studies (total 300 participants): two parallel-group studies and one cross-over study. We assessed varied risks of bias across studies; most limitations arose from the poor reporting of methodological details. We meta-analysed data extracted from the two parallel-group studies, and conducted a narrative synthesis for data from the cross-over study. Both parallel-group studies (270 participants) reported all dichotomous outcomes. Participants taking lamotrigine were almost twice as likely to attain a 50% or greater reduction in primary generalised tonic-clonic seizure frequency than those taking a placebo (RR 1.88, 95% CI 1.43 to 2.45; low-certainty evidence). The results between groups were inconclusive for the likelihood of seizure freedom (RR 1.55, 95% CI 0.89 to 2.72; very low-certainty evidence); treatment withdrawal (RR 1.20, 95% CI 0.72 to 1.99; very low-certainty evidence); and individual adverse effects: ataxia (RR 3.05, 99% CI 0.05 to 199.36); dizziness (RR 0.91, 99% CI 0.29 to 2.86; very low-certainty evidence); fatigue (RR 1.02, 99% CI 0.13 to 8.14; very low-certainty evidence); nausea (RR 1.60, 99% CI 0.48 to 5.32; very low-certainty evidence); and somnolence (RR 3.73, 99% CI 0.36 to 38.90; low-certainty evidence). The cross-over trial (26 participants) reported that 7/14 participants with generalised tonic-clonic seizures experienced a 50% or greater reduction in seizure frequency with add-on lamotrigine compared to placebo. The authors reported four treatment withdrawals, but did not specify during which treatment allocation they occurred. Rash (seven lamotrigine participants; zero placebo participants) and fatigue (five lamotrigine participants; zero placebo participants) were the most frequently reported adverse effects. None of the included studies measured cognition. One parallel-group study (N = 153) evaluated quality of life. They reported inconclusive results for the overall quality of life score between groups (P = 0.74). This review provides insufficient information to inform clinical practice. Low-certainty evidence suggests that lamotrigine reduces the rate of generalised tonic-clonic seizures by 50% or more. Very low-certainty evidence found inconclusive results between groups for all other outcomes. Therefore, we are uncertain to very uncertain that the results reported are accurate, and suggest that the true effect could be grossly different. More trials, recruiting larger populations, over longer periods, are necessary to determine lamotrigine's clinical use.

Current knowledge of SLC6A1-related neurodevelopmental disorders.

Advances in gene discovery have identified genetic variants in the solute carrier family 6 member 1 gene as a monogenic cause of neurodevelopmental disorders, including epilepsy with myoclonic atonic seizures, autism spectrum disorder and intellectual disability. The solute carrier family 6 member 1 gene encodes for the GABA transporter protein type 1, which is responsible for the reuptake of the neurotransmitter GABA, the primary inhibitory neurotransmitter in the central nervous system, from the extracellular space. GABAergic inhibition is essential to counterbalance neuronal excitation, and when significantly disrupted, it negatively impacts brain development leading to developmental differences and seizures. Aggregation of patient variants and observed clinical manifestations expand understanding of the genotypic and phenotypic spectrum of this disorder. Here, we assess genetic and phenotypic features in 116 individuals with solute carrier family 6 member 1 variants, the vast majority of which are likely to lead to GABA transporter protein type 1 loss-of-function. The knowledge acquired will guide therapeutic decisions and the development of targeted therapies that selectively enhance transporter function and may improve symptoms. We analysed the longitudinal and cell type-specific expression of solute carrier family 6 member 1 in humans and localization of patient and control missense variants in a novel GABA transporter protein type 1 protein structure model. In this update, we discuss the progress made in understanding and treating solute carrier family 6 member 1-related disorders thus far, through the concerted efforts of clinicians, scientists and family support groups.

Clinical spectrum of KIAA2022/NEXMIF pathogenic variants in males and females: Report of three patients from Indian kindred with a review of published patients

BackgroundIn the last two decades, with the advent of whole-exome and whole-genome sequencing, supplemented with linkage analysis, more than 150 genes responsible for X-linked intellectual disability have been identified. Some genes like NEXMIF remain an enigmatic entity, as often the carrier females show wide phenotypic diversity ranging from completely asymptomatic to severe intellectual disability and drug-resistant epilepsy. MethodsWe report three patients with pathogenic NEXMIF variants from an Indian family. All of them had language predominant developmental delay and later progressed to moderate intellectual disability with autistic features. We also reviewed the previously published reports of patients with pathogenic NEXMIF variants. ResultsTogether with the presented cases, 45 cases (24 symptomatic females) were identified from 15 relevant research items for analysis. Males have demonstrated a more severe intellectual disability and increasingly delayed walking age, autistic features, central hypotonia, and gastroesophageal reflux. In contrast, females have shown a predominant presentation with drug-resistant epilepsy and mild to moderate intellectual impairment. Notably, the affected females demonstrate a higher incidence of myoclonic, absence, and atonic seizures. The majority of the variants reported are nonsense or frameshift mutations, causing loss of function of the NEXMIF gene, while a considerable proportion possesses chromosomal translocations, microdeletions, and duplications. ConclusionsNEXMIF gene mutations should be suspected in all cases of X-linked ID and autism cases in males or even in refractory epilepsy cases in females.

Atonic seizures in children: a meta-analysis comparing corpus callosotomy to vagus nerve stimulation.

Atonic seizures are associated with a particularly poor response to medical treatment. We performed a systematic review and meta-analysis to compare the efficacy of corpus callosotomy (CC) and vagus nerve stimulation (VNS) in the management of atonic seizures in the pediatric population. A literature search was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and recommendations, focusing on atonic seizures, CC, and VNS in pediatric populations. Pertinent clinical data were extracted and analyzed. Pooled effects between groups were calculated as standardized error (SE) with 95% confidence intervals (CIs). To assess for statistical significance, the Z-test was performed, using the pooled effect size (ES) and 95% CI for each intervention. A total of 31 studies met the inclusion criteria, with 24 studies encompassing 425 children treated with CC and 7 studies encompassing 108 children treated with VNS. Twenty-four studies were included in a meta-analysis. There was a statistically significant difference in the primary outcome of atonic seizure control in favor of CC (overall effect size (ES) 0.73, 95% CI 0.69-0.77 for CC, ES 0.4, 95% CI 0.28-0.51 for VNS, p = 0.003). There was a higher rate of complications requiring reoperation in the CC cohort (6.6% vs. 3.8%) and a 14% rate of symptomatic disconnection syndrome. While both techniques are safe, CC provides a much higher chance of effectively managing this morbid seizure type albeit with a higher risk of re-operation and disconnection syndrome.