The Experts below are selected from a list of 2403 Experts worldwide ranked by ideXlab platform
Rima Nabbout - One of the best experts on this subject based on the ideXlab platform.
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Reply to Dravet, C. Different Outcomes of Acute Encephalopathy after Status Epilepticus in Patients with Dravet Syndrome. How to Avoid Them? Comment on “De Liso et al. Fatal Status Epilepticus in Dravet Syndrome. Brain Sci. 2020, 10, 889”
'MDPI AG', 2021Co-Authors: Paola De Liso, Rima Nabbout, Virginia Pironi, Massimo Mastrangelo, Domenica Battaglia, Dana Craiu, Marina Trivisano, Nicola Specchio, Federico VigevanoAbstract:It has been an honor for us to receive a comment on our article “Fatal Status Epilepticus in Dravet Syndrome” [...
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fenfluramine for treatment resistant seizures in patients with Dravet Syndrome receiving stiripentol inclusive regimens a randomized clinical trial
JAMA Neurology, 2020Co-Authors: Rima Nabbout, Linda Laux, Sameer M Zuberi, Arun Mistry, Nathalie Villeneuve, Antonio Gilnagel, Rocio Sanchezcarpintero, Ulrich Stephani, Elaine C Wirrell, Kelly G. KnuppAbstract:Importance Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet Syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet Syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet Syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%;P Conclusions and Relevance Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet Syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet Syndrome. Trial Registration ClinicalTrials.gov identifier:NCT02926898
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perception of impact of Dravet Syndrome on children and caregivers in multiple countries looking beyond seizures
Developmental Medicine & Child Neurology, 2019Co-Authors: Rima Nabbout, Ingrid E. Scheffer, Catherine Chiron, Renzo Guerrini, Amy L. Schneider, Stéphane Auvin, Helen Cross, Nicola WilliamsonAbstract:AIM: To assess the relevance and generalizability across countries of concepts of the impact of Dravet Syndrome beyond seizures, as recognized by families. METHOD: Caregivers of children with Dravet Syndrome in four countries (Australia [n=8]; USA, UK, and Italy [all n=4]) participated in 1-hour qualitative telephone interviews, identifying key Dravet Syndrome concepts. Interviews were recorded, transcribed, and, where necessary, translated into English for thematic analysis. Conceptual saturation was assessed and findings compared to the previously developed French conceptual disease model. RESULTS: The most common seizure types reported by caregivers were tonic-clonic, absence, or focal-impaired awareness (localized/partial). Fever and physical activity were the most commonly reported triggers. Patient-relevant impacts included impairment in cognition, motor skills, communication, social skills, and behavioural functioning. Caregivers consistently reported negative social, physical, and family impacts. Concepts identified in the interviews showed similarity with the French conceptual model. Minor differences between countries are likely to reflect variations in health care systems. INTERPRETATION: Findings in Italy, Australia, UK, and USA confirm that the key impacts of Dravet Syndrome on children and caregivers identified in France are generalizable across countries. Key symptom and impact concepts relevant to children and parents should be targeted as critical outcomes in new therapy evaluations. WHAT THIS PAPER ADDS: Relevance of the impact of Dravet Syndrome on children and caregivers was confirmed across countries. Patient and caregiver-relevant Dravet Syndrome impacts contribute to poorer health-related quality of life. Indirect seizure impacts were reported to be as important as direct impacts. Country-specific differences in concepts probably reflect differences in health care systems.
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Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
New England Journal of Medicine, 2017Co-Authors: Orrin Devinsky, Eric D. Marsh, Elizabeth A Thiele, Ingrid E. Scheffer, Linda Laux, Ian Miller, Rima Nabbout, Stephen WrightAbstract:BackgroundThe Dravet Syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet Syndrome. MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet Syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period. ResultsThe median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence i...
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motor neuropathy contributes to crouching in patients with Dravet Syndrome
Neurology, 2016Co-Authors: Cyril Gitiaux, Catherine Chiron, Nicole Chemaly, Susana Quijanoroy, Christine Barnerias, Isabelle Desguerre, Marie Hully, Olivier Dulac, Rima NabboutAbstract:Objective: Since SCN1A is expressed in the motor neuron initial segment, we explored whether motor neuron dysfunction could contribute to gait disturbance and orthopedic misalignment in patients with Dravet Syndrome due to SCN1A mutations. Methods: We assessed 12 consecutive patients who presented to our institution between January and March 2013. All of them were older than 2 years and were positive for the SCN1A mutation. We performed nerve conduction velocity studies and needle EMG recordings. Results: We included 4 females and 8 males aged 2 to 17 years (median 7.5 years). All 12 patients showed gait disturbance regardless of age. Tendon reflexes were decreased in 4 of 12 patients. None presented cerebellar signs such as tremor, dysmetria, or adiadochokinesia. Nerve conduction study was normal or nearly normal in all patients, but EMG showed features of chronic denervation. Motor neuropathy/neuronopathy was definite in 7 patients and probable in 3. Conclusions: SCN1A mutations may alter axonal function, causing motor neuropathy/neuronopathy. This may contribute to gait disturbance and orthopedic misalignment, which is characteristic of patients with Dravet Syndrome.
Ingrid E. Scheffer - One of the best experts on this subject based on the ideXlab platform.
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Dravet Syndrome a quick transition guide for the adult neurologist
Epilepsy Research, 2021Co-Authors: Danielle M. Andrade, Kelly G. Knupp, Linda Laux, Sookyong Koh, Ian Miller, Anne T Berg, Veronica Hood, Mary Anne Meskis, Scott M Perry, Ingrid E. SchefferAbstract:Abstract Introduction Dravet Syndrome (DS) is still seen as a “pediatric disease”, where patients receive excellent care in pediatric centers, but care is less than optimal in adult health care systems (HCS). This creates a barrier when young adults need to leave the family-centered pediatric system and enter the adult, patient-centered HCS. Here we create a guide to help with the transition from pediatric to adult for patients with DS. Methods Experts in Dravet Syndrome flagged the main barriers in caring for adults with DS and created a 2-page transition summary guide based on their expertise and a literature review. Results The 2-page guide addresses: DS diagnosis in children and adults; clinical manifestations, including the differences in seizures types and frequencies between children and adults with DS; the natural history of intellectual disability, behavior, gait, motor disorders and dysautonomia; a review of optimal treatments (including medications not commonly used in adult epilepsy settings such as stiripentol and fenfluramine), as well as emergency seizure management; avoidance of triggers, preventive measures, and vaccine administration in adults with DS. Conclusion Several young adults with DS are still followed by their child neurologist. This 2-page transition guide should help facilitate the transition of patients with DS to the adult HCS and should be given to families as well as adult health care providers that may not be familiar with DS.
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perception of impact of Dravet Syndrome on children and caregivers in multiple countries looking beyond seizures
Developmental Medicine & Child Neurology, 2019Co-Authors: Rima Nabbout, Ingrid E. Scheffer, Catherine Chiron, Renzo Guerrini, Amy L. Schneider, Stéphane Auvin, Helen Cross, Nicola WilliamsonAbstract:AIM: To assess the relevance and generalizability across countries of concepts of the impact of Dravet Syndrome beyond seizures, as recognized by families. METHOD: Caregivers of children with Dravet Syndrome in four countries (Australia [n=8]; USA, UK, and Italy [all n=4]) participated in 1-hour qualitative telephone interviews, identifying key Dravet Syndrome concepts. Interviews were recorded, transcribed, and, where necessary, translated into English for thematic analysis. Conceptual saturation was assessed and findings compared to the previously developed French conceptual disease model. RESULTS: The most common seizure types reported by caregivers were tonic-clonic, absence, or focal-impaired awareness (localized/partial). Fever and physical activity were the most commonly reported triggers. Patient-relevant impacts included impairment in cognition, motor skills, communication, social skills, and behavioural functioning. Caregivers consistently reported negative social, physical, and family impacts. Concepts identified in the interviews showed similarity with the French conceptual model. Minor differences between countries are likely to reflect variations in health care systems. INTERPRETATION: Findings in Italy, Australia, UK, and USA confirm that the key impacts of Dravet Syndrome on children and caregivers identified in France are generalizable across countries. Key symptom and impact concepts relevant to children and parents should be targeted as critical outcomes in new therapy evaluations. WHAT THIS PAPER ADDS: Relevance of the impact of Dravet Syndrome on children and caregivers was confirmed across countries. Patient and caregiver-relevant Dravet Syndrome impacts contribute to poorer health-related quality of life. Indirect seizure impacts were reported to be as important as direct impacts. Country-specific differences in concepts probably reflect differences in health care systems.
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stiripentol efficacy and safety in Dravet Syndrome a 12 year observational study
Developmental Medicine & Child Neurology, 2018Co-Authors: Kenneth A Myers, Helen J Cross, Paul Lightfoot, Shekhar Patil, Ingrid E. SchefferAbstract:AIM To assess long-term safety and efficacy of stiripentol as an antiepileptic medication for people with Dravet Syndrome. METHOD A prospective, observational open-label study (2003-2015) of the efficacy and long-term safety of stiripentol in patients with Dravet Syndrome and ongoing seizures. Frequency of generalized tonic-clonic seizures, focal seizures, status epilepticus, and adverse events were recorded. RESULTS Forty-one patients started stiripentol, with median age at enrolment 5 years 7 months (range 11mo-22y) and median duration of treatment 37 months (range 2-141mo). Twenty out of 41 patients had greater than or equal to 50% long-term reduction in frequency of generalized tonic-clonic seizures. Frequency of focal seizures was decreased by greater than or equal to 50% in 11 out of 23 patients over the long-term. Frequency of status epilepticus was decreased by 50% or more in 11 out of 26 patients. The most common adverse events were anorexia, weight loss, sedation, and behavioural changes. One patient had worsening of absence and myoclonic seizures. Another developed recurrent pancreatitis on concurrent valproate. INTERPRETATION Stiripentol improves long-term seizure frequency in approximately 50% of patients with Dravet Syndrome, when used as part of unrestricted polytherapy. Long-term use appears safe. In more than 40% of patients, episodes of status epilepticus markedly decrease after stiripentol initiation. What this paper adds Frequency of status epilepticus is reduced in 40% of patients with Dravet Syndrome after stiripentol initiation. Stiripentol is effective for generalized tonic-clonic and focal seizures. Stiripentol can be safely used with a range of antiepileptic drugs.
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Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
New England Journal of Medicine, 2017Co-Authors: Orrin Devinsky, Eric D. Marsh, Elizabeth A Thiele, Ingrid E. Scheffer, Linda Laux, Ian Miller, Rima Nabbout, Stephen WrightAbstract:BackgroundThe Dravet Syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet Syndrome. MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet Syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period. ResultsThe median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence i...
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Lamotrigine can be beneficial in patients with Dravet Syndrome
Developmental Medicine & Child Neurology, 2014Co-Authors: Linda Dalic, Saul A. Mullen, Eliane Roulet Perez, Ingrid E. SchefferAbstract:Dravet Syndrome, a severe infantile epilepsy Syndrome, is typically resistant to anti-epileptic drugs (AED). Lamotrigine (LTG), an AED that is effective for both focal and generalized seizures, has been reported to aggravate seizures in Dravet Syndrome. Therefore, LTG is usually avoided in Dravet Syndrome. We describe two adults and a child with Dravet Syndrome in whom LTG resulted in decreased seizure duration and frequency. This benefit was highlighted in each patient when LTG was withdrawn after 6 to 15 years, and resulted in an increased frequency of convulsive seizures together with longer seizure duration. A 25-year-old male required hospital admission for frequent seizures for the first time in 7 years, 6 weeks after ceasing LTG. Reintroduction of LTG improved seizure control, suggesting that in some patients with Dravet Syndrome, LTG may be beneficial.
Kelly G. Knupp - One of the best experts on this subject based on the ideXlab platform.
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Dravet Syndrome a quick transition guide for the adult neurologist
Epilepsy Research, 2021Co-Authors: Danielle M. Andrade, Kelly G. Knupp, Linda Laux, Sookyong Koh, Ian Miller, Anne T Berg, Veronica Hood, Mary Anne Meskis, Scott M Perry, Ingrid E. SchefferAbstract:Abstract Introduction Dravet Syndrome (DS) is still seen as a “pediatric disease”, where patients receive excellent care in pediatric centers, but care is less than optimal in adult health care systems (HCS). This creates a barrier when young adults need to leave the family-centered pediatric system and enter the adult, patient-centered HCS. Here we create a guide to help with the transition from pediatric to adult for patients with DS. Methods Experts in Dravet Syndrome flagged the main barriers in caring for adults with DS and created a 2-page transition summary guide based on their expertise and a literature review. Results The 2-page guide addresses: DS diagnosis in children and adults; clinical manifestations, including the differences in seizures types and frequencies between children and adults with DS; the natural history of intellectual disability, behavior, gait, motor disorders and dysautonomia; a review of optimal treatments (including medications not commonly used in adult epilepsy settings such as stiripentol and fenfluramine), as well as emergency seizure management; avoidance of triggers, preventive measures, and vaccine administration in adults with DS. Conclusion Several young adults with DS are still followed by their child neurologist. This 2-page transition guide should help facilitate the transition of patients with DS to the adult HCS and should be given to families as well as adult health care providers that may not be familiar with DS.
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fenfluramine for treatment resistant seizures in patients with Dravet Syndrome receiving stiripentol inclusive regimens a randomized clinical trial
JAMA Neurology, 2020Co-Authors: Rima Nabbout, Linda Laux, Sameer M Zuberi, Arun Mistry, Nathalie Villeneuve, Antonio Gilnagel, Rocio Sanchezcarpintero, Ulrich Stephani, Elaine C Wirrell, Kelly G. KnuppAbstract:Importance Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet Syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet Syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet Syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%;P Conclusions and Relevance Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet Syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet Syndrome. Trial Registration ClinicalTrials.gov identifier:NCT02926898
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Stiripentol for the treatment of seizures in Dravet Syndrome.
Expert Review of Clinical Pharmacology, 2019Co-Authors: Krista Eschbach, Kelly G. KnuppAbstract:INTRODUCTION Dravet Syndrome is an early childhood-onset epilepsy Syndrome characterized by drug-resistant seizures, frequent episodes of status epilepticus, and the development of neurocognitive impairment. Seizure freedom in this condition is rare and there is a higher rate of sudden unexplained death in epilepsy patients (SUDEP) than other epilepsy Syndromes. Stiripentol is a recently approved medication with an indication specifically for the treatment of seizures in children with Dravet Syndrome. Areas covered: Review of relevant literature including the current and emerging treatment of seizures in children with Dravet Syndrome, with a focus on stiripentol. This includes a review of the literature regarding the mechanism of action, clinical efficacy, and safety/tolerability of stiripentol. Expert opinion: Stiripentol has been available through expanded access programs resulting in a reduction of seizures and episodes of status epilepticus. With the Federal Drug Administration (FDA) approval, this treatment option will be more readily available to the Dravet Syndrome population in the United States. The approval comes at a time of other treatment options also receiving approval (cannabidiol) and several products in ongoing studies (fenfluramine, TAK-935) providing additional treatment options and hope on the horizon for those impacted by this severe epilepsy Syndrome.
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Clemizole and modulators of serotonin signalling suppress seizures in Dravet Syndrome
Brain, 2017Co-Authors: Aliesha Griffin, Kelly G. Knupp, Kyla R. Hamling, Soongweon Hong, Luke P. Lee, Scott C BarabanAbstract:Dravet Syndrome is a catastrophic childhood epilepsy with early-onset seizures, delayed language and motor development, sleep disturbances, anxiety-like behaviour, severe cognitive deficit and an increased risk of fatality. It is primarily caused by de novo mutations of the SCN1A gene encoding a neuronal voltage-activated sodium channel. Zebrafish with a mutation in the SCN1A homologue recapitulate spontaneous seizure activity and mimic the convulsive behavioural movements observed in Dravet Syndrome. Here, we show that phenotypic screening of drug libraries in zebrafish scn1 mutants rapidly and successfully identifies new therapeutics. We demonstrate that clemizole binds to serotonin receptors and its antiepileptic activity can be mimicked by drugs acting on serotonin signalling pathways e.g. trazodone and lorcaserin. Coincident with these zebrafish findings, we treated five medically intractable Dravet Syndrome patients with a clinically-approved serotonin receptor agonist (lorcaserin, Belviq®) and observed some promising results in terms of reductions in seizure frequency and/or severity. Our findings demonstrate a rapid path from preclinical discovery in zebrafish, through target identification, to potential clinical treatments for Dravet Syndrome.
Sameer M Zuberi - One of the best experts on this subject based on the ideXlab platform.
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fenfluramine for treatment resistant seizures in patients with Dravet Syndrome receiving stiripentol inclusive regimens a randomized clinical trial
JAMA Neurology, 2020Co-Authors: Rima Nabbout, Linda Laux, Sameer M Zuberi, Arun Mistry, Nathalie Villeneuve, Antonio Gilnagel, Rocio Sanchezcarpintero, Ulrich Stephani, Elaine C Wirrell, Kelly G. KnuppAbstract:Importance Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet Syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet Syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet Syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%;P Conclusions and Relevance Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet Syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet Syndrome. Trial Registration ClinicalTrials.gov identifier:NCT02926898
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Dravet Syndrome from epileptic encephalopathy to channelopathy
Epilepsia, 2014Co-Authors: Andreas Brunklaus, Sameer M ZuberiAbstract:Mutations in the gene encoding the α1 subunit of the voltage gated sodium channel (SCN1A) are associated with several epilepsy Syndromes, ranging from relatively mild phenotypes found in families with genetic epilepsy with febrile seizures plus (GEFS+) to the severe infant-onset epilepsy Dravet Syndrome. Evidence has emerged of the consequences of SCN1α dysfunction in different neuronal networks across the brain pointing toward a channelopathy model causing the neurologic features of Dravet Syndrome that is beyond purely seizure related damage. A genetic change will present according to its severity, the genetic background of the individual, and environmental factors, and will affect a variety of neuronal networks according to channel distribution. This already-vulnerable system may be susceptible to secondary aggravating events such as status epilepticus. The channelopathy model implies that pharmacologic treatment and the restoration of impaired γ-aminobutyric acid (GABA)ergic neurotransmission might not only help prevent seizures but might affect the comorbidities of the Syndrome. This critical review explores recent evidence relating to the pathogenicity of SCN1A mutations in Dravet Syndrome and the effect these have on the wider disease phenotype and discusses whether knowledge of specific genotypes can influence clinical practice. Genetic technology is currently advancing at unprecedented speed and will increase our knowledge of new genes and interacting genetic networks. Clinicians and geneticists will have to work in close collaboration to guarantee good delivery and counseling of genetic testing results.
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prognostic clinical and demographic features in scn1a mutation positive Dravet Syndrome
Brain, 2012Co-Authors: Rachael Ellis, Andreas Brunklaus, Eleanor Reavey, G H Forbes, Sameer M ZuberiAbstract:Dravet Syndrome is a severe infantile onset epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. To date no large studies have systematically examined the prognostic, clinical and demographic features of the disease. We prospectively collected data on a UK cohort of individuals with Dravet Syndrome during a 5-year study period and analysed demographic information based on UK population and birth figures. From structured referral data we examined a range of clinical characteristics including epilepsy phenotype, seizure precipitants, electroencephalography data, imaging studies, mutation class and response to medication. Predictors of developmental outcome were determined by logistic regression. We identified 241 cases with SCN1A mutation-positive Dravet Syndrome, 207 of which were UK-based. The incidence of mutation-positive Dravet Syndrome is at least 1:40 900 UK births. Clinical features predicting a worse developmental outcome included status epilepticus (odds ratio = 3.1; confidence interval = 1.5-6.3; P = 0.003), interictal electroencephalography abnormalities in the first year of life (odds ratio = 5.7; confidence interval = 1.9-16.8; P = 0.002) and motor disorder (odds ratio = 3.3; confidence interval = 1.7-6.4; P < 0.001). No significant effect was seen for seizure precipitants, magnetic resonance imaging abnormalities or mutation class (truncating versus missense). Abnormal magnetic resonance imaging was documented in 11% of cases, principally with findings of non-specific brain atrophy or hippocampal changes. Sodium valproate, benzodiazepines and topiramate were reported as being the most helpful medications at the time of referral. Aggravation of seizures was reported for carbamazepine and lamotrigine. The identification of factors influencing prognosis both aids counselling and encourages early, Syndrome-specific therapy. Prevention of status epilepticus with regular medication and emergency protocols is important and may influence developmental outcome.
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comorbidities and predictors of health related quality of life in Dravet Syndrome
Epilepsia, 2011Co-Authors: Andreas Brunklaus, Liam Dorris, Sameer M ZuberiAbstract:Summary Purpose: Health-related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual’s physical, social, and mental well-being. There is a paucity of data focusing on HRQOL in specific epilepsy Syndromes and their associated needs. In this study our aim was to describe the comorbidities and disease-related predictors for HRQOL in Dravet Syndrome, an epileptic encephalopathy, with defined genetic etiology. We anticipate that this will help us to better recognize and understand the needs of children and families and aid treatment planning in this severe epilepsy Syndrome. Methods: One hundred sixty-three individuals with Dravet Syndrome and their families participated in the study. Detailed clinical and demographic information was available for each case. HRQOL was evaluated with two epilepsy-specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL); a generic HRQOL instrument; the Pediatric Quality of Life Inventory (PedsQL); and a behavioral screening tool, the Strength and Difficulties Questionnaire (SDQ). Key Findings: HRQOL was significantly lower for children with Dravet Syndrome compared to normative data (p < 0.001). A cross-sectional evaluation of measures across different age groups revealed that PedsQL generic core and cognitive function scales decreased in older age categories, indicating worse HRQOL (p < 0.001). Assessment of epilepsy severity demonstrated that symptoms were rated very severe in 10 (6%) of 162 cases, somewhat severe in 78 (48%) of 162, moderate in 51 (32%) of 162, and mild in 23 (14%) of 162 cases. The epilepsy severity correlated significantly with the IPES total impact score (r = 0.466, p < 0.001, n = 162). The IPES total impact scores in the Dravet group (n = 162) were significantly higher than scores measured in the original validation sample of epileptic children with and without learning difficulties (± SD) (21.0 ± 8.7 vs. 11.6 ± 5.4, t = 8.95, p < 0.001, n = 46). On the SDQ, 35% of children scored in the abnormal range for “conduct problems,” 66% for “hyperactivity/ inattention,” and 76% for “peer relationships.” Regression analysis revealed that young age at seizure onset (p = 0.019), presence of myoclonic seizures (p = 0.029), motor disorder (p = 0.048), learning difficulties (p = 0.002), epilepsy severity (p < 0.001), and behavioral difficulties (p < 0.001) each independently predicted poorer HRQOL. Behavioral problems such as hyperactivity/inattention were the strongest predictors of poorer HRQOL. Significance: This is the first comprehensive study of HRQOL in an etiologically well-defined epilepsy Syndrome. HRQOL in Dravet Syndrome depends on a series of independent factors including seizure control, behavior, cognitive, and motor problems. Identification of specific comorbidities in Dravet Syndrome will facilitate a distinct and multidisciplinary approach to management, addressing seizure control, behavior problems, cognitive difficulties, and motor impairment.
Linda Laux - One of the best experts on this subject based on the ideXlab platform.
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Dravet Syndrome a quick transition guide for the adult neurologist
Epilepsy Research, 2021Co-Authors: Danielle M. Andrade, Kelly G. Knupp, Linda Laux, Sookyong Koh, Ian Miller, Anne T Berg, Veronica Hood, Mary Anne Meskis, Scott M Perry, Ingrid E. SchefferAbstract:Abstract Introduction Dravet Syndrome (DS) is still seen as a “pediatric disease”, where patients receive excellent care in pediatric centers, but care is less than optimal in adult health care systems (HCS). This creates a barrier when young adults need to leave the family-centered pediatric system and enter the adult, patient-centered HCS. Here we create a guide to help with the transition from pediatric to adult for patients with DS. Methods Experts in Dravet Syndrome flagged the main barriers in caring for adults with DS and created a 2-page transition summary guide based on their expertise and a literature review. Results The 2-page guide addresses: DS diagnosis in children and adults; clinical manifestations, including the differences in seizures types and frequencies between children and adults with DS; the natural history of intellectual disability, behavior, gait, motor disorders and dysautonomia; a review of optimal treatments (including medications not commonly used in adult epilepsy settings such as stiripentol and fenfluramine), as well as emergency seizure management; avoidance of triggers, preventive measures, and vaccine administration in adults with DS. Conclusion Several young adults with DS are still followed by their child neurologist. This 2-page transition guide should help facilitate the transition of patients with DS to the adult HCS and should be given to families as well as adult health care providers that may not be familiar with DS.
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fenfluramine for treatment resistant seizures in patients with Dravet Syndrome receiving stiripentol inclusive regimens a randomized clinical trial
JAMA Neurology, 2020Co-Authors: Rima Nabbout, Linda Laux, Sameer M Zuberi, Arun Mistry, Nathalie Villeneuve, Antonio Gilnagel, Rocio Sanchezcarpintero, Ulrich Stephani, Elaine C Wirrell, Kelly G. KnuppAbstract:Importance Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet Syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. Objective To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet Syndrome who were taking stiripentol-inclusive regimens. Design, Setting, and Participants This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet Syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. Interventions Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients’ assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. Main Outcomes and Measures The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. Results A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%;P Conclusions and Relevance Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet Syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet Syndrome. Trial Registration ClinicalTrials.gov identifier:NCT02926898
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fenfluramine hydrochloride for the treatment of seizures in Dravet Syndrome a randomised double blind placebo controlled trial
The Lancet, 2019Co-Authors: Lieven Lagae, Renzo Guerrini, Linda Laux, Orrin Devinsky, Joseph Sullivan, Tilman Polster, Marina Nikanorova, Helen J Cross, Dinesh TalwarAbstract:Summary Background Dravet Syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet Syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet Syndrome. Methods In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet Syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863 . Findings Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p Interpretation In Dravet Syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet Syndrome. Funding Zogenix.
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Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome
New England Journal of Medicine, 2017Co-Authors: Orrin Devinsky, Eric D. Marsh, Elizabeth A Thiele, Ingrid E. Scheffer, Linda Laux, Ian Miller, Rima Nabbout, Stephen WrightAbstract:BackgroundThe Dravet Syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet Syndrome. MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet Syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period. ResultsThe median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence i...
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stiripentol in Dravet Syndrome results of a retrospective u s study
Epilepsia, 2013Co-Authors: Elaine C Wirrell, Linda Laux, Orrin Devinsky, Joseph Sullivan, David Neal Franz, Russell P Saneto, Richard P Morse, Harry T Chugani, Angel Hernandez, Lorie HamiwkaAbstract:Summary Purpose To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet Syndrome. Methods U.S. clinicians who had prescribed stiripentol for two or more children with Dravet Syndrome between March 2005 and 2012 were contacted to request participation in this retrospective study. Data collected included overall seizure frequency, frequency of prolonged seizures, and use of rescue medications and emergency room (ER)/hospital visits in the year preceding stiripentol initiation, and with stiripentol therapy. We separately assessed efficacy in the following treatment groups: group A, stiripentol without clobazam or valproate; group B, stiripentol with clobazam but without valproate; group C, stiripentol with valproate but without clobazam; and group D, stiripentol with clobazam and valproate. In addition, adverse effects were recorded. Key Findings Thirteen of 16 clinicians contacted for study participated and provided data on 82 children. Stiripentol was initiated a median of 6.0 years after seizure onset and 1.2 years after diagnosis of Dravet Syndrome. Compared to baseline, overall seizure frequency was reduced in 2/6 in group A, 28/35 in group B, 8/14 in group C, and 30/48 in group D. All children with prolonged seizure frequency greater than quarterly during the baseline period experienced a reduction in this frequency on the various treatment arms with stiripentol. Similarly, 2/4 patients in group A, 25/25 in group B, 5/10 in group C, and 26/33 in group D experienced reduction in frequency of rescue medication use and 1/1 in group A, 12/12 in group B, 3/5 in group C, and 18/19 in group D had reduction in frequency of ER/hospital visits. Adverse effects were reported in 38, most commonly sedation and reduced appetite. Four patients (5%) discontinued stiripentol for adverse effects and two (2%) for lack of efficacy. Significance Stiripentol is an effective and well-tolerated therapy that markedly reduced frequency of prolonged seizures in Dravet Syndrome.
