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Epilepsy Research Aug 2019Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which... (Clinical Trial)
Clinical Trial
BACKGROUND
Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016.
METHODS
Children and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2-10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25-50 mg/kg/day. Patient visits were every 2-4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks.
RESULTS
Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0-10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1-146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%).
CONCLUSIONS
Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.
Topics: Adolescent; Adult; Anticonvulsants; Cannabidiol; Child; Child, Preschool; Diarrhea; Drug Resistant Epilepsy; Duration of Therapy; Epilepsies, Myoclonic; Female; Humans; Infant; Lennox Gastaut Syndrome; Male; Middle Aged; Sleepiness; Treatment Outcome; Young Adult
PubMed: 31022635
DOI: 10.1016/j.eplepsyres.2019.03.015 -
Human Gene Therapy Jun 2022Dravet syndrome (DS) is a developmental and epileptic encephalopathy caused by monoallelic loss-of-function variants in the gene. encodes for the alpha subunit of the...
Cell-Selective Adeno-Associated Virus-Mediated Gene Regulation Therapy Rescues Mortality and Seizure Phenotypes in a Dravet Syndrome Mouse Model and Is Well Tolerated in Nonhuman Primates.
Dravet syndrome (DS) is a developmental and epileptic encephalopathy caused by monoallelic loss-of-function variants in the gene. encodes for the alpha subunit of the voltage-gated type I sodium channel (Na1.1), the primary voltage-gated sodium channel responsible for generation of action potentials in GABAergic inhibitory interneurons. In these studies, we tested the efficacy of an adeno-associated virus serotype 9 (AAV9) gene regulation therapy, AAV9-RE-eTF, designed to target transgene expression to GABAergic inhibitory neurons and reduce off-target expression within excitatory cells, in the mouse model of DS. Biodistribution and preliminary safety were evaluated in nonhuman primates (NHPs). AAV9-RE-eTF was engineered to upregulate expression levels within GABAergic inhibitory interneurons to correct the underlying haploinsufficiency and circuit dysfunction. A single bilateral intracerebroventricular (ICV) injection of AAV9-RE-eTF in postnatal day 1 mice led to increased mRNA transcripts, specifically within GABAergic inhibitory interneurons, and Na1.1 protein levels in the brain. This was associated with a significant decrease in the occurrence of spontaneous and hyperthermia-induced seizures, and prolonged survival for over a year. In NHPs, delivery of AAV9-RE-eTF by unilateral ICV injection led to widespread vector biodistribution and transgene expression throughout the brain, including key structures involved in epilepsy and cognitive behaviors, such as hippocampus and cortex. AAV9-RE-eTF was well tolerated, with no adverse events during administration, no detectable changes in clinical observations, no adverse findings in histopathology, and no dorsal root ganglion-related toxicity. Our results support the clinical development of AAV9-RE-eTF (ETX101) as an effective and targeted disease-modifying approach to SCN1A DS.
Topics: Animals; Dependovirus; Disease Models, Animal; Epilepsies, Myoclonic; Epileptic Syndromes; Mice; NAV1.1 Voltage-Gated Sodium Channel; Phenotype; Primates; Seizures; Spasms, Infantile; Tissue Distribution; gamma-Aminobutyric Acid
PubMed: 35435735
DOI: 10.1089/hum.2022.037 -
Revue Neurologique Sep 2022Developmental and epileptic encephalopathies are conditions where there is developmental impairment related to both the underlying etiology independent of epileptiform... (Review)
Review
Developmental and epileptic encephalopathies are conditions where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. Usually they have multiple etiologies. Therefore, long-term outcome is related to both etiology-related factors and epilepsy-related factors-age at onset of epilepsy, type(s) of seizure(s), type of electroencephalographic abnormalities, duration of the epileptic disorder. This paper focuses on long-term outcome of six developmental and epileptic encephalopathies with onset from the neonatal period to childhood: early epileptic encephalopathy with suppression bursts, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, epilepsy with myoclonic atonic seizures and epileptic encephalopathy with continuous spike and waves during slow-wave sleep including Landau-Kleffner syndrome. For each syndrome, definition, main etiologies if multiple, and long-term outcome are discussed.
Topics: Child; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Humans; Infant, Newborn; Lennox Gastaut Syndrome; Seizures; Spasms, Infantile
PubMed: 35489823
DOI: 10.1016/j.neurol.2022.01.009 -
Brain & Development Jun 2021Our goal was to investigate the long-term clinical course of juvenile myoclonic epilepsy (JME) in a cohort of patients and to identify prognostic factors for... (Review)
Review
OBJECTIVE
Our goal was to investigate the long-term clinical course of juvenile myoclonic epilepsy (JME) in a cohort of patients and to identify prognostic factors for refractoriness and seizure relapse after anti-seizure medications (ASMs) withdrawal. A literature review is also presented to consolidate and compare our findings with the previously reported cases.
METHODS
We retrospectively studied a series of patients diagnosed with JME with 15 years or more of evolution. We collected clinical, neurophysiological and neuroimaging data from patients who met defined inclusion and exclusion criteria.
RESULTS
Study involved 61 patients (65.5% female) with mean age at study of 37.6 years, and mean age at its outset of 14.8 years. Median follow-up was 31.0 years (mean 28.9, range 15-53). They presented more frequently with a combination of myoclonic and generalized tonic-clonic seizures (GTCS) (65.6%). Sixty-five percent of patients (n = 40) had a 5-year terminal remission with a mean age at last seizure of 27.4 years. Thirty-two percent of seizure-free patients (n = 13) withdrew ASMs: 6 out of 13 had a recurrence of the seizures while 7 remained seizure-free (mean age at ASMs withdrawal 21.0 versus 35.7 years, p < 0.05). In the multivariate model, a high GTCS frequency at onset (p = 0.026) was a prognostic factor of drug resistance.
CONCLUSION
JME is often regarded as a benign epileptic syndrome, although a quarter of the individuals have refractory epilepsy. The possibility of withdrawing ASMs in patients who have been free of seizures over an extended time seems feasible.
Topics: Adult; Anticonvulsants; Drug Resistant Epilepsy; Female; Humans; Longitudinal Studies; Male; Middle Aged; Myoclonic Epilepsy, Juvenile; Outcome Assessment, Health Care; Prognosis; Remission Induction; Retrospective Studies; Risk Factors
PubMed: 33781581
DOI: 10.1016/j.braindev.2021.02.005 -
Practical Neurology Jan 2024A young man from Pakistan had his first-ever tonic-clonic seizure while playing cricket. Since age 12 years, he had reported involuntary jerks and tremulousness,...
A young man from Pakistan had his first-ever tonic-clonic seizure while playing cricket. Since age 12 years, he had reported involuntary jerks and tremulousness, sometimes with falls, particularly with bright lights. Family history included a brother who developed seizures with myoclonus in his mid-20s and parental consanguinity. Developmental history was normal. Examination identified cognitive impairment with action myoclonus. His clinical presentation raised suspicion of a progressive myoclonus epilepsy. MR scan of the brain showed white matter changes suggesting leucodystrophy with cortical atrophy. Electroencephalogram showed generalised epileptiform abnormalities with photoparoxysmal responses, including at low frequencies (1 Hz). Cortical hyperexcitability was confirmed with giant median somatosensory evoked potentials and long loop reflexes at rest. Multichannel electromyography showed action myoclonus with variable synchronous and asynchronous agonist and antagonist muscle activation with short-burst duration of 25-75 ms, and jerk-locked back-averaging showed premyoclonic potentials consistent with cortical myoclonus. Genetic sequencing identified a homozygous missense variant in the gene (c.768C>G p.(Asp256Glu), confirming Kufs disease type A.
Topics: Male; Adult; Humans; Child; Myoclonus; Neuronal Ceroid-Lipofuscinoses; Brain; Electroencephalography; Myoclonic Epilepsies, Progressive; Seizures; Electromyography; Membrane Proteins
PubMed: 37802651
DOI: 10.1136/pn-2022-003652 -
Seizure Aug 2021Epileptic syndromes are well-defined conditions comprising particular clinical features [seizure types, age of onset, response to treatment] and characteristic... (Review)
Review
Epileptic syndromes are well-defined conditions comprising particular clinical features [seizure types, age of onset, response to treatment] and characteristic electroencephalographic changes, while their etiology and subsequent prognosis may vary. The recognition of these syndromes is fundamental for pediatric neurology practice, representing an essential learning topic in this field. Nevertheless, many epileptic syndromes are still quite unfamiliar to students, residents and even neurologists, because of their low incidence and their minimal representation in the literature. This narrative review discusses the concept of epileptic syndromes and revisits seven lesser-known or uncommon syndromes in order to summarize their core clinical features, which can become important clues for daily neurological practice, namely epilepsy of infancy with migrating focal seizures, myoclonic epilepsy of infancy, self-limited infantile epilepsy, myoclonic encephalopathy in nonprogressive disorders, Jeavons syndrome, and epilepsy with myoclonic absences.
Topics: Child; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Reflex; Epileptic Syndromes; Humans; Incidence
PubMed: 34023208
DOI: 10.1016/j.seizure.2021.05.005 -
Arquivos de Neuro-psiquiatria May 2022Cannabidiol (CBD) has become a promising therapeutic option in the treatment of epilepsy. Recent studies provide robust evidence that CBD is effective and safe.... (Review)
Review
BACKGROUND
Cannabidiol (CBD) has become a promising therapeutic option in the treatment of epilepsy. Recent studies provide robust evidence that CBD is effective and safe. Limitations in current knowledge and regulatory issues still limit CBD use. CBD use regarding epilepsy types still lacks clear guidelines.
OBJECTIVE
To critically review the main current pharmacological features and clinical issues regarding CBD use in epilepsy, to provide current regulatory background regarding CBD use in Brazil, and to suggest a practical CBD therapeutic guide in Brazil.
METHODS
Non-systematic literature review (up to February 2022) of current concepts of CBD and epilepsy, including the authors' personal experience.
RESULTS
Five pivotal trials have led to CBD approval as an adjunctive treatment for Dravet and Lennox-Gastaut syndromes, and for the tuberous sclerosis complex. Efficacy of CBD in other drug-resistant epilepsies remains not completely understood. CBD adverse event profile and drug interactions are better understood. CBD is well tolerated. In Brazil, CBD is not classified as a medication, but as a product subject to a distinct regulatory legislation. CBD is still not offered by the National Brazilian health system, but can be purchased in authorized pharmacies or imported under prescription and signed informed consent.
CONCLUSION
CBD is a recognized novel treatment for epilepsy. Future well-designed studies and public health strategies are needed to offer widespread access to CBD, and to improve the quality of life of people living with epilepsy in Brazil.
Topics: Anticonvulsants; Brazil; Cannabidiol; Epilepsies, Myoclonic; Epilepsy; Humans; Quality of Life
PubMed: 35976327
DOI: 10.1590/0004-282X-ANP-2022-S137 -
Seizure Jul 2023The late onset myoclonic epilepsy in Down Syndrome (LOMEDS) is a peculiar epilepsy type characterized by cortical myoclonus and generalized tonic-clonic seizures (GTCS),... (Review)
Review
INTRODUCTION
The late onset myoclonic epilepsy in Down Syndrome (LOMEDS) is a peculiar epilepsy type characterized by cortical myoclonus and generalized tonic-clonic seizures (GTCS), in people suffering from cognitive decline in Down syndrome (DS). In this review, we analyzed available data on the diagnostic and therapeutic management of individuals with LOMEDS.
METHODS
We performed a systematic search of the literature to identify the diagnostic and therapeutic management of patients with LOMEDS. The following databases were used: PubMed, Google Scholar, EMBASE, CrossRef. The protocol was registered on PROSPERO (registration code: CRD42023390748).
RESULTS
Data from 46 patients were included. DS was diagnosed according to the patient's clinical and genetic characteristics. Diagnosis of Alzheimer's dementia (AD) preceded the onset of epilepsy in all cases. Both myoclonic seizures (MS) and generalized tonic-clonic seizures (GTCS) were reported, the latter preceding the onset of MS in 28 cases. EEG was performed in 45 patients, showing diffuse theta/delta slowing with superimposed generalized spike-and-wave or polyspike-and-wave. A diffuse cortical atrophy was detected in 34 patients on neuroimaging. Twenty-seven patients were treated with antiseizure medication (ASM) monotherapy, with reduced seizure frequency in 17 patients. Levetiracetam and valproic acid were the most used ASMs. Up to 41% of patients were unresponsive to first-line treatment and needed adjunctive therapy for seizure control.
CONCLUSIONS
AD-related pathological changes in the brain may play a role in LOMEDS onset, although the mechanism underlying this phenomenon is still unknown. EEG remains the most relevant investigation to be performed. A significant percentage of patients developed a first-line ASM refractory epilepsy. ASMs which modulate the glutamatergic system may represent a good therapeutic option.
Topics: Humans; Down Syndrome; Epilepsy; Epilepsies, Myoclonic; Levetiracetam; Seizures; Alzheimer Disease; Electroencephalography; Anticonvulsants; Epilepsy, Generalized
PubMed: 37267668
DOI: 10.1016/j.seizure.2023.05.017 -
Epilepsia Mar 2024KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a...
OBJECTIVE
KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort.
METHODS
Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized.
RESULTS
Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years).
SIGNIFICANCE
This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.
Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Young Adult; Electroencephalography; Epilepsies, Myoclonic; Myoclonic Epilepsies, Progressive; Potassium Channels; Seizures; Unverricht-Lundborg Syndrome
PubMed: 38231304
DOI: 10.1111/epi.17880 -
Drugs Nov 2019Stiripentol (Diacomit) is an orally-active, structurally unique anti-epileptic drug (AED) with multiple potential mechanisms of action, including enhancement of central... (Review)
Review
Stiripentol (Diacomit) is an orally-active, structurally unique anti-epileptic drug (AED) with multiple potential mechanisms of action, including enhancement of central γ-aminobutyric acid transmission. In the EU, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with Dravet syndrome (DS; previously known as severe myoclonic epilepsy of infancy), whose seizures are not adequately controlled with clobazam and valproate. This approval (and similar DS indications in the USA, Canada and Japan), reflect the results of the STICLO studies, two small, randomized controlled trials in which stiripentol as adjunctive therapy was associated with a markedly superior response rate after 2 months compared with placebo in patients aged between 3 and ≈ 21 years with DS that was inadequately controlled with clobazam and valproate. These short-term results have subsequently been supported and extended by findings from longer-term, open-label, observational studies, including a retrospective longitudinal cohort study, which showed that the efficacy of combining stiripentol with clobazam and valproate when started at paediatric age was maintained in mid-adulthood with up to 24 years of exposure, and up to 40 years of age. Drowsiness, appetite loss, weight loss, ataxia and tremor are the most common adverse events associated with the addition of stiripentol to clobazam and valproate. Based on the available evidence, stiripentol, as an adjunct to clobazam and valproate, is a demonstrably beneficial and generally well-tolerated second-line treatment for patients with DS.
Topics: Anticonvulsants; Dioxolanes; Epilepsies, Myoclonic; Humans; Seizures
PubMed: 31617141
DOI: 10.1007/s40265-019-01204-y