RARE DISEASE
Juvenile myoclonic epilepsy
Juvenile myoclonic epilepsy
Juvenile myoclonic epilepsy
Synonyms: JME, Juvenile myoclonus epilepsy
Synonyms: JME, Juvenile myoclonus epilepsy
Synonyms: JME, Juvenile myoclonus epilepsy
Drug discovery
0
drugs
With orphan designations
Overview
Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy syndrome characterized by myoclonic jerks, generalized tonic-clonic seizures, and sometimes absence seizures, typically emerging in adolescence (12–18 years). Triggered by sleep deprivation, alcohol, or stress, it features 3–5.5 Hz polyspike-wave EEG patterns and photosensitivity. Valproate remains first-line therapy, though alternatives like levetiracetam are preferred for women of childbearing age. Lifelong treatment is often required due to high relapse rates [1][2][3][18].
Burden
Categories: rare genetic diseases, rare neurological diseases
Research Papers
363 drug discovery papers about Juvenile myoclonic epilepsy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
363 drug discovery papers about Juvenile myoclonic epilepsy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-09 | Comparative Efficacy of Valproate and Levetiracetam Monotherapy in Women of Childbearing Age with Juvenile Myoclonic Epilepsy: A Retrospective Cohort from Latin America (P4-10.002)
To compare seizure freedom between valproate (VPA) and levetiracetam (LEV) monotherapy in women of childbearing age with Juvenile Myoclonic Epilepsy (JME).
2026-05-31 | Impact of valproate discontinuation on seizure control in women of reproductive age.
To evaluate seizure control in women of reproductive age treated with valproic acid and to compare seizure outcomes between those who continued valproic acid and those who were switched to other anti-seizure medications. Data of women with epilepsy were analyzed from prospectively maintained electronic medical records between 2013 and 2022 at a tertiary epilepsy referral center. Women aged 18 to 45 years with generalized or focal epilepsy who were well controlled on valproic acid were included. Clinical characteristics, anti-seizure medication use, seizure control during valproic acid treatment and after switching to other anti-seizure medications, adverse effects, and pregnancy-related complications were analyzed. Sixty-nine women with epilepsy who were seizure-free for at least one year on valproic acid were included. Of these, 28 had juvenile myoclonic epilepsy, 30 had other idiopathic generalized epilepsy subtypes, and 11 had focal epilepsy. Only 26 patients (37.68%) required a valproic acid dose greater than 800 milligrams per day for seizure control. Eighteen patients were switched from valproic acid to other anti-seizure medications, of whom 10 (55.55%) experienced seizure recurrence at 12-month follow-up. Among patients who continued valproic acid, teratogenicity occurred in three patients (5.88%), with a mean daily dose of 1133 milligrams. The requirement for polytherapy was higher in the switch group compared to the valproic acid continuation group (44.44% versus 11.80%). In women with epilepsy who are well controlled on low-dose valproic acid, switching to alternative anti-seizure medications is associated with a high risk of seizure recurrence and increased need for polytherapy. Decisions regarding withdrawal of valproic acid should be individualized, planned well in advance of pregnancy, and made after detailed discussion with the patient, balancing the risks of losing seizure control against potential teratogenic effects.
2026-05-01 | Brivaracetam monotherapy in juvenile myoclonic epilepsy: a safety and efficacy evaluation.
The treatment of juvenile myoclonic epilepsy (JME) is limited, with most patients requiring long-term medication and over half experiencing seizure recurrence upon drug withdrawal. As a third-generation antiseizure medication, brivaracetam (BRV) has emerged as a promising therapeutic option. Its efficacy has been investigated in focal epilepsies and genetic generalized epilepsies (GGEs), with promising results. This study aims to evaluate the safety and preliminary efficacy of BRV as an off-label initial monotherapy in patients with newly diagnosed JME, with a specific focus on the control of myoclonic seizures. A prospective, single-center, and observational study. This study prospectively enrolled drug-naïve patients with JME. All participants received BRV monotherapy. Clinical data were collected at baseline and after a 6-month follow-up period, including demographic characteristics, electroencephalography (EEG), cranial magnetic resonance imaging (MRI), and comprehensive neuropsychological assessments. Changes in seizure frequency, cognitive function, levels of anxiety and depression, sleep quality, and quality of life from baseline to the 6-month follow-up were analyzed and compared. A total of 19 patients were included with a mean age of 20.26 ± 6.88 years (median: 18, interquartile range: 8), and a male-to-female ratio of 12:7. The average age of onset was 14.58 ± 3.42 years, and the average duration of epilepsy prior to BRV treatment was 5.71 ± 7.40 years (median: 2, interquartile range: 5). The mean frequency of myoclonic seizures at baseline was 38.79 ± 45.60 times per month (median: 10, interquartile range: 86). Eighteen patients (94.73%) experienced both generalized tonic-clonic seizures (GTCS) and myoclonic seizures, one patient only experienced myoclonic seizures, The MRI findings were negative in all patients (100%). The EEG of all patients at baseline was abnormal, revealing 3-5.5 Hz generalized spike-and-wave or polyspike-and-wave discharges. At the 6-month evaluation, all patients achieved seizure-free status (p < 0.001), neuropsychological assessments also demonstrated significant improvement, including Montreal Cognitive Assessment (MoCA; p < 0.001), Hamilton Anxiety Scale (HAMA; p < 0.001), Hamilton Depression Scale (HAMD; p < 0.001), Pittsburgh Sleep Quality Index (PSQI; p < 0.001), and Quality of Life in Epilepsy-31 (QOLIE-31; p < 0.001). Only one patient complained of poor sleep after BRV administration. This study suggests that BRV may offer promising efficacy, specifically in controlling myoclonic seizures and favorable tolerability as an off-label initial monotherapy for JME patients. While the evaluation of efficacy against GTCS requires longer follow-up, our findings support the potential of BRV as a therapeutic option for JME. Further randomized controlled trials are warranted to validate these observations.
2026-04-17 | Thermodynamic rigidity of harmonic brain states relates to general mental ability in juvenile myoclonic epilepsy.
Cognitive difficulties are increasingly recognized in juvenile myoclonic epilepsy (JME), but scalable biomarkers linking resting-state brain dynamics to general mental ability remain limited. Here, we combined topological data analysis, graph signal processing, machine learning, inverse Langevin modeling, and biophysical simulations to test whether EEG-derived network dynamics capture individual differences in general mental ability in JME. We studied 54 patients with JME and 45 healthy controls using resting-state high-density EEG and the raw estimated full-scale score derived from the Wechsler Abbreviated Scale of Intelligence (WASI), used here as an index of general mental ability. Subject-specific low-alpha activity was reconstructed with generalized eigendecomposition, and graph-derived features were extracted from the projection of topological and alpha-power signals onto the functional connectome, providing a graph-harmonic description of large-scale brain-state dynamics. In controls, dynamic EEG-derived features significantly predicted general mental ability, whereas the same framework failed in JME. Because prediction in controls was driven mainly by dynamic measures of smoothness (Dirichlet energy), we next examined the temporal organization of alpha-power smoothness using an inverse Langevin framework. Within the patient group, greater thermodynamic rigidity-that is, stronger confinement of fluctuations around preferred network states-was associated with lower general mental ability. Relative to controls, patients also showed lower thermodynamic noise, indicating a reduced tendency to explore alternative network regimes. Biophysical simulations suggested that reduced dendritic arborization can generate rigidity directly, whereas pharmacological stabilization of hyperexcitable circuits can shift the system toward a more rigid, lower-noise regime. Together, these findings suggest that cognition in JME is linked not only to altered resting-state network dynamics but also to stronger confinement of network-state fluctuations, with both intrinsic circuit abnormalities and treatment-related stabilization representing plausible routes to this rigid phenotype.
2026-03-27 | A Stroke of Insight? Possible Bidirectional Relationship Between Stroke and Epilepsy
Background: Observational studies have established a relationship between stroke and epilepsy. While most studies have reported an increased risk of epilepsy following a stroke, fewer have concluded that a diagnosis of epilepsy increases the risk of future strokes. Precisely describing the causal relationship between epilepsy and stroke has clinical and public health implications. Methods: We performed a two-sample Mendelian Randomization (MR) to analyze the relationship between epilepsy and stroke. We identified genetic instruments from the Stroke Multiancestry Genome-Wide Association Study [GCST005838 (67,162 cases and 454,450 controls)] and the International League Against Epilepsy Consortium on Complex Epilepsies [Generalized epilepsy (GE): GCST007343 (n_case=3769, n_control=29677), Focal epilepsy (FE): GCST007352 (n_case=9671, n_control=29677)]. We used a significance threshold of p -value <5 × 10 (−5) for genetic instrument identification. We included the following epilepsy phenotypes: GE, FE, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy, GE with tonic-clonic seizures, FE with hippocampal sclerosis (focal HS), and focal lesion-negative epilepsy. Linkage disequilibrium reference panel of 1000 Genome Project pruning with Pearson correlation r 2 < 0.2 was applied to ensure that the analysis is restricted to independent variants. We used Steiger filtering for reverse causality and Z -scores for GE and FE. We employed the following methods for causal effect estimation: Inverse-variance weighted (IVW), MR-Egger, MR-RAPS, and MRPRESSO. Results: For the association between GE and stroke (GE > stroke), stroke and GE (stroke > GE), FE and stroke (FE > stroke), and stroke and FE (stroke > FE), the number of single nucleotide polymorphisms was respectively 253, 213, 187, and 210. GE was associated with an increased risk of stroke [IVW, 95% confidence interval: 0.058 (0.028-0.088)], and stroke was also associated with an increased risk of GE [IVW: 0.059 (0.026-0.092)]. FE was associated with an increased risk of stroke [IVW: 0.066 (0.029-0.102)] and stroke was associated with an increased risk of FE [IVW: 0.037(0.005-0.068)]. The analysis by epilepsy subtypes revealed an increased risk only among patients with stroke and for the following epilepsy subtypes: JAE, CAE, Focal HS, and Focal lesion negative epilepsy. Conclusion: Our findings support a bidirectional relationship between stroke and epilepsy. Studies on post-stroke epilepsy should account for this bidirectional relationship.
gene therapies
2024-05-01 | Attention-Deficit Disorders and Epilepsy
Abstract Attention-deficit/hyperactivity disorder (ADHD) is a common comorbidity in patients with epilepsy. A polygenic predisposition likely interacts with environmental factors to determine the ultimate likelihood and severity of comorbid attention deficits. Epilepsy syndromes such as Dravet syndrome, juvenile myoclonic epilepsy, childhood absence epilepsy, and fragile X syndrome all have a high prevalence of ADHD. Many of these epilepsy syndromes are associated with monogenic mutations that have been implicated in inhibitory neurotransmission (Scn1a, GABRA1, Cacna1a, SNAP25, and FMR1, respectively). Monogenic rodent models carrying these genetic mutations have recapitulated varying degrees of epilepsy, hyperactivity, and attention deficits. Specifically testing various aspects of attention in rodents has been performed with validated procedures such as the Attention Set-Shifting task (ASST) or the 5-Choice Serial Reaction Time task (5-CSRTT). Recent studies have found cell-type-specific dysfunction in subsets of inhibitory neurons, most prominently in parvalbumin-expressing neurons. This underlying dysfunction likely leads to the symptomatic expression of both seizures and attention deficits. Both can be treated independently with antiseizure drugs and stimulant therapy, respectively. However, there remain no specific therapies for the underlying epileptogenic insult. Further studies should aim to combine the pathophysiological insight gained from monogenic models with targeted therapies on the genetic, molecular, cellular, and/or network levels. These therapies can then be screened on mutant rodent models using the ASST or 5-CSRTT to identify therapies with the greatest chance of improving quality of life in patients with comorbid epilepsy and ADHD.
2023-07-31 | Astrocytes as a target for therapeutic strategies in epilepsy: current insights
Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na+/K+/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosine-metabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells.
2018-11-05 | Association of GABAA Receptor Gene with Epilepsy Syndromes.
GABA has always been an inviting target in the etiology and treatment of epilepsy. The GABRA1, GABRG2, and GABRD genes provide instructions for making α1, ϒ2, and δ subunits of GABAA receptor protein respectively. GABAA is considered as one of the most important proteins and has found to play an important role in many neurological disorders. We explored the association of GABAA receptor gene mutation/SNPs in JME and LGS patients in Indian population. A total of 100 epilepsy syndrome patients (50 JME and 50 LGS) and 100 healthy control subjects were recruited and analyzed by AS-PCR and RFLP-PCR techniques. In our study, GABRA1 965 C > A mutation and 15 A > G polymorphism gene may play an important role in modulating the drug efficacy in LGS patients. The GABRA1 15 A > G polymorphism may also play an important role in the susceptibility of LGS and the inheritance of GG genotype of this polymorphism may provide an increased risk of development of LGS. The GABRG2 588 C > T polymorphism may decrease the duration of seizures in JME patients. The GABRD 659 G > A polymorphism may play an important role in the susceptibility of JME and LGS and this polymorphism may also increase the duration of postictal period in JME patients but may decrease the duration of seizure in LGS patients.
2018-03-01 | The management of epilepsy in children and adults
The International League Against Epilepsy has recently published a new classification of epileptic seizures and epilepsies to reflect the major scientific advances in our understanding of the epilepsies since the last formal classification 28 years ago. The classification emphasises the importance of aetiology, which allows the optimisation of management. Antiepileptic drugs (AEDs) are the main approach to epilepsy treatment and achieve seizure freedom in about two-thirds of patients. More than 15 second generation AEDs have been introduced since the 1990s, expanding opportunities to tailor treatment for each patient. However, they have not substantially altered the overall seizure-free outcomes. Epilepsy surgery is the most effective treatment for drug-resistant focal epilepsy and should be considered as soon as appropriate trials of two AEDs have failed. The success of epilepsy surgery is influenced by different factors, including epilepsy syndrome, presence and type of epileptogenic lesion, and duration of post-operative follow-up. For patients who are not eligible for epilepsy surgery or for whom surgery has failed, trials of alternative AEDs or other non-pharmacological therapies, such as the ketogenic diet and neurostimulation, may improve seizure control. Ongoing research into novel antiepileptic agents, improved techniques to optimise epilepsy surgery, and other non-pharmacological therapies fuel hope to reduce the proportion of individuals with uncontrolled seizures. With the plethora of gene discoveries in the epilepsies, “precision therapies” specifically targeting the molecular underpinnings are beginning to emerge and hold great promise for future therapeutic approaches.
2016-01-23 | Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5-6.0 Hz polyspike waves.
Abstract Juvenile myoclonic epilepsy ( JME ), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME ( CAE / JME ; pedigree 1), JME with adolescent onset pyknoleptic absence ( JME / pA ; pedigree 2), and classic JME ( cJME ; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5–6.0 Hz polyspike waves, and asymptomatic persons with normal EEG s. Two‐point parametric linkage analyses were performed with 5185 single‐nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/ EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2–q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage ( Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3–q31.2 ( Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease‐causing genes, favoring the concept of JME as several distinct diseases. Whole‐exome sequencing will likely identify a CAE / JME gene in 2q21.2–2q31.1, a JME / pA gene in 13q13.3–q31.2, and a cJME gene in 17q12.
proteins
2022-02-17 | Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention
Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.
small molecules
2026-06-09 | Comparative Efficacy of Valproate and Levetiracetam Monotherapy in Women of Childbearing Age with Juvenile Myoclonic Epilepsy: A Retrospective Cohort from Latin America (P4-10.002)
To compare seizure freedom between valproate (VPA) and levetiracetam (LEV) monotherapy in women of childbearing age with Juvenile Myoclonic Epilepsy (JME).
2026-05-31 | Impact of valproate discontinuation on seizure control in women of reproductive age.
To evaluate seizure control in women of reproductive age treated with valproic acid and to compare seizure outcomes between those who continued valproic acid and those who were switched to other anti-seizure medications. Data of women with epilepsy were analyzed from prospectively maintained electronic medical records between 2013 and 2022 at a tertiary epilepsy referral center. Women aged 18 to 45 years with generalized or focal epilepsy who were well controlled on valproic acid were included. Clinical characteristics, anti-seizure medication use, seizure control during valproic acid treatment and after switching to other anti-seizure medications, adverse effects, and pregnancy-related complications were analyzed. Sixty-nine women with epilepsy who were seizure-free for at least one year on valproic acid were included. Of these, 28 had juvenile myoclonic epilepsy, 30 had other idiopathic generalized epilepsy subtypes, and 11 had focal epilepsy. Only 26 patients (37.68%) required a valproic acid dose greater than 800 milligrams per day for seizure control. Eighteen patients were switched from valproic acid to other anti-seizure medications, of whom 10 (55.55%) experienced seizure recurrence at 12-month follow-up. Among patients who continued valproic acid, teratogenicity occurred in three patients (5.88%), with a mean daily dose of 1133 milligrams. The requirement for polytherapy was higher in the switch group compared to the valproic acid continuation group (44.44% versus 11.80%). In women with epilepsy who are well controlled on low-dose valproic acid, switching to alternative anti-seizure medications is associated with a high risk of seizure recurrence and increased need for polytherapy. Decisions regarding withdrawal of valproic acid should be individualized, planned well in advance of pregnancy, and made after detailed discussion with the patient, balancing the risks of losing seizure control against potential teratogenic effects.
2026-05-01 | Brivaracetam monotherapy in juvenile myoclonic epilepsy: a safety and efficacy evaluation.
The treatment of juvenile myoclonic epilepsy (JME) is limited, with most patients requiring long-term medication and over half experiencing seizure recurrence upon drug withdrawal. As a third-generation antiseizure medication, brivaracetam (BRV) has emerged as a promising therapeutic option. Its efficacy has been investigated in focal epilepsies and genetic generalized epilepsies (GGEs), with promising results. This study aims to evaluate the safety and preliminary efficacy of BRV as an off-label initial monotherapy in patients with newly diagnosed JME, with a specific focus on the control of myoclonic seizures. A prospective, single-center, and observational study. This study prospectively enrolled drug-naïve patients with JME. All participants received BRV monotherapy. Clinical data were collected at baseline and after a 6-month follow-up period, including demographic characteristics, electroencephalography (EEG), cranial magnetic resonance imaging (MRI), and comprehensive neuropsychological assessments. Changes in seizure frequency, cognitive function, levels of anxiety and depression, sleep quality, and quality of life from baseline to the 6-month follow-up were analyzed and compared. A total of 19 patients were included with a mean age of 20.26 ± 6.88 years (median: 18, interquartile range: 8), and a male-to-female ratio of 12:7. The average age of onset was 14.58 ± 3.42 years, and the average duration of epilepsy prior to BRV treatment was 5.71 ± 7.40 years (median: 2, interquartile range: 5). The mean frequency of myoclonic seizures at baseline was 38.79 ± 45.60 times per month (median: 10, interquartile range: 86). Eighteen patients (94.73%) experienced both generalized tonic-clonic seizures (GTCS) and myoclonic seizures, one patient only experienced myoclonic seizures, The MRI findings were negative in all patients (100%). The EEG of all patients at baseline was abnormal, revealing 3-5.5 Hz generalized spike-and-wave or polyspike-and-wave discharges. At the 6-month evaluation, all patients achieved seizure-free status (p < 0.001), neuropsychological assessments also demonstrated significant improvement, including Montreal Cognitive Assessment (MoCA; p < 0.001), Hamilton Anxiety Scale (HAMA; p < 0.001), Hamilton Depression Scale (HAMD; p < 0.001), Pittsburgh Sleep Quality Index (PSQI; p < 0.001), and Quality of Life in Epilepsy-31 (QOLIE-31; p < 0.001). Only one patient complained of poor sleep after BRV administration. This study suggests that BRV may offer promising efficacy, specifically in controlling myoclonic seizures and favorable tolerability as an off-label initial monotherapy for JME patients. While the evaluation of efficacy against GTCS requires longer follow-up, our findings support the potential of BRV as a therapeutic option for JME. Further randomized controlled trials are warranted to validate these observations.
2026-04-17 | Thermodynamic rigidity of harmonic brain states relates to general mental ability in juvenile myoclonic epilepsy.
Cognitive difficulties are increasingly recognized in juvenile myoclonic epilepsy (JME), but scalable biomarkers linking resting-state brain dynamics to general mental ability remain limited. Here, we combined topological data analysis, graph signal processing, machine learning, inverse Langevin modeling, and biophysical simulations to test whether EEG-derived network dynamics capture individual differences in general mental ability in JME. We studied 54 patients with JME and 45 healthy controls using resting-state high-density EEG and the raw estimated full-scale score derived from the Wechsler Abbreviated Scale of Intelligence (WASI), used here as an index of general mental ability. Subject-specific low-alpha activity was reconstructed with generalized eigendecomposition, and graph-derived features were extracted from the projection of topological and alpha-power signals onto the functional connectome, providing a graph-harmonic description of large-scale brain-state dynamics. In controls, dynamic EEG-derived features significantly predicted general mental ability, whereas the same framework failed in JME. Because prediction in controls was driven mainly by dynamic measures of smoothness (Dirichlet energy), we next examined the temporal organization of alpha-power smoothness using an inverse Langevin framework. Within the patient group, greater thermodynamic rigidity-that is, stronger confinement of fluctuations around preferred network states-was associated with lower general mental ability. Relative to controls, patients also showed lower thermodynamic noise, indicating a reduced tendency to explore alternative network regimes. Biophysical simulations suggested that reduced dendritic arborization can generate rigidity directly, whereas pharmacological stabilization of hyperexcitable circuits can shift the system toward a more rigid, lower-noise regime. Together, these findings suggest that cognition in JME is linked not only to altered resting-state network dynamics but also to stronger confinement of network-state fluctuations, with both intrinsic circuit abnormalities and treatment-related stabilization representing plausible routes to this rigid phenotype.
2026-03-27 | A Stroke of Insight? Possible Bidirectional Relationship Between Stroke and Epilepsy
Background: Observational studies have established a relationship between stroke and epilepsy. While most studies have reported an increased risk of epilepsy following a stroke, fewer have concluded that a diagnosis of epilepsy increases the risk of future strokes. Precisely describing the causal relationship between epilepsy and stroke has clinical and public health implications. Methods: We performed a two-sample Mendelian Randomization (MR) to analyze the relationship between epilepsy and stroke. We identified genetic instruments from the Stroke Multiancestry Genome-Wide Association Study [GCST005838 (67,162 cases and 454,450 controls)] and the International League Against Epilepsy Consortium on Complex Epilepsies [Generalized epilepsy (GE): GCST007343 (n_case=3769, n_control=29677), Focal epilepsy (FE): GCST007352 (n_case=9671, n_control=29677)]. We used a significance threshold of p -value <5 × 10 (−5) for genetic instrument identification. We included the following epilepsy phenotypes: GE, FE, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy, GE with tonic-clonic seizures, FE with hippocampal sclerosis (focal HS), and focal lesion-negative epilepsy. Linkage disequilibrium reference panel of 1000 Genome Project pruning with Pearson correlation r 2 < 0.2 was applied to ensure that the analysis is restricted to independent variants. We used Steiger filtering for reverse causality and Z -scores for GE and FE. We employed the following methods for causal effect estimation: Inverse-variance weighted (IVW), MR-Egger, MR-RAPS, and MRPRESSO. Results: For the association between GE and stroke (GE > stroke), stroke and GE (stroke > GE), FE and stroke (FE > stroke), and stroke and FE (stroke > FE), the number of single nucleotide polymorphisms was respectively 253, 213, 187, and 210. GE was associated with an increased risk of stroke [IVW, 95% confidence interval: 0.058 (0.028-0.088)], and stroke was also associated with an increased risk of GE [IVW: 0.059 (0.026-0.092)]. FE was associated with an increased risk of stroke [IVW: 0.066 (0.029-0.102)] and stroke was associated with an increased risk of FE [IVW: 0.037(0.005-0.068)]. The analysis by epilepsy subtypes revealed an increased risk only among patients with stroke and for the following epilepsy subtypes: JAE, CAE, Focal HS, and Focal lesion negative epilepsy. Conclusion: Our findings support a bidirectional relationship between stroke and epilepsy. Studies on post-stroke epilepsy should account for this bidirectional relationship.
gene therapies
2024-05-01 | Attention-Deficit Disorders and Epilepsy
Abstract Attention-deficit/hyperactivity disorder (ADHD) is a common comorbidity in patients with epilepsy. A polygenic predisposition likely interacts with environmental factors to determine the ultimate likelihood and severity of comorbid attention deficits. Epilepsy syndromes such as Dravet syndrome, juvenile myoclonic epilepsy, childhood absence epilepsy, and fragile X syndrome all have a high prevalence of ADHD. Many of these epilepsy syndromes are associated with monogenic mutations that have been implicated in inhibitory neurotransmission (Scn1a, GABRA1, Cacna1a, SNAP25, and FMR1, respectively). Monogenic rodent models carrying these genetic mutations have recapitulated varying degrees of epilepsy, hyperactivity, and attention deficits. Specifically testing various aspects of attention in rodents has been performed with validated procedures such as the Attention Set-Shifting task (ASST) or the 5-Choice Serial Reaction Time task (5-CSRTT). Recent studies have found cell-type-specific dysfunction in subsets of inhibitory neurons, most prominently in parvalbumin-expressing neurons. This underlying dysfunction likely leads to the symptomatic expression of both seizures and attention deficits. Both can be treated independently with antiseizure drugs and stimulant therapy, respectively. However, there remain no specific therapies for the underlying epileptogenic insult. Further studies should aim to combine the pathophysiological insight gained from monogenic models with targeted therapies on the genetic, molecular, cellular, and/or network levels. These therapies can then be screened on mutant rodent models using the ASST or 5-CSRTT to identify therapies with the greatest chance of improving quality of life in patients with comorbid epilepsy and ADHD.
2023-07-31 | Astrocytes as a target for therapeutic strategies in epilepsy: current insights
Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na+/K+/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosine-metabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells.
2018-11-05 | Association of GABAA Receptor Gene with Epilepsy Syndromes.
GABA has always been an inviting target in the etiology and treatment of epilepsy. The GABRA1, GABRG2, and GABRD genes provide instructions for making α1, ϒ2, and δ subunits of GABAA receptor protein respectively. GABAA is considered as one of the most important proteins and has found to play an important role in many neurological disorders. We explored the association of GABAA receptor gene mutation/SNPs in JME and LGS patients in Indian population. A total of 100 epilepsy syndrome patients (50 JME and 50 LGS) and 100 healthy control subjects were recruited and analyzed by AS-PCR and RFLP-PCR techniques. In our study, GABRA1 965 C > A mutation and 15 A > G polymorphism gene may play an important role in modulating the drug efficacy in LGS patients. The GABRA1 15 A > G polymorphism may also play an important role in the susceptibility of LGS and the inheritance of GG genotype of this polymorphism may provide an increased risk of development of LGS. The GABRG2 588 C > T polymorphism may decrease the duration of seizures in JME patients. The GABRD 659 G > A polymorphism may play an important role in the susceptibility of JME and LGS and this polymorphism may also increase the duration of postictal period in JME patients but may decrease the duration of seizure in LGS patients.
2018-03-01 | The management of epilepsy in children and adults
The International League Against Epilepsy has recently published a new classification of epileptic seizures and epilepsies to reflect the major scientific advances in our understanding of the epilepsies since the last formal classification 28 years ago. The classification emphasises the importance of aetiology, which allows the optimisation of management. Antiepileptic drugs (AEDs) are the main approach to epilepsy treatment and achieve seizure freedom in about two-thirds of patients. More than 15 second generation AEDs have been introduced since the 1990s, expanding opportunities to tailor treatment for each patient. However, they have not substantially altered the overall seizure-free outcomes. Epilepsy surgery is the most effective treatment for drug-resistant focal epilepsy and should be considered as soon as appropriate trials of two AEDs have failed. The success of epilepsy surgery is influenced by different factors, including epilepsy syndrome, presence and type of epileptogenic lesion, and duration of post-operative follow-up. For patients who are not eligible for epilepsy surgery or for whom surgery has failed, trials of alternative AEDs or other non-pharmacological therapies, such as the ketogenic diet and neurostimulation, may improve seizure control. Ongoing research into novel antiepileptic agents, improved techniques to optimise epilepsy surgery, and other non-pharmacological therapies fuel hope to reduce the proportion of individuals with uncontrolled seizures. With the plethora of gene discoveries in the epilepsies, “precision therapies” specifically targeting the molecular underpinnings are beginning to emerge and hold great promise for future therapeutic approaches.
2016-01-23 | Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5-6.0 Hz polyspike waves.
Abstract Juvenile myoclonic epilepsy ( JME ), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME ( CAE / JME ; pedigree 1), JME with adolescent onset pyknoleptic absence ( JME / pA ; pedigree 2), and classic JME ( cJME ; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5–6.0 Hz polyspike waves, and asymptomatic persons with normal EEG s. Two‐point parametric linkage analyses were performed with 5185 single‐nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/ EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2–q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage ( Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3–q31.2 ( Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease‐causing genes, favoring the concept of JME as several distinct diseases. Whole‐exome sequencing will likely identify a CAE / JME gene in 2q21.2–2q31.1, a JME / pA gene in 13q13.3–q31.2, and a cJME gene in 17q12.
proteins
2022-02-17 | Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention
Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.
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