RARE DISEASE
Childhood absence epilepsy
Childhood absence epilepsy
Childhood absence epilepsy
Synonyms: Pyknolepsy
Synonyms: Pyknolepsy
Synonyms: Pyknolepsy
Drug discovery
3
drugs
With orphan designations
Overview
Childhood absence epilepsy (CAE) is an idiopathic generalized epilepsy syndrome characterized by frequent (≥4/day), brief (4-20 second) absence seizures with abrupt consciousness loss and 3 Hz generalized spike-wave EEG patterns [1][4][16]. Onset peaks at 5-7 years (range 4-10), with strong female predominance (F:M ratio 1.3:1 to 2:1) [1][12][16]. While 65-90% achieve seizure remission by adolescence, neuropsychological comorbidities (ADHD, anxiety) affect 30-60% [6][12][16]. First-line therapies include ethosuximide (most effective), valproate (GTC seizure coverage), and lamotrigine [3][6][17].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
353 drug discovery papers about Childhood absence epilepsy, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
353 drug discovery papers about Childhood absence epilepsy, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | Can One Predict Persistence beyond Adolescence in Childhood Absence Epilepsy?
Although typical childhood absence epilepsy is common and drug-resistance is not uncommon, predictors of drug resistance and its persistence beyond adolescence have not been well studied. To predict recalcitrant childhood absence epilepsy (CAE). Retrospective data analysis of 153 CAE patients was done. Controlled CAE group (cCAE) had seizure control within 2 years of starting antiseizure medication regimen (ASM) and electroencephalographic (EEG) normalization at <16 years of age. The remaining cohort was classified as drug-resistant CAE group (rCAE). The factors which may affect outcome were analyzed. Seizure freedom was defined as 10 years of clinical seizure-free period with at least 5 years off ASM. Of 153 patients, 104 (67.97%) qualified for cCAE and 79 (75.96%) responded to the first ASM. All in cCAE also achieved seizure freedom. The comparison of initial EEG abnormalities to ASM efficacy proved divalproex sodium (VPA) superiority for patients with poly spike and wave discharges (PSW), Fisher's exact test, P = 0.021, but not ethosuximide (ESM), Fisher's exact test, P = 0.00058; both ASM were equally effective for single spike and wave discharges (SSW); and VPA equally effective for SSW and PSW. Of 49 patients in rCAE, 11 (22.45%) eventually achieved seizure freedom. None in cCAE but 17 (34.69%) in rCAE developed other seizure types which included 9 (18.37%) who developed juvenile myoclonic epilepsy (JME). The majority of CAE patients attained seizure control over 2 years with EEG normalization before the age of 16 years, and all of them went on to achieve seizure freedom. Almost 3/4th of the patients who are likely to attain seizure control and achieve seizure freedom will do so with the first-line ASM. In addition, ESM should be the first ASM for patients with CAE with SSW, but VPA may be used as the first ASM for patients with CAE with PSW. Furthermore, seizure control and freedom are still possible in some patients with rCAE. Persistent PSW and later development of additional seizure type may predict refractory status and, in some patients, evolving JME.
2026-09-23 | Sleep spindle deficits in childhood absence epilepsy improve with antiseizure treatment and disease resolution
Abstract Childhood absence epilepsy (CAE), the most common childhood epilepsy syndrome, is associated with bursts of generalized thalamocortical spike-wave discharges and cognitive impairment, yet the physiological mechanisms linking disease activity, treatment, and cognition remain unclear. Sleep spindles, generated by thalamocortical circuits, are associated with cognitive function and may be disrupted by epileptic activity. Here, we retrospectively studied 87 EEGs from 53 children with active and resolved CAE and 87 age- and sex-matched controls to evaluate sleep spindle activity across disease states and its association with antiseizure medication (ASM) exposure. We found that children with active CAE had reduced spindle rates across all cortical regions compared to those with resolved CAE and controls, with the largest reduction in the frontal region, where epileptic spike activity was also most prominent. Spindle rate was inversely correlated with epileptic spike rate, consistent with a shared thalamocortical circuitry. The association between ASM exposure and spindle rate varied by disease state. In active CAE, treated children had higher spindle rates than untreated children. In resolved CAE, treated children had lower spindle rates than untreated children. In contrast, ASM-related differences in spike rate were more limited, although a medication-specific reduction was observed in active CAE. These findings support sleep spindle rate as a candidate physiological marker of disease state and ASM exposure in children with CAE. Given the established role of sleep spindles in memory consolidation, these findings support testing of whether spindle disruption provides a mechanistic link between epileptic thalamocortical activity and cognitive vulnerability in CAE. Significance Statement Childhood absence epilepsy (CAE) is a common childhood generalized epilepsy characterized by abnormal thalamocortical activity and cognitive difficulties. Here, we show that sleep spindle activity is globally reduced during active CAE, particularly in frontal regions, and normalizes after disease resolution. Spindle activity was anticorrelated with epileptic spike rate and impacted by antiseizure medication exposure. These results support the hypothesis that epileptic spikes and sleep spindles share thalamocortical circuitry and promote sleep spindles as a candidate physiological biomarker to link epileptic activity with cognitive vulnerability in CAE.
2026-07-31 | Parvalbumin interneuron activation rescues both seizures and impaired social novelty in digenic absence epilepsy mice.
Childhood absence epilepsy (CAE) is a common genetic epilepsy with a frequently complex polygenic etiology, for which a genetically tractable animal model is lacking. Current anti-seizure medications fail to address the significant neurocognitive and social comorbidities of CAE, highlighting a critical unmet need for comprehensive therapies and a better understanding of the underlying mechanisms. To address this, we developed a digenic mouse model (Cacng2stargazer/+;Cacna1a+/-, hereafter DiGstg+Ca1A) that mimics human polygenicity. The double mutant mice exhibit both absence seizures and altered social novelty preference. We found that ethosuximide, a first-line anti-CAE medication targeting thalamic low-threshold T-type calcium currents, suppressed seizures in DiGstg+Ca1A mice but failed to rescue their social deficit. Similarly, deletion of Cacna1g, which encodes the T-type Ca2+ channel CaV3.1, prevented seizure generation but did not ameliorate the social deficit. These findings reveal a dissociation between the T-type current that mediates seizures and the mechanism underlying the social deficits. We further demonstrate that in Cacng2stargazer/+ mice, selective deletion of one copy of Cacna1a in stargazin-enriched parvalbumin (PV) interneurons induced absence seizures and impaired social behavior. Remarkably, chemogenetic activation of cortical and thalamic PV interneurons using DREADDs not only suppressed seizures but also rescued the impaired social behavior. Together, our results suggest that selective modulation of PV interneuron activity in polygenic absence epilepsy could serve as a promising therapeutic strategy to address both absence seizures, and the often treatment-resistant neurocognitive comorbidities observed in CAE.
2026-07-16 | Convergent Inhibitory Cortical Circuit Disruption Drives Genetically Distinct Absence Seizures
Abstract Absence seizures, the most common childhood epilepsy, are characterized by brief involuntary lapses in consciousness and 3-Hz spike-wave EEG discharges (SWD). Despite extensive documentation of pathogenic thalamic remodeling, the cortical circuit abnormalities driving this highly stereotyped SWD remain elusive. Using two of the best characterized mouse models of absence epilepsy carrying point mutations in distinct genes altering pre and postsynaptic transmission, stargazer ( Cacng2 ) and tottering ( Cacna1a ), we show that a specific translaminar inhibitory circuit motif defined by layer 6 corticothalamic neurons (L6 CT) and a novel Tac1 + Pvalb interneuron subtype is selectively disrupted in both models. This early functional defect was accompanied by a secondary synaptic collapse of deep-layer somatostatin-expressing ( Sst ) interneurons that precisely coincides with the developmental onset of seizures. Crucially, we established the serial causality of these cascading defects by demonstrating that chemogenetic disruption of L6 CT-Tac1 + Pvalb circuit motif alone in wild-type mice is sufficient to induce both the secondary Sst interneuron collapse and contemporaneous emergence of SWDs. Together, these findings reveal a sequential translaminar synaptic failure or ‘domino effect’ wherein a primary defect triggers broader circuit adaptations permitting spike-wave hypersynchrony. Our results thus identify a convergent, causative cortical circuit pathology that is shared by genetically heterogeneous absence epilepsy models, highlighting a common functional target for therapeutic intervention.
2026-06-09 | Kv7 and K2P Potassium Channels in Thalamocortical Function and Their Therapeutic Potential in Childhood Absence Epilepsy.
Potassium (K+) channels are one of the key regulators of neuronal excitability and network stability. Among all the potassium channels, the voltage-gated Kv7 (KCNQ) and the two-pore domain potassium (K2P) channels play an important role in stabilizing and maintaining the resting potential of neurons. They are involved in controlling the input resistance and in the generation of rhythmic activity in the thalamocortical network. The main functions of the thalamocortical system are the regulation of sensory processing and the generation of brain rhythms underlying sleep and wakefulness. By this, it is essential to many aspects of cognition. The thalamocortical system is explicitly sensitive to fine changes in potassium conductance. The dysregulation of thalamocortical oscillation, also known as thalamocortical dysrhythmia, has been known to be involved in several psychiatric and neurological disorders. A prototypical thalamocortical dysrhythmia is childhood absence epilepsy (CAE), in which hypersynchronous activity in the form of spike and wave discharges (SWD) induces sudden losses of conscious awareness in patients. This review will summarize the current knowledge on Kv7 and K2P channels in the regulation of synchrony and excitability in the brain and the thalamocortical system in particular, outlining future research directions, highlighting the therapeutic potential of these channels for the treatment of thalamocortical dysrhythmias in general and CAE specifically.
oligonucleotides
2026-02-28 | Absence Seizures: Current Concepts in Genetics, Molecular Mechanisms, Classification, Diagnosis, and Contemporary Management
Absence seizures are generalized nonmotor epileptic events characterized by transient impairment of consciousness associated with generalized spike-and-wave discharges on electroencephalography (EEG). [1,2] Traditionally regarded as benign pediatric epileptic phenomena, contemporary evidence increasingly demonstrates that absence seizures comprise a heterogeneous neurobiological spectrum involving complex genetic, molecular, electrophysiological, and thalamocortical network abnormalities. [3,4] Although childhood absence epilepsy remains the prototypical syndrome, absence seizures also occur in juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with eyelid myoclonia, and several developmental and epileptic encephalopathies. [5,6] The pathogenesis of absence seizures involves pathological oscillatory synchronization within cortico-thalamo-cortical circuits mediated by abnormal γ-aminobutyric acid (GABAergic) neurotransmission, T-type calcium channel dysfunction, altered glutamatergic signaling, and genetically determined neuronal hyperexcitability. [4,7] Advances in molecular genetics have identified multiple susceptibility genes including CACNA1H, CACNG3, GABRG2, SLC2A1, SCN1A, and HCN1, thereby highlighting the polygenic and heterogeneous nature of generalized epileptogenesis. [8-10] Clinically, absence seizures manifest as sudden behavioral arrest, impaired awareness, staring episodes, automatisms, eyelid fluttering, and interruption of ongoing activity. [2] Despite their apparently subtle presentation, recurrent absence seizures may substantially impair academic performance, attention, psychosocial functioning, and neurocognitive development. [11] Diagnostic delays remain common because episodes are frequently misinterpreted as daydreaming, inattentiveness, behavioral disorders, or psychogenic events. [12] Electroencephalography remains the cornerstone of diagnosis, classically demonstrating bilateral synchronous 3-Hz generalized spike-and-wave discharges. [1] Contemporary management includes ethosuximide, valproate, and lamotrigine as first-line therapies, while emerging therapeutic research focuses on precision medicine, network neuromodulation, and molecular-targeted interventions. [13,14] This comprehensive descriptive review examines the genetics, molecular genetics, classifications, epidemiology, pathogenesis, clinical manifestations, diagnostic evaluation, differential diagnosis, treatment strategies, prognosis, contemporary controversies, research limitations, and future directions relating to absence seizures
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.
2024-03-26 | Unraveling the shared genetics of common epilepsies and general cognitive ability.
Objective: Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the potential shared genetic basis of common epilepsies and general cognitive ability (COG). Methods: We applied linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR) to analyze different aspects of genetic overlap between COG and epilepsies. We used the largest available genome–wide association study data on COG ( n = 269,867) and common epilepsies ( n = 27,559 cases, 42,436 controls), including the broad phenotypes ′all epilepsy ′, focal epilepsies and genetic generalized epilepsies (GGE), and as well as specific subtypes. We functionally annotated the identified loci using a variety of biological resources and validated the results in independent samples. Results: Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than ′all epilepsy′, GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k — 2.9k variants). The other epilepsy phenotypes were insufficiently powered for analysis. We show extensive genetic overlap between COG and epilepsies with significant negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and ′all epilepsy′, and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), ′all epilepsy′ (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 1.0 × 10 -14 ; ′all epilepsy′: p = 5.6 × 10 -3 ). Significance: Our study demonstrates a substantial genetic basis shared between epilepsies and COG and identifies novel overlapping genomic loci. Enhancing our understanding of the relationship between epilepsies and COG may lead to the development of novel comorbidity–targeted epilepsy treatments.
2021-12-17 | Clptm1 Downregulation Exerts Antiepileptic Activity by Regulating GABAAR-mediated Inhibitory Synaptic Transmission in PTZ-induced Epileptic Model
Abstract Background: Disruption of GABA A R synaptic clustering and a decrease number in their cell surface are thought to contribute to the alteration in the balance between excitatory and inhibitory neurotransmission, which contributes to seizure induction and propagation. Cleft lip and palate transmembrane protein 1 (Clptm1), a multi-pass transmembrane protein, has been showed that it is an intracellular molecule that controls forward trafficking of GABA A R. Clptm1 downregulating increased miniature inhibitory postsynaptic current (mIPSC) in vivo. Thus, Clptm1 controls phasic and tonic inhibitory transmission in brain. In this study, we hypothesized that Clptm1 may be involved in epileptic seizure by regulating GABA A R-mediated inhibitory synaptic transmission in epileptic model. Methods and Results: In PTZ-induced epileptic model, we found that Clptm1 was increased in temporal lobe epilepsy (TLE) patients as well as in epileptic model. Then, we showed that Clptm1 downregulation exerted antiepileptic activities in epileptic model, which was associated to the increased surface GABA A Rγ2 expression and mIPSCs amplitudes. Conclusions: Clptm1 downregulation exerted antiepileptic activities in epileptic model, thus, it may be a promising target for antiepileptic treatments.
2020-08-21 | Maladaptive myelination promotes epileptogenesis in absence epilepsy
Summary Neuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. We hypothesized that in seizure disorders, aberrant neuronal activity may promote maladaptive myelination that contributes to pathogenesis. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats and Scn8a +/mut mice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in the Scn8a +/mut mouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.
antibodies
2025-09-15 | Investigating the Effects of NMDAR and LGI1 Antibodies on Absence Seizures: Insights from Genetic Absence Epilepsy Rats and Acute Pharmacological Model of Absence Seizures.
Childhood Absence Epilepsy, a subtype of genetic generealised epilepsy, is characterised by sudden and brief episodes of impaired consciousness. The Leucine-rich glioma-inactivated protein 1 (LGI1) and N-methyl-D-aspartate receptor (NMDAR) are key proteins involved in regulating neuronal excitability. In conditions like anti-LGI1 encephalitis and anti-NMDAR encephalitis, autoantibodies target and disrupt these proteins, causing memory deficits, behavioural changes, sleep disturbances, and epileptic seizures. However, the roles of LGI1 and NMDAR dysfunction in the pathophysiology of absence of seizures remain unclear. This study aims to investigate the effects of LGI1 and NMDAR antibodies on absence seizures using two experimental models: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and a low-dose pentylenetetrazol (PTZ) model of absence seizures. IgG purified from the peripheral blood of healthy controls (HC IgG), and patients with anti-NMDAR, and anti-LGI1 encephalitis, was administered intracerebroventricularly into GAERS and Wistar rats every other day for 11 days. Before and after antibody administration, electroencephalography (EEG) recordings were performed to analyse spontaneous spike-and-wave discharges (SWDs) in GAERS. In Wistar rats, after the completion of antibody infusions, PTZ was administered (35 mg/kg) on the 12 th day to induce absence seizures. The occurrence of PTZ-induced SWDs was quantified. NMDAR IgG significantly increased the duration and number of SWDs in GAERS compared to HC IgG. LGI1 IgG had no significant effect, suggesting a differential role of NMDAR and LGI1 antibodies in modulating SWD activity. Similarly, NMDAR IgG-treated Wistar rats showed increased susceptibility to PTZ-induced absence seizures, while LGI1 IgG did not cause significant changes in PTZ-induced SWDs. These results reveal a distinct pro-epileptogenic effect of NMDAR antibodies in both genetic and pharmacological models of absence epilepsy, while LGI1 antibodies appear to have a negligible effect. These findings suggest a specific role for NMDAR dysfunction in absence seizure pathophysiology and support further investigation into antibody-mediated seizure mechanisms.
2021-07-20 | A Case of Refractory Absence Epilepsy Precedes Anti-MOG Associated Optic Neuritis
Childhood absence epilepsy (CAE) is one of the most common forms of pediatric epilepsy. While most patients become seizure free with anti-epileptic drug therapy approximately 20% do not achieve seizure remission and are defined as having refractory CAE. Epilepsy is generally thought of as a grey matter disease but has also been associated with abnormal white matter. Optic neuritis (ON), on the other hand, is typically a white matter disorder characterized by inflammation and demyelination of the myelin sheath due to autoantibodies, such as the anti-myelin oligodendrocyte glycoprotein (MOG) antibody. We present the case of an 11-year-old female with refractory CAE who developed anti-MOG antibody positive ON. CAE and ON are not commonly co-morbid and to our knowledge their co-occurrence in a patient has not been previously described. However, in this case, the CAE and ON may be related as her seizures dramatically improved after initiating immunomodulatory treatments for the ON. This may indicate a relationship between ON (potentially specific to anti-MOG positive ON) and CAE, or may suggest that there is an inflammatory component to CAE and that immunomodulatory therapies may have a role in seizure control. Thus, in cases of treatment resistant absence epilepsy, an immune work up may be helpful.
gene therapies
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.
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
2026-09-24 | Can One Predict Persistence beyond Adolescence in Childhood Absence Epilepsy?
Although typical childhood absence epilepsy is common and drug-resistance is not uncommon, predictors of drug resistance and its persistence beyond adolescence have not been well studied. To predict recalcitrant childhood absence epilepsy (CAE). Retrospective data analysis of 153 CAE patients was done. Controlled CAE group (cCAE) had seizure control within 2 years of starting antiseizure medication regimen (ASM) and electroencephalographic (EEG) normalization at <16 years of age. The remaining cohort was classified as drug-resistant CAE group (rCAE). The factors which may affect outcome were analyzed. Seizure freedom was defined as 10 years of clinical seizure-free period with at least 5 years off ASM. Of 153 patients, 104 (67.97%) qualified for cCAE and 79 (75.96%) responded to the first ASM. All in cCAE also achieved seizure freedom. The comparison of initial EEG abnormalities to ASM efficacy proved divalproex sodium (VPA) superiority for patients with poly spike and wave discharges (PSW), Fisher's exact test, P = 0.021, but not ethosuximide (ESM), Fisher's exact test, P = 0.00058; both ASM were equally effective for single spike and wave discharges (SSW); and VPA equally effective for SSW and PSW. Of 49 patients in rCAE, 11 (22.45%) eventually achieved seizure freedom. None in cCAE but 17 (34.69%) in rCAE developed other seizure types which included 9 (18.37%) who developed juvenile myoclonic epilepsy (JME). The majority of CAE patients attained seizure control over 2 years with EEG normalization before the age of 16 years, and all of them went on to achieve seizure freedom. Almost 3/4th of the patients who are likely to attain seizure control and achieve seizure freedom will do so with the first-line ASM. In addition, ESM should be the first ASM for patients with CAE with SSW, but VPA may be used as the first ASM for patients with CAE with PSW. Furthermore, seizure control and freedom are still possible in some patients with rCAE. Persistent PSW and later development of additional seizure type may predict refractory status and, in some patients, evolving JME.
2026-09-23 | Sleep spindle deficits in childhood absence epilepsy improve with antiseizure treatment and disease resolution
Abstract Childhood absence epilepsy (CAE), the most common childhood epilepsy syndrome, is associated with bursts of generalized thalamocortical spike-wave discharges and cognitive impairment, yet the physiological mechanisms linking disease activity, treatment, and cognition remain unclear. Sleep spindles, generated by thalamocortical circuits, are associated with cognitive function and may be disrupted by epileptic activity. Here, we retrospectively studied 87 EEGs from 53 children with active and resolved CAE and 87 age- and sex-matched controls to evaluate sleep spindle activity across disease states and its association with antiseizure medication (ASM) exposure. We found that children with active CAE had reduced spindle rates across all cortical regions compared to those with resolved CAE and controls, with the largest reduction in the frontal region, where epileptic spike activity was also most prominent. Spindle rate was inversely correlated with epileptic spike rate, consistent with a shared thalamocortical circuitry. The association between ASM exposure and spindle rate varied by disease state. In active CAE, treated children had higher spindle rates than untreated children. In resolved CAE, treated children had lower spindle rates than untreated children. In contrast, ASM-related differences in spike rate were more limited, although a medication-specific reduction was observed in active CAE. These findings support sleep spindle rate as a candidate physiological marker of disease state and ASM exposure in children with CAE. Given the established role of sleep spindles in memory consolidation, these findings support testing of whether spindle disruption provides a mechanistic link between epileptic thalamocortical activity and cognitive vulnerability in CAE. Significance Statement Childhood absence epilepsy (CAE) is a common childhood generalized epilepsy characterized by abnormal thalamocortical activity and cognitive difficulties. Here, we show that sleep spindle activity is globally reduced during active CAE, particularly in frontal regions, and normalizes after disease resolution. Spindle activity was anticorrelated with epileptic spike rate and impacted by antiseizure medication exposure. These results support the hypothesis that epileptic spikes and sleep spindles share thalamocortical circuitry and promote sleep spindles as a candidate physiological biomarker to link epileptic activity with cognitive vulnerability in CAE.
2026-07-31 | Parvalbumin interneuron activation rescues both seizures and impaired social novelty in digenic absence epilepsy mice.
Childhood absence epilepsy (CAE) is a common genetic epilepsy with a frequently complex polygenic etiology, for which a genetically tractable animal model is lacking. Current anti-seizure medications fail to address the significant neurocognitive and social comorbidities of CAE, highlighting a critical unmet need for comprehensive therapies and a better understanding of the underlying mechanisms. To address this, we developed a digenic mouse model (Cacng2stargazer/+;Cacna1a+/-, hereafter DiGstg+Ca1A) that mimics human polygenicity. The double mutant mice exhibit both absence seizures and altered social novelty preference. We found that ethosuximide, a first-line anti-CAE medication targeting thalamic low-threshold T-type calcium currents, suppressed seizures in DiGstg+Ca1A mice but failed to rescue their social deficit. Similarly, deletion of Cacna1g, which encodes the T-type Ca2+ channel CaV3.1, prevented seizure generation but did not ameliorate the social deficit. These findings reveal a dissociation between the T-type current that mediates seizures and the mechanism underlying the social deficits. We further demonstrate that in Cacng2stargazer/+ mice, selective deletion of one copy of Cacna1a in stargazin-enriched parvalbumin (PV) interneurons induced absence seizures and impaired social behavior. Remarkably, chemogenetic activation of cortical and thalamic PV interneurons using DREADDs not only suppressed seizures but also rescued the impaired social behavior. Together, our results suggest that selective modulation of PV interneuron activity in polygenic absence epilepsy could serve as a promising therapeutic strategy to address both absence seizures, and the often treatment-resistant neurocognitive comorbidities observed in CAE.
2026-07-16 | Convergent Inhibitory Cortical Circuit Disruption Drives Genetically Distinct Absence Seizures
Abstract Absence seizures, the most common childhood epilepsy, are characterized by brief involuntary lapses in consciousness and 3-Hz spike-wave EEG discharges (SWD). Despite extensive documentation of pathogenic thalamic remodeling, the cortical circuit abnormalities driving this highly stereotyped SWD remain elusive. Using two of the best characterized mouse models of absence epilepsy carrying point mutations in distinct genes altering pre and postsynaptic transmission, stargazer ( Cacng2 ) and tottering ( Cacna1a ), we show that a specific translaminar inhibitory circuit motif defined by layer 6 corticothalamic neurons (L6 CT) and a novel Tac1 + Pvalb interneuron subtype is selectively disrupted in both models. This early functional defect was accompanied by a secondary synaptic collapse of deep-layer somatostatin-expressing ( Sst ) interneurons that precisely coincides with the developmental onset of seizures. Crucially, we established the serial causality of these cascading defects by demonstrating that chemogenetic disruption of L6 CT-Tac1 + Pvalb circuit motif alone in wild-type mice is sufficient to induce both the secondary Sst interneuron collapse and contemporaneous emergence of SWDs. Together, these findings reveal a sequential translaminar synaptic failure or ‘domino effect’ wherein a primary defect triggers broader circuit adaptations permitting spike-wave hypersynchrony. Our results thus identify a convergent, causative cortical circuit pathology that is shared by genetically heterogeneous absence epilepsy models, highlighting a common functional target for therapeutic intervention.
2026-06-09 | Kv7 and K2P Potassium Channels in Thalamocortical Function and Their Therapeutic Potential in Childhood Absence Epilepsy.
Potassium (K+) channels are one of the key regulators of neuronal excitability and network stability. Among all the potassium channels, the voltage-gated Kv7 (KCNQ) and the two-pore domain potassium (K2P) channels play an important role in stabilizing and maintaining the resting potential of neurons. They are involved in controlling the input resistance and in the generation of rhythmic activity in the thalamocortical network. The main functions of the thalamocortical system are the regulation of sensory processing and the generation of brain rhythms underlying sleep and wakefulness. By this, it is essential to many aspects of cognition. The thalamocortical system is explicitly sensitive to fine changes in potassium conductance. The dysregulation of thalamocortical oscillation, also known as thalamocortical dysrhythmia, has been known to be involved in several psychiatric and neurological disorders. A prototypical thalamocortical dysrhythmia is childhood absence epilepsy (CAE), in which hypersynchronous activity in the form of spike and wave discharges (SWD) induces sudden losses of conscious awareness in patients. This review will summarize the current knowledge on Kv7 and K2P channels in the regulation of synchrony and excitability in the brain and the thalamocortical system in particular, outlining future research directions, highlighting the therapeutic potential of these channels for the treatment of thalamocortical dysrhythmias in general and CAE specifically.
oligonucleotides
2026-02-28 | Absence Seizures: Current Concepts in Genetics, Molecular Mechanisms, Classification, Diagnosis, and Contemporary Management
Absence seizures are generalized nonmotor epileptic events characterized by transient impairment of consciousness associated with generalized spike-and-wave discharges on electroencephalography (EEG). [1,2] Traditionally regarded as benign pediatric epileptic phenomena, contemporary evidence increasingly demonstrates that absence seizures comprise a heterogeneous neurobiological spectrum involving complex genetic, molecular, electrophysiological, and thalamocortical network abnormalities. [3,4] Although childhood absence epilepsy remains the prototypical syndrome, absence seizures also occur in juvenile absence epilepsy, juvenile myoclonic epilepsy, epilepsy with eyelid myoclonia, and several developmental and epileptic encephalopathies. [5,6] The pathogenesis of absence seizures involves pathological oscillatory synchronization within cortico-thalamo-cortical circuits mediated by abnormal γ-aminobutyric acid (GABAergic) neurotransmission, T-type calcium channel dysfunction, altered glutamatergic signaling, and genetically determined neuronal hyperexcitability. [4,7] Advances in molecular genetics have identified multiple susceptibility genes including CACNA1H, CACNG3, GABRG2, SLC2A1, SCN1A, and HCN1, thereby highlighting the polygenic and heterogeneous nature of generalized epileptogenesis. [8-10] Clinically, absence seizures manifest as sudden behavioral arrest, impaired awareness, staring episodes, automatisms, eyelid fluttering, and interruption of ongoing activity. [2] Despite their apparently subtle presentation, recurrent absence seizures may substantially impair academic performance, attention, psychosocial functioning, and neurocognitive development. [11] Diagnostic delays remain common because episodes are frequently misinterpreted as daydreaming, inattentiveness, behavioral disorders, or psychogenic events. [12] Electroencephalography remains the cornerstone of diagnosis, classically demonstrating bilateral synchronous 3-Hz generalized spike-and-wave discharges. [1] Contemporary management includes ethosuximide, valproate, and lamotrigine as first-line therapies, while emerging therapeutic research focuses on precision medicine, network neuromodulation, and molecular-targeted interventions. [13,14] This comprehensive descriptive review examines the genetics, molecular genetics, classifications, epidemiology, pathogenesis, clinical manifestations, diagnostic evaluation, differential diagnosis, treatment strategies, prognosis, contemporary controversies, research limitations, and future directions relating to absence seizures
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.
2024-03-26 | Unraveling the shared genetics of common epilepsies and general cognitive ability.
Objective: Cognitive impairment is prevalent among individuals with epilepsy, and it is possible that genetic factors can underlie this relationship. Here, we investigated the potential shared genetic basis of common epilepsies and general cognitive ability (COG). Methods: We applied linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR) to analyze different aspects of genetic overlap between COG and epilepsies. We used the largest available genome–wide association study data on COG ( n = 269,867) and common epilepsies ( n = 27,559 cases, 42,436 controls), including the broad phenotypes ′all epilepsy ′, focal epilepsies and genetic generalized epilepsies (GGE), and as well as specific subtypes. We functionally annotated the identified loci using a variety of biological resources and validated the results in independent samples. Results: Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than ′all epilepsy′, GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k — 2.9k variants). The other epilepsy phenotypes were insufficiently powered for analysis. We show extensive genetic overlap between COG and epilepsies with significant negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and ′all epilepsy′, and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), ′all epilepsy′ (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 1.0 × 10 -14 ; ′all epilepsy′: p = 5.6 × 10 -3 ). Significance: Our study demonstrates a substantial genetic basis shared between epilepsies and COG and identifies novel overlapping genomic loci. Enhancing our understanding of the relationship between epilepsies and COG may lead to the development of novel comorbidity–targeted epilepsy treatments.
2021-12-17 | Clptm1 Downregulation Exerts Antiepileptic Activity by Regulating GABAAR-mediated Inhibitory Synaptic Transmission in PTZ-induced Epileptic Model
Abstract Background: Disruption of GABA A R synaptic clustering and a decrease number in their cell surface are thought to contribute to the alteration in the balance between excitatory and inhibitory neurotransmission, which contributes to seizure induction and propagation. Cleft lip and palate transmembrane protein 1 (Clptm1), a multi-pass transmembrane protein, has been showed that it is an intracellular molecule that controls forward trafficking of GABA A R. Clptm1 downregulating increased miniature inhibitory postsynaptic current (mIPSC) in vivo. Thus, Clptm1 controls phasic and tonic inhibitory transmission in brain. In this study, we hypothesized that Clptm1 may be involved in epileptic seizure by regulating GABA A R-mediated inhibitory synaptic transmission in epileptic model. Methods and Results: In PTZ-induced epileptic model, we found that Clptm1 was increased in temporal lobe epilepsy (TLE) patients as well as in epileptic model. Then, we showed that Clptm1 downregulation exerted antiepileptic activities in epileptic model, which was associated to the increased surface GABA A Rγ2 expression and mIPSCs amplitudes. Conclusions: Clptm1 downregulation exerted antiepileptic activities in epileptic model, thus, it may be a promising target for antiepileptic treatments.
2020-08-21 | Maladaptive myelination promotes epileptogenesis in absence epilepsy
Summary Neuronal activity can influence the generation of new oligodendrocytes (oligodendrogenesis) and myelination. In health, this is an adaptive process that can increase synchrony within distributed neuronal networks and contribute to cognitive function. We hypothesized that in seizure disorders, aberrant neuronal activity may promote maladaptive myelination that contributes to pathogenesis. Absence epilepsy is a disease defined by increasingly frequent behavioral arrest seizures over time, thought to be due to thalamocortical network hypersynchrony. We tested the hypothesis that activity-dependent myelination resulting from absence seizures promotes epileptogenesis. Using two distinct models of absence epilepsy, Wag/Rij rats and Scn8a +/mut mice, we found increased oligodendrogenesis and myelination specifically within the absence seizure network. These changes are evident only after seizure onset in both models and are prevented with pharmacological inhibition of seizures. Genetic blockade of activity-dependent myelination during epileptogenesis markedly decreased seizure frequency in the Scn8a +/mut mouse model of absence epilepsy. Taken together, these findings indicate that activity-dependent myelination driven by absence seizures contributes to seizure kindling during epileptogenesis.
antibodies
2025-09-15 | Investigating the Effects of NMDAR and LGI1 Antibodies on Absence Seizures: Insights from Genetic Absence Epilepsy Rats and Acute Pharmacological Model of Absence Seizures.
Childhood Absence Epilepsy, a subtype of genetic generealised epilepsy, is characterised by sudden and brief episodes of impaired consciousness. The Leucine-rich glioma-inactivated protein 1 (LGI1) and N-methyl-D-aspartate receptor (NMDAR) are key proteins involved in regulating neuronal excitability. In conditions like anti-LGI1 encephalitis and anti-NMDAR encephalitis, autoantibodies target and disrupt these proteins, causing memory deficits, behavioural changes, sleep disturbances, and epileptic seizures. However, the roles of LGI1 and NMDAR dysfunction in the pathophysiology of absence of seizures remain unclear. This study aims to investigate the effects of LGI1 and NMDAR antibodies on absence seizures using two experimental models: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and a low-dose pentylenetetrazol (PTZ) model of absence seizures. IgG purified from the peripheral blood of healthy controls (HC IgG), and patients with anti-NMDAR, and anti-LGI1 encephalitis, was administered intracerebroventricularly into GAERS and Wistar rats every other day for 11 days. Before and after antibody administration, electroencephalography (EEG) recordings were performed to analyse spontaneous spike-and-wave discharges (SWDs) in GAERS. In Wistar rats, after the completion of antibody infusions, PTZ was administered (35 mg/kg) on the 12 th day to induce absence seizures. The occurrence of PTZ-induced SWDs was quantified. NMDAR IgG significantly increased the duration and number of SWDs in GAERS compared to HC IgG. LGI1 IgG had no significant effect, suggesting a differential role of NMDAR and LGI1 antibodies in modulating SWD activity. Similarly, NMDAR IgG-treated Wistar rats showed increased susceptibility to PTZ-induced absence seizures, while LGI1 IgG did not cause significant changes in PTZ-induced SWDs. These results reveal a distinct pro-epileptogenic effect of NMDAR antibodies in both genetic and pharmacological models of absence epilepsy, while LGI1 antibodies appear to have a negligible effect. These findings suggest a specific role for NMDAR dysfunction in absence seizure pathophysiology and support further investigation into antibody-mediated seizure mechanisms.
2021-07-20 | A Case of Refractory Absence Epilepsy Precedes Anti-MOG Associated Optic Neuritis
Childhood absence epilepsy (CAE) is one of the most common forms of pediatric epilepsy. While most patients become seizure free with anti-epileptic drug therapy approximately 20% do not achieve seizure remission and are defined as having refractory CAE. Epilepsy is generally thought of as a grey matter disease but has also been associated with abnormal white matter. Optic neuritis (ON), on the other hand, is typically a white matter disorder characterized by inflammation and demyelination of the myelin sheath due to autoantibodies, such as the anti-myelin oligodendrocyte glycoprotein (MOG) antibody. We present the case of an 11-year-old female with refractory CAE who developed anti-MOG antibody positive ON. CAE and ON are not commonly co-morbid and to our knowledge their co-occurrence in a patient has not been previously described. However, in this case, the CAE and ON may be related as her seizures dramatically improved after initiating immunomodulatory treatments for the ON. This may indicate a relationship between ON (potentially specific to anti-MOG positive ON) and CAE, or may suggest that there is an inflammatory component to CAE and that immunomodulatory therapies may have a role in seizure control. Thus, in cases of treatment resistant absence epilepsy, an immune work up may be helpful.
gene therapies
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.
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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Drug Discovery Landscape
3 orphan drug designations for Childhood absence epilepsy.
3 orphan drug designations for Childhood absence epilepsy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
flunarizine | small molecules | FDA | Xenon Pharmaceuticals Inc. | |
brivaracetam | small molecules | FDA | UCB, Inc. | |
cannabidiol | small molecules | FDA | Benuvia Operations LLC |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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