-
Neurological Sciences : Official... May 2024Drug-resistant juvenile myoclonic epilepsy (DR-JME) remains a significant challenge in neurology. Traditional management strategies often fail to achieve satisfactory...
BACKGROUND
Drug-resistant juvenile myoclonic epilepsy (DR-JME) remains a significant challenge in neurology. Traditional management strategies often fail to achieve satisfactory control, necessitating innovative treatments.
OBJECTIVE
This case report aims to evaluate the efficacy and safety of deep brain stimulation (DBS) targeting the subthalamic nucleus (STN-DBS) in a patient with DR-JME.
METHODS
We describe the treatment of a patient with DR-JME using STN-DBS. The patient underwent implantation and received high-frequency stimulation (HFS) at the STN.
RESULTS
One year post-implantation, the patient demonstrated a substantial reduction in motor seizure frequency by 87.5%, with improvements in quality of life and seizure severity by 52.0% and 46.7%, respectively. No adverse events were reported during the follow-up period.
CONCLUSIONS
This case represents the first report of favorable outcomes with STN-DBS in a patient with DR-JME, suggesting that long-term HFS of the STN may be a promising treatment option for patients suffering from this condition.
PubMed: 38740728
DOI: 10.1007/s10072-024-07553-1 -
International Journal of Molecular... Apr 2024A significant number of patients with genetic epilepsy do not obtain seizure freedom, despite developments in new antiseizure drugs, suggesting a need for novel...
Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome.
A significant number of patients with genetic epilepsy do not obtain seizure freedom, despite developments in new antiseizure drugs, suggesting a need for novel therapeutic approaches. Many genetic epilepsies are associated with misfolded mutant proteins, including -associated Dravet syndrome, which we have previously shown to result in intracellular accumulation of mutant GABA receptor γ2(Q390X) subunit protein. Thus, a potentially promising therapeutic approach is modulation of proteostasis, such as increasing endoplasmic reticulum (ER)-associated degradation (ERAD). To that end, we have here identified an ERAD-associated E3 ubiquitin ligase, HRD1, among other ubiquitin ligases, as a strong modulator of wildtype and mutant γ2 subunit expression. Overexpressing HRD1 or knockdown of HRD1 dose-dependently reduced the γ2(Q390X) subunit. Additionally, we show that zonisamide (ZNS)-an antiseizure drug reported to upregulate HRD1-reduces seizures in the mouse. We propose that a possible mechanism for this effect is a partial rescue of surface trafficking of GABA receptors, which are otherwise sequestered in the ER due to the dominant-negative effect of the γ2(Q390X) subunit. Furthermore, this partial rescue was not due to changes in ER chaperones BiP and calnexin, as total expression of these chaperones was unchanged in γ2(Q390X) models. Our results here suggest that leveraging the endogenous ERAD pathway may present a potential method to degrade neurotoxic mutant proteins like the γ2(Q390X) subunit. We also demonstrate a pharmacological means of regulating proteostasis, as ZNS alters protein trafficking, providing further support for the use of proteostasis regulators for the treatment of genetic epilepsies.
Topics: Epilepsies, Myoclonic; Receptors, GABA-A; Animals; Endoplasmic Reticulum; Mice; Humans; Proteolysis; Seizures, Febrile; Endoplasmic Reticulum-Associated Degradation; Ubiquitin-Protein Ligases; Molecular Chaperones; Mutation; HEK293 Cells; Endoplasmic Reticulum Chaperone BiP
PubMed: 38731820
DOI: 10.3390/ijms25094601 -
Molecules (Basel, Switzerland) Apr 2024It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat... (Review)
Review
It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.
Topics: Humans; Cannabidiol; Epilepsy; Anticonvulsants; Randomized Controlled Trials as Topic; Lennox Gastaut Syndrome; Child; Treatment Outcome; Epilepsies, Myoclonic
PubMed: 38731471
DOI: 10.3390/molecules29091981 -
Journal of Neurology May 2024To determine the efficacy and safety of perampanel (PER) as an adjunctive therapy in children aged 4-12 years with epilepsy.
OBJECTIVE
To determine the efficacy and safety of perampanel (PER) as an adjunctive therapy in children aged 4-12 years with epilepsy.
METHODS
We performed a non-randomized, open-label, placebo-uncontrolled, real-world self-controlled study that included 216 young children (aged 4-12 years) with epilepsy who received PER as adjunctive therapy at the children's hospital affiliated with Chongqing Medical University from July 4, 2020, to September 20, 2023.
RESULTS
(1) The efficacy rates of adjunctive PER therapy at 3, 6, 9, and 12 months were 62.8%, 67.8%, 65.3%, and 61.2%, respectively. PER showed efficacy in alleviating focal seizures, generalized tonic-clonic seizures, myoclonic seizures, and absence seizures. The efficacy rates for variants of self-limited epilepsy with centrotemporal spikes (SeLECTS) and Lennox-Gastaut syndrome (LGS) were 89.5% and 66.7%, respectively. (2) Focal non-motor onset seizures with or without impaired awareness, focal to bilateral tonic-clonic seizures (FBTCS), LGS, variants of SeLECTS, the number of concomitant antiseizure medications (ASMs), a family history of epilepsy, and focal lesions on cranial magnetic resonance imaging were independent factors affecting efficacy. The order of PER addition did not affect efficacy. The retention rates at 3, 6, 9, and 12 months were 90.7%, 84.7%, 74.7%, 64.9%, respectively. (3) Adverse reactions occurred in 45 patients (45/216, 20.8%), with irritability/aggressive behavior (18/216, 8.3%) and somnolence (14/216, 6.5%) being the most common. Twelve patients (12/216, 5.6%) withdrew from the study because of adverse reactions.
CONCLUSION
In young Chinese children with epilepsy, PER is effective, safe, and well-tolerated as an adjunctive therapy, making it a viable option for use with broad-spectrum ASMs.
PubMed: 38717610
DOI: 10.1007/s00415-024-12416-y -
Neurological Sciences : Official... May 2024Juvenile myoclonic epilepsy (JME) is characterized by altered patterns of brain functional connectivity (FC). However, the nature and extent of alterations in the...
BACKGROUND
Juvenile myoclonic epilepsy (JME) is characterized by altered patterns of brain functional connectivity (FC). However, the nature and extent of alterations in the spatiotemporal characteristics of dynamic FC in JME patients remain elusive. Dynamic networks effectively encapsulate temporal variations in brain imaging data, offering insights into brain network abnormalities and contributing to our understanding of the seizure mechanisms and origins.
METHODS
Resting-state functional magnetic resonance imaging (rs-fMRI) data were procured from 37 JME patients and 37 healthy counterparts. Forty-seven network nodes were identified by group-independent component analysis (ICA) to construct the dynamic network. Ultimately, patients' and controls' spatiotemporal characteristics, encompassing temporal clustering and variability, were contrasted at the whole-brain, large-scale network, and regional levels.
RESULTS
Our findings reveal a marked reduction in temporal clustering and an elevation in temporal variability in JME patients at the whole-brain echelon. Perturbations were notably pronounced in the default mode network (DMN) and visual network (VN) at the large-scale level. Nodes exhibiting anomalous were predominantly situated within the DMN and VN. Additionally, there was a significant correlation between the severity of JME symptoms and the temporal clustering of the VN.
CONCLUSIONS
Our findings suggest that excessive temporal changes in brain FC may affect the temporal structure of dynamic brain networks, leading to disturbances in brain function in patients with JME. The DMN and VN play an important role in the dynamics of brain networks in patients, and their abnormal spatiotemporal properties may underlie abnormal brain function in patients with JME in the early stages of the disease.
PubMed: 38704479
DOI: 10.1007/s10072-024-07506-8 -
Cognitive Neurodynamics Apr 2024Juvenile myoclonic epilepsy (JME) as an idiopathic generalized epilepsy has been studied by many advanced neuroimaging techniques to elucidate its neuroanatomical basis... (Review)
Review
Juvenile myoclonic epilepsy (JME) as an idiopathic generalized epilepsy has been studied by many advanced neuroimaging techniques to elucidate its neuroanatomical basis and pathophysiological mechanisms. In this paper, we used co-activation patterns (CAPs) to explore the differences of dynamic brain activity changes in resting state between JME patients and healthy controls. 27 cases JME patients and 27 cases healthy of fMRI data were collected. The structural image data of the subjects were analyzed by voxel-based morphological analysis, and the regions with gray matter volume atrophy and high voxel were selected as the regions of interest. Further, the mean disease duration was used as boundary to divide the patients' data into the below-average time and the above-average time groups, which were defined as patient disease duration groups. And these data were used to construct CAPs and to compare changes in brain dynamics. It was found that the number of patterns occurrences and the possibility of switching between patterns were smaller than those in the healthy control, which indicated patients with damage to brain regions. For the patient time control group, the number of patterns occurrences and the possibility of switching between patterns were similar, while there was linear regression between the three values and disease duration. Collectively, this study provides important evidence for revealing the key brain regions of JME by studying the transformation between CAPs. Future studies could investigate the effects of receiving treatment on patient dynamic brain activity.
PubMed: 38699614
DOI: 10.1007/s11571-022-09838-7 -
European Journal of Neurology May 2024Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, lysosomal storage disorder that causes pediatric onset neurodegenerative disease. It is characterized by...
Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, lysosomal storage disorder that causes pediatric onset neurodegenerative disease. It is characterized by mutations in the TPP1 gene. Symptoms begin between 2 and 4 years of age with loss of previously acquired motor, cognitive, and language abilities. Cerliponase alfa, a recombinant human TPP1 enzyme, is the only approved therapy. We report the first presymptomatic cerliponase alfa intraventricular treatment in a familial case of CLN2 related to a classical TPP1 variant. Sister 1 presented with motor, cognitive, and language decline and progressive myoclonic epilepsy since the age of 3 years, evolved with severe diffuse encephalopathy, received no specific treatment, and died at 11 years. Sister 2 had a CLN2 presymptomatic diagnosis and has been treated with cerliponase since she was 12 months old. She is now 6 years 8 months and has no CLN2 symptom except one generalized seizure 1 year ago. No serious adverse event has occurred. Repeated Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition standardized index scores are heterogeneous in the extremely low to low average ranges. Mean length of utterances, a global index of sentence complexity, showed a delay, but a gradual improvement. The reported case enhances the major contribution of presymptomatic diagnosis and significant middle-term treatment benefit for patients with CLN2.
PubMed: 38693756
DOI: 10.1111/ene.16324 -
Epilepsy & Behavior : E&B Jul 2024Dravet syndrome (DS) is a Developmental and Epileptic Encephalopathy (DEE) with onset typically in infancy. Seizures are pharmaco-resistant, and neurodevelopment is...
BACKGROUND
Dravet syndrome (DS) is a Developmental and Epileptic Encephalopathy (DEE) with onset typically in infancy. Seizures are pharmaco-resistant, and neurodevelopment is compromised in almost all children. There is limited data on the impact of the condition on the family, support needs and hopes and fears in Sweden.
METHODS
Interviews were undertaken with the caregivers of 36 of 48 (75%) living children with DS in Sweden focusing on the perceived impact on the family, current supports and hopes and fears for the future. Data from the interviews were analyzed by two raters using reflexive thematic analysis.
RESULTS
The analysis revealed seven main themes focusing on the perceived negative impact the disease has on caregivers and family functioning. These negative impacts concerned: caregiver sleep (e.g., frequent night waking), siblings (e.g., gets less attention/time), social life (e.g., limited vacations), family finances (e.g., limited career progression), parental health (both mental and physical) and need for constant supervision (e.g., child's need for constant supervision for fear of seizures). Another theme concerned the impact on family relationships. Whilst some caregivers perceived the impact to be negative (e.g., limited time for each other) others felt that having a child with DS lead to stronger relationships and more 'teamwork'. With respect to supports, the caregivers identified a number of areas where they felt the family could access appropriate supports. Themes regarding supports included: support from the wider family and friends, support from DS support groups (online or in-person), support from the child's hospital or disability service and respite care (e.g., child was looked after on weekends or had paid carers in the home). Regarding hopes and fears for the future, responses focused mainly on fears, including concerns about premature death of the child, transition to adult healthcare services and care arrangements for child when parents are dead. Hopes for the future included better treatment for epilepsy and associated neurodevelopmental problems and finding a cure for DS.
CONCLUSIONS
Caregivers of children with DS report that the disease can have a very comprehensive negative impact on caregiver and family functioning. Identifying and providing the supports to ameliorate these negative impacts is vital to optimize caregiver and family wellbeing and quality of life.
Topics: Humans; Caregivers; Epilepsies, Myoclonic; Male; Female; Fear; Child; Adult; Qualitative Research; Child, Preschool; Sweden; Family; Hope; Adolescent; Social Support; Middle Aged; Young Adult; Perception; Infant
PubMed: 38692022
DOI: 10.1016/j.yebeh.2024.109790 -
Frontiers in Neurology 2024Epilepsy, characterized by recurrent seizures, impacts 70-80% of patients, leading to cognitive deficits. The intricate relationship between seizure control and...
Epilepsy, characterized by recurrent seizures, impacts 70-80% of patients, leading to cognitive deficits. The intricate relationship between seizure control and cognitive impairment remains complex. Epileptic encephalopathy (EE), an intensified form often rooted in genetic factors, is detectable through next-generation sequencing, aiding in precise diagnoses, family counseling, and potential treatment strategies. We present a case involving two sisters with refractory generalized seizures evolving into dysarthria, dysphagia, ataxia, and cognitive decline. Despite normal physical exams, abnormal electroencephalogram results consistent with epilepsy were noted. Whole Exome Sequencing identified heterozygous variants in the alanyl-tRNA synthetase (AARS) and Calcium Voltage-Gated Channel Subunit Alpha 1 (CACNA1A) genes. The AARS variant (c.C2083T, p.R695*) was maternal, while the CACNA1A variant (c.G7400C, p.R2467P) was paternal. Patients A and B exhibited a unique blend of neurological and psychiatric conditions, distinct from common disorders that begin adolescence, like Juvenile Myoclonic Epilepsy. Whole Exome Sequencing uncovered an AARS gene and CACNA1A gene, linked to various autosomal dominant phenotypes. Presence in both parents, coupled with familial reports of migraines and seizures, provides insight into accelerated symptom progression. This study underscores the importance of genetic testing in decoding complex phenotypes and emphasizes the value of documenting family history for anticipating related symptoms and future health risks.
PubMed: 38689878
DOI: 10.3389/fneur.2024.1376643 -
Epilepsy & Behavior : E&B Jul 2024Dravet syndrome is a rare, early childhood-onset epileptic and developmental encephalopathy. Responses to placebo in clinical trials for epilepsy therapies range widely,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Dravet syndrome is a rare, early childhood-onset epileptic and developmental encephalopathy. Responses to placebo in clinical trials for epilepsy therapies range widely, but factors influencing placebo response remain poorly understood. This study explored placebo response and its effects on safety, efficacy, and quality of life outcomes in patients with Dravet syndrome.
METHODS
We performed exploratory post-hoc analyses of pooled data from placebo-treated patients from the GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials, comparing cannabidiol and matched placebo in 2-18 year old Dravet syndrome patients. All patients had ≥4 convulsive seizures during a baseline period of 4 weeks.
RESULTS
124 Dravet syndrome-treated patients were included in the analysis (2-5 years: n = 35; 6-12 years: n = 52; 13-18 years: n = 37). Convulsive seizures were experienced by all placebo group patients at all timepoints, with decreased median convulsive seizure frequency during the treatment period versus baseline; the number of convulsive seizure-free days was similar to baseline. Convulsive seizure frequency had a nominally significant positive correlation with age and a nominally significant negative correlation with body mass index. Most placebo-treated patients experienced a treatment-emergent adverse event; however, most resolved quickly, and serious adverse events were infrequent. Placebo treatment had very little effect on reported Caregiver Global Impression of Change outcomes versus baseline.
INTERPRETATION
Placebo had little impact on convulsive seizure-free days and Caregiver Global Impression of Change versus baseline, suggesting that these metrics may help differentiate placebo and active treatment effects in future studies. However, future research should further assess placebo responses to confirm these results.
Topics: Humans; Epilepsies, Myoclonic; Adolescent; Child; Female; Male; Cannabidiol; Child, Preschool; Placebo Effect; Anticonvulsants; Quality of Life; Treatment Outcome; Double-Blind Method
PubMed: 38677101
DOI: 10.1016/j.yebeh.2024.109805