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The Lancet Regional Health. Southeast... May 2023Infantile Epileptic Spasms Syndrome (IESS), commonly known as West syndrome, is the most common cause of infantile-onset epileptic encephalopathy. There is a peculiar... (Review)
Review
Infantile Epileptic Spasms Syndrome (IESS), commonly known as West syndrome, is the most common cause of infantile-onset epileptic encephalopathy. There is a peculiar epidemiological profile of IESS in South Asia. Specific features identified were a preponderance of acquired structural aetiology, male gender dominance, a long treatment lag, limited availability of adrenocorticotropic hormone (ACTH) and vigabatrin, and use of carboxymethyl cellulose derivative of ACTH. Because of the significant disease burden and limited resources, there are distinctive challenges to the optimal care of children with IESS in the South Asian region. Also, there are unique opportunities to bridge these challenges and improve outcomes. This review provides an overview of the landscape of IESS in South Asia and highlights its peculiarities, various challenges, and way forward.
PubMed: 37384052
DOI: 10.1016/j.lansea.2023.100170 -
Annals of Indian Academy of Neurology 2021Biotin-thiamine-responsive basal ganglia disease is a rare, autosomal recessive, treatable, neurometabolic disorder associated with biallelic pathogenic variations in... (Review)
Review
Biotin-thiamine-responsive basal ganglia disease is a rare, autosomal recessive, treatable, neurometabolic disorder associated with biallelic pathogenic variations in the gene. The condition may present as an early-childhood encephalopathy, an early-infantile lethal encephalopathy with lactic acidosis, with or without infantile spasms, or a late-onset Wernicke-like encephalopathy. The key radiological features are bilateral, symmetrical lesions in the caudate, putamen, and medial thalamus, with variable extension into the brain stem, cerebral cortex, and cerebellum. Treatment is life long and includes initiation of high dose biotin and thiamine. Genetic testing confirms the diagnosis. The prognosis depends on the time from diagnosis to the time of vitamin supplementation. The genotype-phenotype correlations are not clear yet, but the early infantile phenotype portends a poorer prognosis. We provide a brief overview of the disorder and emphasize the initiation of high-dose biotin and thiamine in infants and children with unexplained encephalopathy and basal ganglia involvement.
PubMed: 34220059
DOI: 10.4103/aian.AIAN_952_20 -
Brain Sciences Feb 2022(1) Background: West syndrome is a severe, refractory, epileptic syndrome that usually appears in infancy or early childhood. ACTH is one of the more effective drugs for...
(1) Background: West syndrome is a severe, refractory, epileptic syndrome that usually appears in infancy or early childhood. ACTH is one of the more effective drugs for treating this condition. (2) Aim of the study and methods: The objective of our study was to examine short-term efficacy (during treatment schedule) and long-term outcome of intramuscular 0.02 mg/kg/day ACTH (tetracosactide) depot, used concomitantly with other antiepileptic drugs (AEDs) in patients with infantile spasms who did not achieve seizure cessation or relapse when taking only the AEDs. The drug efficacy was evaluated in retrospective and prospective analyses of 50 patients diagnosed with infantile spasms. (3) Results: Complete cessation of spasms was achieved in 42 cases (84%). EEG improvement was seen in 41 (82%) patients who responded to ACTH therapy. Information on the clinical course of 28 patients was obtained duringlong-term follow-up. In 17 (60.7%) cases, seizures were still present. Normal or near-normal development was observed in 11 out of 28 children (39%). ACTH used concomitantly with other AEDis a highly effective treatment with acceptable side effects. (4) Conclusion: Randomized controlled clinical trialswith long-term follow-up are needed to compare the effectiveness of ACTH in polytherapy and monotherapy. Dyskinesias as a potential side effect observed in our study group should be investigated in the following studies.
PubMed: 35204017
DOI: 10.3390/brainsci12020254 -
Frontiers in Neurology 2021This study aimed to analyze the genotypes and phenotypes of variants in a Chinese cohort. Seven male and four female patients with variants were enrolled, including...
This study aimed to analyze the genotypes and phenotypes of variants in a Chinese cohort. Seven male and four female patients with variants were enrolled, including siblings of brothers. Ten different variants (nine missense and one splicing site) were identified, among which six were novel. All the variants were confirmed to be in peripheral blood DNA. Eight (73%, 8/11) patients had epilepsy; the seizure onset age ranged from 6 h after birth to 4 months (median age, 2.5 months). Focal seizures were observed in all eight patients, epileptic spasms occurred in six (75%, 6/8), tonic spasm in four (50%, 4/8), tonic seizures in two, atypical absence in one, and generalized tonic-clonic seizures in one. Seven patients had multiple seizure types. Eight (73%, 8/11) patients had movement disorders, seven of them having only dystonia, and one having dystonia with choreoathetosis. Varying degrees of developmental delay (DD) were present in all 11 patients. The phenotypes were diagnosed as early infantile epileptic encephalopathy (EIEE) in two (18%) patients, which were further diagnosed as West syndrome. Movement disorders (MD) with developmental delay were diagnosed in two (18%) brothers. EIEE and MD were overlapped in six (55%) patients, among which two were diagnosed with West syndrome, one with Ohtahara syndrome, and the other three with non-specific EIEE. One (9%) patient was diagnosed as DD alone. The onset age of -related disorders was early infancy. The phenotypic spectrum of included EIEE, MD with DD, and DD alone.
PubMed: 34122306
DOI: 10.3389/fneur.2021.662162 -
Epilepsia Open Jun 2023This systematic review and meta-analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed,... (Meta-Analysis)
Meta-Analysis Review
This systematic review and meta-analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta-analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR = 0.37, 95% CI = 0.20-0.67) for patients with new-onset IESS. Meta-analysis of the nine OSs agrees with the result from RCTs (OR = 0.61, 95% CI = 0.43-0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR = 5.59, 95% CI = 2.17-14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR = 0.75, 95% CI = 0.09-6.45). Hormonal monotherapy is better than VGB monotherapy for non-TSC-associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy.
Topics: Humans; Vigabatrin; Anticonvulsants; Spasms, Infantile; Syndrome; Spasm
PubMed: 36740237
DOI: 10.1002/epi4.12703 -
Epilepsy Research Nov 2021Dravet syndrome (DS) is still seen as a "pediatric disease", where patients receive excellent care in pediatric centers, but care is less than optimal in adult health... (Review)
Review
INTRODUCTION
Dravet syndrome (DS) is still seen as a "pediatric disease", where patients receive excellent care in pediatric centers, but care is less than optimal in adult health care systems (HCS). This creates a barrier when young adults need to leave the family-centered pediatric system and enter the adult, patient-centered HCS. Here we create a guide to help with the transition from pediatric to adult for patients with DS.
METHODS
Experts in Dravet syndrome flagged the main barriers in caring for adults with DS and created a 2-page transition summary guide based on their expertise and a literature review.
RESULTS
The 2-page guide addresses: DS diagnosis in children and adults; clinical manifestations, including the differences in seizures types and frequencies between children and adults with DS; the natural history of intellectual disability, behavior, gait, motor disorders and dysautonomia; a review of optimal treatments (including medications not commonly used in adult epilepsy settings such as stiripentol and fenfluramine), as well as emergency seizure management; avoidance of triggers, preventive measures, and vaccine administration in adults with DS.
CONCLUSION
Several young adults with DS are still followed by their child neurologist. This 2-page transition guide should help facilitate the transition of patients with DS to the adult HCS and should be given to families as well as adult health care providers that may not be familiar with DS.
Topics: Anticonvulsants; Child; Epilepsies, Myoclonic; Fenfluramine; Humans; Neurologists; Spasms, Infantile; Young Adult
PubMed: 34624600
DOI: 10.1016/j.eplepsyres.2021.106743 -
Epilepsy & Behavior : E&B May 2023Chromosome 15q duplication (Dup15q) syndrome and cyclin‑dependent kinase-like 5 deficiency disorder (CDD) are rare neurodevelopmental disorders associated with...
Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase II study (ARCADE).
OBJECTIVE
Chromosome 15q duplication (Dup15q) syndrome and cyclin‑dependent kinase-like 5 deficiency disorder (CDD) are rare neurodevelopmental disorders associated with epileptic encephalopathies, with a lack of specifically approved treatment options. ARCADE assessed the efficacy and safety of adjunctive soticlestat (TAK-935) for the treatment of seizures in patients with Dup15q syndrome or CDD (NCT03694275).
METHODS
ARCADE was a phase II, open-label, pilot study of soticlestat (≤300 mg/day twice daily, weight-adjusted) in pediatric and adult patients 2-55 years of age with Dup15q syndrome or CDD who experienced ≥3 motor seizures per month in the 3 months before screening and at baseline. The 20-week treatment period consisted of a dose-optimization period and a 12-week maintenance period. Efficacy endpoints included the change from baseline in motor seizure frequency during the maintenance period and the proportion of treatment responders. Safety endpoints included the incidence of treatment-emergent adverse effects (TEAEs).
RESULTS
The modified-intent-to-treat population included 20 participants who received ≥1 dose of soticlestat and had ≥1 efficacy assessment (Dup15q syndrome, n = 8; CDD, n = 12). Soticlestat administration during the maintenance period was associated with a median change from baseline in motor seizure frequency of +11.7% in the Dup15q syndrome group and -23.6% in the CDD group. Reductions in all seizure frequency of -23.4% and -30.5% were also observed during the maintenance period in the Dup15q syndrome group and the CDD group, respectively. Most TEAEs were of mild or moderate severity. Serious TEAEs were reported by three patients (15.0%); none were considered drug related. The most common TEAEs were constipation, rash, and seizure. No deaths were reported.
CONCLUSIONS
Adjunctive soticlestat treatment was associated with a decrease in motor seizure frequency from baseline in patients with CDD and a decrease in all seizure frequency in both patient groups. Soticlestat treatment was associated with an increase in motor seizure frequency in patients with Dup15q syndrome.
Topics: Adult; Humans; Child; Infant; Anticonvulsants; Pilot Projects; Treatment Outcome; Drug Therapy, Combination; Seizures; Spasms, Infantile; Drug-Related Side Effects and Adverse Reactions; Double-Blind Method; Protein Serine-Threonine Kinases
PubMed: 37011526
DOI: 10.1016/j.yebeh.2023.109173 -
Molecular Genetics & Genomic Medicine Jul 2022West syndrome (WS) is an epileptic encephalopathy (EE) that begins in children 4-7 months of age (in rare cases older than 2 years). To date, over 30 genes that have... (Review)
Review
BACKGROUND
West syndrome (WS) is an epileptic encephalopathy (EE) that begins in children 4-7 months of age (in rare cases older than 2 years). To date, over 30 genes that have been reported to be related to WS. Reports involving the extremely rare pathogenic gene, transducin beta-like 1-X- linked receptor 1(TBL1XR1) are quite limited.
METHODS
We performed exome sequencing (ES) of family trios for this infant. We also collected and summarized the clinical data for reported heterozygous germline variants of TBL1XR1. Moreover, we reviewed all published cases and summarized the clinical features and genetic variants of TBL1XR1.
RESULTS
ES revealed a de novo variant in TBL1XR1 [NM_024665.5: exon4: c.187G > A (p.Glu63Lys)]. This variant was classified as likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines and was verified by Sanger sequencing. Further conservation analyses revealed a high conservation among several species. There was clinical heterogeneity among all patients with TBL1XR1-related West syndrome.
CONCLUSION
Our results expand the pathogenic variant spectrum of TBL1XR1 and strengthen the pathogenic evidence of TBL1XR1 in West syndrome.
Topics: Child; Child, Preschool; Heterozygote; Humans; Infant; Receptors, Cytoplasmic and Nuclear; Repressor Proteins; Spasms, Infantile; Exome Sequencing
PubMed: 35611576
DOI: 10.1002/mgg3.1991 -
AJNR. American Journal of Neuroradiology Oct 2022West syndrome is a developmental and epileptic encephalopathy characterized by epileptic spasms, neurodevelopmental regression, and a specific EEG pattern called...
BACKGROUND AND PURPOSE
West syndrome is a developmental and epileptic encephalopathy characterized by epileptic spasms, neurodevelopmental regression, and a specific EEG pattern called hypsarrhythmia. Our aim was to investigate the brain activities related to hypsarrhythmia at onset and focal epileptiform discharges in the remote period in children with West syndrome using simultaneous electroencephalography and fMRI recordings.
MATERIALS AND METHODS
Fourteen children with West syndrome underwent simultaneous electroencephalography and fMRI at the onset of West syndrome. Statistically significant blood oxygen level-dependent responses related to hypsarrhythmia were analyzed using an event-related design of 4 hemodynamic response functions with peaks at 3, 5, 7, and 9 seconds after the onset of each event. Six of 14 children had focal epileptiform discharges after treatment and underwent simultaneous electroencephalography and fMRI from 12 to 25 months of age.
RESULTS
At onset, positive blood oxygen level-dependent responses were seen in the brainstem (14/14 patients), thalami (13/14), basal ganglia (13/14), and hippocampi (13/14), in addition to multiple cerebral cortices. Group analysis using hemodynamic response functions with peaks at 3, 5, and 7 seconds showed positive blood oxygen level-dependent responses in the brainstem, thalamus, and hippocampus, while positive blood oxygen level-dependent responses in multiple cerebral cortices were seen using hemodynamic response functions with peaks at 5 and 7 seconds. In the remote period, 3 of 6 children had focal epileptiform discharge-related positive blood oxygen level-dependent responses in the thalamus, hippocampus, and brainstem.
CONCLUSIONS
Positive blood oxygen level-dependent responses with hypsarrhythmia appeared in the brainstem, thalamus, and hippocampus on earlier hemodynamic response functions than the cerebral cortices, suggesting the propagation of epileptogenic activities from the deep brain structures to the neocortices. Activation of the hippocampus, thalamus, and brainstem was still seen in half of the patients with focal epileptiform discharges after adrenocorticotropic hormone therapy.
Topics: Child; Humans; Spasms, Infantile; Magnetic Resonance Imaging; Electroencephalography; Brain Stem; Brain; Hippocampus; Thalamus
PubMed: 36137665
DOI: 10.3174/ajnr.A7646 -
Neurobiology of Disease Jun 2023Mutations in the CDKL5 gene are the cause of CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental condition characterized by early-onset epilepsy, motor...
Mutations in the CDKL5 gene are the cause of CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental condition characterized by early-onset epilepsy, motor impairment, intellectual disability, and autistic features. A mouse model of CDD, the Cdkl5 KO mouse, that recapitulates several aspects of CDD symptomology, has helped to highlight brain alterations leading to CDD neurological defects. Studies of brain morphogenesis in adult Cdkl5 KO mice showed defects in dendritic arborization of pyramidal neurons and in synaptic connectivity, a hypocellularity of the hippocampal dentate gyrus, and a generalized microglia over-activation. Nevertheless, no studies are available regarding the presence of these brain alterations in Cdkl5 KO pups, and their severity in early stages of life compared to adulthood. A deeper understanding of the CDKL5 deficient brain during an early phase of postnatal development would represent an important milestone for further validation of the CDD mouse model, and for the identification of the optimum time window for treatments that target defects in brain development. In sight of this, we comparatively evaluated the dendritic arborization and spines of cortical pyramidal neurons, cortical excitatory and inhibitory connectivity, microglia activation, and proliferation and survival of granule cells of the hippocampal dentate gyrus in hemizygous Cdkl5 KO male (-/Y) mice aged 7, 14, 21, and 60 days. We found that most of the structural alterations in Cdkl5 -/Y brains are already present in pups aged 7 days and do not worsen with age. In contrast, the difference in the density of excitatory and inhibitory terminals between Cdkl5 -/Y and wild-type mice changes with age, suggesting an age-dependent cortical excitatory/inhibitory synaptic imbalance. Confirming the precocious presence of brain defects, Cdkl5 -/Y pups are characterized by an impairment in neonatal sensory-motor reflexes.
Topics: Male; Animals; Mice; Protein Serine-Threonine Kinases; Spasms, Infantile; Epileptic Syndromes; Brain; Mice, Knockout
PubMed: 37164289
DOI: 10.1016/j.nbd.2023.106146