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Brain : a Journal of Neurology Dec 2023STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental end...
STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental end points, have not yet been described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1281 cumulative patient-years of seizure and developmental histories in 162 individuals with STXBP1-related disorders and established a natural history framework. STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions in STXBP1 (n = 39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n = 30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales. Quantification of end points revealed high variability during the first 5 years of life, with emerging stratification between clinical subgroups. An earlier epilepsy onset was associated with lower developmental abilities, most prominently when assessing gross motor development and expressive communication. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range of trial success probabilities across the age span, with the highest probability in early childhood between 1 year and 3.5 years. In summary, we delineated epilepsy and developmental trajectories in STXBP1-related disorders using standardized measures, providing a foundation to interpret future therapeutic strategies and inform rational trial design.
Topics: Infant, Newborn; Child; Child, Preschool; Humans; Infant; Anticonvulsants; Spasms, Infantile; Epilepsy; Topiramate; Seizures; Munc18 Proteins
PubMed: 38015929
DOI: 10.1093/brain/awad287 -
Indian Journal of Pediatrics Jan 2022To study the effectiveness, tolerability, and safety of oral nitrazepam in children with resistant West syndrome (WS). (Observational Study)
Observational Study
OBJECTIVES
To study the effectiveness, tolerability, and safety of oral nitrazepam in children with resistant West syndrome (WS).
METHODS
This prospective observational study was conducted at a tertiary care hospital in North India from January 2019 to October 2020. Children with WS resistant to standard therapy were enrolled within 7 d of initiation of nitrazepam and prospectively followed-up for cessation of spasms and adverse events.
RESULTS
Forty-one children with resistant WS initiated on nitrazepam therapy were evaluated. The median age at onset of spasms was 6 mo (Q1, Q3: 4, 8). There was a preponderance of male gender (71%) and structural causes (78%). More than half of the enrolled children had failed four or more antiseizure medications (ASM) for epileptic spasms. The study participants had a long lead-time-to-treatment (LTTT) for the initial standard therapy (median: 2 mo; Q1, Q3: 1, 5) and nitrazepam (median: 11 mo; Q1, Q3: 8, 16). Nitrazepam was instituted as monotherapy in 7 (17%) children and as an adjunct in the rest. Twenty-one (51%) children achieved persistent cessation of epileptic spasms. However, the electroclinical response was observed in 17 (42%) children. Drowsiness, sialorrhea, and decreased appetite were the most commonly observed adverse events. Most adverse events were mild to moderate in severity and did not require dose reduction or change of medication. There was no significant difference between the responders and nonresponders in terms of LTTT, age at onset, or etiology.
CONCLUSIONS
Nitrazepam is a safe and feasible treatment alternative in children with resistant WS resulting in persistent cessation of spasms and electroclinical response in nearly half of patients.
Topics: Anticonvulsants; Child; Electroencephalography; Humans; Infant; Male; Nitrazepam; Prospective Studies; Spasm; Spasms, Infantile
PubMed: 34169452
DOI: 10.1007/s12098-021-03823-4 -
Indian Journal of Pediatrics Dec 2020Infantile spasms, though long recognised, are still a cause of significant morbidity in children. The knowledge of their etiology and pathogenesis is still evolving.... (Review)
Review
Infantile spasms, though long recognised, are still a cause of significant morbidity in children. The knowledge of their etiology and pathogenesis is still evolving. Even the management strategies vary among different centres. Hormonal treatments and vigabatrin have been recognised as effective but controversies prevail on the exact protocols that best balance the risk benefit ratio. Collaborative studies have begun to provide some clarity on some of the management issues but further large scale studies that further standardise protocols are a felt need. This article attempts to provide a clinically relevant summary of the current knowledge.
Topics: Anticonvulsants; Humans; Infant; Risk Assessment; Spasms, Infantile; Vigabatrin
PubMed: 32557136
DOI: 10.1007/s12098-020-03279-y -
The Lancet. Neurology Aug 2022
Topics: Electroencephalography; Epilepsy; Humans; Infant; Spasms, Infantile
PubMed: 35841906
DOI: 10.1016/S1474-4422(22)00267-8 -
Seminars in Pediatric Neurology Jul 2021The term infantile spasms has been used inconsistently within the medical literature for decades. We are also without formal consensus on the diagnostic criteria for... (Review)
Review
The term infantile spasms has been used inconsistently within the medical literature for decades. We are also without formal consensus on the diagnostic criteria for West syndrome. Author-specific definitions for these terms will determine the populations studied within research studies and thus impact the relevance of the data acquired. In addition, how one defines these terms may have serious consequences for children presenting with infantile spasms such as the inappropriate withholding of standard therapy in those who fail to meet criteria for West syndrome. The overreliance on the term hypsarhythmia is particularly problematic given that many children presenting with infantile spasms will not have this classic pattern and because the determination of hypsarhythmia has poor inter-rater reliability. Herein I review historical perspectives, relying heavily on published monographs and consensus statements, and promote practical definitions and diagnostic criteria for infantile spasms and West syndrome. In an effort to encourage best clinical practice and research methodology, I include guidance for the diagnosis of infantile spasms (a seizure type) and West syndrome (an epilepsy syndrome).
Topics: Anticonvulsants; Child; Humans; Infant; Reproducibility of Results; Seizures; Spasms, Infantile
PubMed: 34183140
DOI: 10.1016/j.spen.2021.100893 -
Boletin Medico Del Hospital Infantil de... 2023CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism...
BACKGROUND
CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism spectrum disorder to early-onset epilepsy refractory to treatment. Initially, until the gene was discovered, it was considered an atypical form of Rett syndrome. This study aimed to describe the clinical and molecular heterogeneity in CDLK5 disorders among three female patients with CDKL5 pathogenic variants.
CASE REPORTS
We reported three unrelated Mexican female patients evaluated for global developmental delay and epilepsy. All three cases were hemizygotes to a CDKL5 pathogenic variant. In one patient, we performed a 306 gene panel associated with epilepsy. In the other two cases, a human genomic microarray was performed. We describe their clinical features electroencephalogram and brain magnetic resonance evaluations.
CONCLUSIONS
CDKL5 deficiency syndrome represents a challenge for clinicians since the clinical manifestations, electroencephalographic and neuroimaging studies can be non-specific. This syndrome should be suspected in the presence of global developmental delay, autistic behavioral phenotype and epilepsy, associated or not with dysmorphia. Given the similarity between various epileptic encephalopathies, multigene panels including sequencing and duplication/deletion analysis should be requested in which this gene and its possible differential diagnoses are considered, without forgetting the usefulness of genomic techniques in unclear cases.
Topics: Humans; Female; Autism Spectrum Disorder; Spasms, Infantile; Epilepsy; Rett Syndrome
PubMed: 37490689
DOI: 10.24875/BMHIM.22000100 -
Epilepsy Research Aug 2021We analyzed the records of 198 patients with West syndrome (WS) seen at a single pediatric neurology center in Argentina between June 2004 and June 2017. Five patients...
OBJECTIVE
We analyzed the records of 198 patients with West syndrome (WS) seen at a single pediatric neurology center in Argentina between June 2004 and June 2017. Five patients with infection-related spontaneous remission of the electroclinical manifestations were identified.
METHODS
The following parameters were investigated: personal and family history, clinical characteristics of the seizures - mainly spasms - and EEG findings, type of treatment, and outcome. The inclusion criteria for WS were epileptic spasms (ES) in clusters, hypsarrhythmia, and mental deterioration. Infants with ES without hypsarrhythmia and other epileptic encephalopathies with ES were excluded.
RESULTS
Five children, four boys and one girl, met the inclusion criteria of WS with spontaneous remission after a viral infection. The etiology of ES was unknown in four patients and one had a structural etiology. All patients had spontaneous remission of the ES and normalization of the EEG following acute upper respiratory infection in four and exanthema subitum in one; all of them had fever between 38.5 and 40 °C.
CONCLUSION
We report five patients with spontaneous remission of WS following acute viral infection, associated with a respiratory virus in four and exanthema subitum in one.
Topics: Child; Electroencephalography; Female; Fever; Humans; Infant; Male; Remission, Spontaneous; Seizures; Spasm; Spasms, Infantile
PubMed: 33989887
DOI: 10.1016/j.eplepsyres.2021.106663 -
No Shinkei Geka. Neurological Surgery Jan 2023Callosotomy is widely used today as a treatment option for medically refractory epilepsy in patients with generalized or unknown-onset seizures. Other surgical...
Callosotomy is widely used today as a treatment option for medically refractory epilepsy in patients with generalized or unknown-onset seizures. Other surgical indications include bilaterally distributed, most often synchronous, epileptiform discharges on EEG and some epilepsy syndromes, including Lennox-Gastaut syndrome and infantile spasms/West syndrome. Patients with drop attacks, mainly caused by epileptic spasms or atonic seizures, are most likely to benefit from this procedure. A more favorable seizure outcome was observed after a one-stage total callosal section in pediatric patients. For older children and adults, anterior callosotomy should initially be applied, and staged complete sections should be considered if the seizure outcome is insufficient. In terms of complications, most surgically associated brain and vascular injuries are avoidable in this era of microsurgery, and some less invasive newer methods, including endoscopic and stereotactic methods, are being explored. Disconnection syndrome is an unavoidable condition. However, it is usually transient in most cases and does not outweigh the improvement in symptoms of epilepsy in most patients, particularly in children who have compensatory functions or plasticity of the developing brain.
Topics: Adult; Humans; Child; Adolescent; Treatment Outcome; Epilepsy; Lennox Gastaut Syndrome; Seizures; Spasms, Infantile; Corpus Callosum
PubMed: 36682756
DOI: 10.11477/mf.1436204722 -
Neural Networks : the Official Journal... Sep 2022The common age-dependent West syndrome can be diagnosed accurately by electroencephalogram (EEG), but its pathogenesis and evolution remain unclear. Existing research...
The common age-dependent West syndrome can be diagnosed accurately by electroencephalogram (EEG), but its pathogenesis and evolution remain unclear. Existing research mainly aims at the study of West seizure markers in time/frequency domain, while less literature uses a graph-theoretic approach to analyze changes among different brain regions. In this paper, the scalp EEG based functional connectivity (including Correlation, Coherence, Time Frequency Cross Mutual Information, Phase-Locking Value, Phase Lag Index, Weighted Phase Lag Index) and network topology parameters (including Clustering coefficient, Feature path length, Global efficiency, and Local efficiency) are comprehensively studied for the prognostic analysis of the West episode cycle. The scalp EEGs of 15 children with clinically diagnosed string spasticity seizures are used for prospective study, where the signal is divided into pre-seizure, seizure, and post-seizure states in 5 typical brain wave rhythm frequency bands (δ (1-4 Hz), θ (4-8 Hz), α (8-13 Hz), β (13-30 Hz), and γ (30-80 Hz)) for functional connectivity analysis. The study shows that recurrent West seizures weaken connections between brain regions responsible for cognition and intelligence, while brain regions responsible for information synergy and visual reception have greater variability in connectivity during seizures. It is observed that the changes inβandγfrequency bands of the multiband brain network connectivity patterns calculated by Corr and WPLI can be preliminarily used as judgment of seizure cycle changes in West syndrome.
Topics: Brain; Child; Electroencephalography; Humans; Infant; Prospective Studies; Scalp; Seizures; Spasms, Infantile
PubMed: 35714423
DOI: 10.1016/j.neunet.2022.05.029 -
Indian Journal of Pediatrics Aug 2022To determine epilepsy and neurodevelopmental outcomes beyond 2 y of age and their putative prognostic factors in children with West syndrome (WS).
OBJECTIVE
To determine epilepsy and neurodevelopmental outcomes beyond 2 y of age and their putative prognostic factors in children with West syndrome (WS).
METHODS
This cross-sectional study was initiated after approval from Institutional Ethics Committee. A follow-up cohort of 114 children (aged ≥ 2 y) diagnosed and treated for WS at the authors' center were assessed in-person for epilepsy and neurodevelopmental outcomes using Vineland Social Maturity Scale - Malin's adaptation for Indian children. Subsequently, age at onset, lead-time-to-treatment, etiology, and response to any of the standard therapies were analyzed as possible predictors of these outcomes.
RESULTS
Of 114 children (mean age: 55 ± 32 mo, 91 boys), structural etiology was the predominant underlying etiology (79.8%) for WS. At 2 y of age, 64% had ongoing seizures. At the last follow-up, 76% had social quotient < 55, and 39% had cerebral palsy (spastic quadriparesis in 21%). An underlying structural etiology was associated with ongoing seizures [OR (95% CI) 3.5 (1.4-9); p = 0.008] at 2 y of age and poor developmental outcomes [OR (95% CI): 3.3 (1.3-8.9); p = 0.016]. Complete cessation of spasms with the standard therapy was significantly associated with better seizure control [OR (95% CI): 5.4 (2.3-13); p < 0.001] and neurodevelopmental outcome [OR (95% CI): 5.2 (1.8-14.9); p < 0.001].
CONCLUSION
The majority of children with WS have a poor neurodevelopmental outcome and epilepsy control on follow-up. The underlying etiology and response to initial standard therapy for epileptic spasms have a prognostic role in predicting the neurological outcome in these patients on follow-up.
Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Child; Child, Preschool; Cross-Sectional Studies; Electroencephalography; Epilepsy; Humans; Infant; Male; Middle Aged; Retrospective Studies; Seizures; Spasm; Spasms, Infantile; Young Adult
PubMed: 34623615
DOI: 10.1007/s12098-021-03918-y