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Epilepsia Nov 2013The first description of epileptic encephalopathies dates back to Dr. West who, in 1857, described the syndrome that took his name. In addition to West syndrome, in the... (Review)
Review
The first description of epileptic encephalopathies dates back to Dr. West who, in 1857, described the syndrome that took his name. In addition to West syndrome, in the last century other epileptic syndromes entered into the chapter of epileptic encephalopathies. Henry Gastaut has the virtue of having created the modern concept of epileptic encephalopathy and entering it into the official terminology of the International League Against Epilepsy (ILAE). After the first proposal, it was further defined and refined over time.
Topics: Brain Diseases; Epilepsy; History, 19th Century; History, 20th Century; Humans; Infant; Spasms, Infantile
PubMed: 24571110
DOI: 10.1111/epi.12416 -
Epilepsy Research Oct 2019Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified...
Infantile spasms (IS) is a developmental and epileptic encephalopathy with heterogeneous etiologies including many genetic causes. Genetic studies have identified pathogenic variants in over 30 genes as causes of IS. Many of these genetic causes are extremely rare, with only one reported incidence in an individual with IS. To better understand the genetic landscape of IS, we used targeted sequencing to screen 42 candidate IS genes and 53 established developmental and epileptic encephalopathy genes in 92 individual with IS. We identified a genetic diagnosis for 7.6% of our cohort, including pathogenic variants in KCNB1 (n = 2), GNAO1 (n = 1), STXBP1 (n = 1), SLC35A2 (n = 1), TBL1XR1 (n = 1), and KIF1A (n = 1). Our data emphasize the genetic heterogeneity of IS and will inform the diagnosis and management of individuals with this devastating disorder.
Topics: Child, Preschool; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Infant; Kinesins; Monosaccharide Transport Proteins; Mutation; Receptors, Cytoplasmic and Nuclear; Repressor Proteins; Shab Potassium Channels; Spasms, Infantile
PubMed: 31394400
DOI: 10.1016/j.eplepsyres.2019.106181 -
Indian Journal of Pediatrics Aug 2023
Topics: Humans; COVID-19; Spasms, Infantile; SARS-CoV-2
PubMed: 37129756
DOI: 10.1007/s12098-023-04617-6 -
The Cochrane Database of Systematic... Jun 2013Infantile spasms (West's Syndrome) is a syndrome that includes a peculiar type of epileptic seizure-the spasms-and an electroencephalographic (EEG) abnormality often... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Infantile spasms (West's Syndrome) is a syndrome that includes a peculiar type of epileptic seizure-the spasms-and an electroencephalographic (EEG) abnormality often called hypsarrhythmia. Psychomotor retardation is frequently found at follow-up. Approximately two-thirds of affected infants will have a detectable underlying neurological abnormality, but still little is known about the pathophysiological basis for infantile spasms, and treatment remains problematic.
OBJECTIVES
To compare the effects of single pharmaceutical therapies used to treat infantile spasms in terms of control of the spasms, resolution of the EEG, relapse rates, psychomotor development, subsequent epilepsy, side effects, and mortality.
SEARCH METHODS
To identify published data, we searched the Cochrane Epilepsy Group Specialised Register (October 2012), CENTRAL (The Cochrane Library 2012, Issue 9), MEDLINE (1946 to September Week 4, 2012), EMBASE (1980 to March 2003), and the reference lists of all retrieved articles.To identify unpublished data, we searched the ISRCTN Register (www.controlled-trials.com), corresponded with colleagues and drug companies, and made requests at international conferences.
SELECTION CRITERIA
All randomised controlled trials (RCTs) of the administration of drug therapy to patients with infantile spasms.
DATA COLLECTION AND ANALYSIS
Data collection from all relevant publications was independently undertaken by three review authors (before 2010) or by two review authors using a standard proforma. Analysis included assessment of study quality and a search for sources of heterogeneity.
MAIN RESULTS
We found 16 small RCTs (fewer than 100 patients enrolled) and 2 larger RCTs (more than 100 patients enrolled). These 18 studies looked at a total of 916 patients treated with a total of 12 different pharmaceutical agents. Overall methodology of the studies was poor, in part because of ethical dilemmas such as giving placebo injections to children. Two studies showed that placebo was not as good as active treatment in resolving the spasms. The strongest evidence suggested that hormonal treatment (prednisolone or tetracosactide depot) leads to resolution of spasms faster and in more infants than does vigabatrin. Responses without subsequent relapse may be no different. The same study suggests that hormonal treatments might improve the long-term developmental outcome compared with vigabatrin in infants not found to have an underlying cause for their infantile spasms.
AUTHORS' CONCLUSIONS
To date, few well-designed RCTs have considered the treatment of infantile spasms, and the numbers of patients enrolled have been small. In the majority, methodology has been poor, hence it is not clear which treatment is optimal in the treatment of this epilepsy syndrome. Hormonal treatment resolves spasms in more infants than vigabatrin, but this may or may not translate into better long-term outcomes. If prednisolone or vigabatrin is used, high dosage is recommended. Vigabatrin may be the treatment of choice in tuberous sclerosis. Resolution of the EEG features may be important, but this has not been proven. Further research using large studies with robust methodology is required.
Topics: Anticonvulsants; Cosyntropin; Hormones; Humans; Infant; Prednisolone; Psychomotor Performance; Randomized Controlled Trials as Topic; Spasms, Infantile; Vigabatrin
PubMed: 23740534
DOI: 10.1002/14651858.CD001770.pub3 -
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 -
Epilepsia Open Dec 2023Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration...
OBJECTIVE
Literature on the genotypic spectrum of Infantile Epileptic Spasms Syndrome (IESS) in children is scarce in developing countries. This multicentre collaboration evaluated the genotypic and phenotypic landscape of genetic IESS in Indian children.
METHODS
Between January 2021 and June 2022, this cross-sectional study was conducted at six centers in India. Children with genetically confirmed IESS, without definite structural-genetic and structural-metabolic etiology, were recruited and underwent detailed in-person assessment for phenotypic characterization. The multicentric data on the genotypic and phenotypic characteristics of genetic IESS were collated and analyzed.
RESULTS
Of 124 probands (60% boys, history of consanguinity in 15%) with genetic IESS, 105 had single gene disorders (104 nuclear and one mitochondrial), including one with concurrent triple repeat disorder (fragile X syndrome), and 19 had chromosomal disorders. Of 105 single gene disorders, 51 individual genes (92 variants including 25 novel) were identified. Nearly 85% of children with monogenic nuclear disorders had autosomal inheritance (dominant-55.2%, recessive-14.2%), while the rest had X-linked inheritance. Underlying chromosomal disorders included trisomy 21 (n = 14), Xq28 duplication (n = 2), and others (n = 3). Trisomy 21 (n = 14), ALDH7A1 (n = 10), SCN2A (n = 7), CDKL5 (n = 6), ALG13 (n = 5), KCNQ2 (n = 4), STXBP1 (n = 4), SCN1A (n = 4), NTRK2 (n = 4), and WWOX (n = 4) were the dominant single gene causes of genetic IESS. The median age at the onset of epileptic spasms (ES) and establishment of genetic diagnosis was 5 and 12 months, respectively. Pre-existing developmental delay (94.3%), early age at onset of ES (<6 months; 86.2%), central hypotonia (81.4%), facial dysmorphism (70.1%), microcephaly (77.4%), movement disorders (45.9%) and autistic features (42.7%) were remarkable clinical findings. Seizures other than epileptic spasms were observed in 83 children (66.9%). Pre-existing epilepsy syndrome was identified in 21 (16.9%). Nearly 60% had an initial response to hormonal therapy.
SIGNIFICANCE
Our study highlights a heterogenous genetic landscape and phenotypic pleiotropy in children with genetic IESS.
Topics: Male; Humans; Child; Infant; Female; Down Syndrome; Cross-Sectional Studies; Spasms, Infantile; Seizures; Spasm; N-Acetylglucosaminyltransferases
PubMed: 37583270
DOI: 10.1002/epi4.12811 -
Epilepsia Nov 2013The pathophysiology of epileptic encephalopathies has long been debated. Recently, some authors proposed the new concept of so-called system epilepsies. This hypothesis... (Review)
Review
The pathophysiology of epileptic encephalopathies has long been debated. Recently, some authors proposed the new concept of so-called system epilepsies. This hypothesis postulates that system epilepsies are produced by the enduring propensity to generate seizures in different cerebral areas that, alone, are unable to create a specific electroclinical phenotype. This goes beyond the classical dichotomy between focal and generalized epilepsy. Epileptic encephalopathies, in general, have the ideal profile to be considered as system epilepsies, and West syndrome and Lennox-Gastaut syndrome are two of the best examples. Apart from the conventional neurophysiologic methods for studying brain activities and the pathophysiologic mechanisms underlying epileptic syndromes, other new methods of neuroimaging support this hypothesis.
Topics: Brain Diseases; Epilepsy; Humans; Infant; Intellectual Disability; Lennox Gastaut Syndrome; Models, Biological; Spasms, Infantile
PubMed: 24571115
DOI: 10.1111/epi.12421 -
Clinical Neurophysiology : Official... May 2021Perinatal arterial ischemic stroke (PAIS) is associated with epileptic spasms of West syndrome (WS) and long term Focal epilepsy (FE). The mechanism of epileptogenic...
OBJECTIVE
Perinatal arterial ischemic stroke (PAIS) is associated with epileptic spasms of West syndrome (WS) and long term Focal epilepsy (FE). The mechanism of epileptogenic network generation causing hypsarrhythmia of WS is unknown. We hypothesized that Modulation index (MI) [strength of phase-amplitude coupling] and Synchronization likelihood (SL) [degree of connectivity] could interrogate the epileptogenic network in hypsarrhythmia of WS secondary to PAIS.
METHODS
We analyzed interictal scalp electroencephalography (EEG) in 10 WS and 11 FE patients with unilateral PAIS. MI between gamma (30-70 Hz) and slow waves (3-4 Hz) was calculated to measure phase-amplitude coupling. SL between electrode pairs was analyzed in 9-frequency bands (5-delta, theta, alpha, beta, gamma) to examine inter- and intra-hemispheric connectivity.
RESULTS
MI was higher in affected hemispheres in WS (p = 0.006); no differences observed in FE. Inter-hemispheric SL of 3-delta, theta, alpha, beta, gamma bands was significantly higher in WS (p < 0.001). In WS, modified Z-Score of intra-hemispheric SL values in 3-delta, theta, alpha, beta and gamma in the affected hemispheres were significantly higher than those in the unaffected hemispheres (p < 0.001) as well as 0.5-4 Hz (p = 0.004).
CONCLUSIONS
The significantly higher modulation in affected hemisphere and stronger inter- and intra-hemispheric connectivity generate hypsarrhythmia of WS secondary to PAIS.
SIGNIFICANCE
Epileptogenic cortical-subcortical transcallosal networks from affected hemisphere post-PAIS provokes infantile spasms.
Topics: Brain Waves; Child; Child, Preschool; Cortical Synchronization; Female; Humans; Infant; Ischemic Stroke; Male; Spasms, Infantile
PubMed: 33674213
DOI: 10.1016/j.clinph.2020.12.028 -
Epilepsia Jul 2010Infantile spasms are the classical seizure type of West syndrome. Infantile spasms often herald a dismal prognosis, due to the high probability to evolve into... (Review)
Review
Infantile spasms are the classical seizure type of West syndrome. Infantile spasms often herald a dismal prognosis, due to the high probability to evolve into intractable forms of epilepsies with significant cognitive deficits, especially if not adequately treated. The current therapies-high doses of adrenocorticotropic hormone, steroids, or the gamma-aminobutyric acid (GABA) transaminase inhibitor vigabatrin--are often toxic and may not always be effective. The need to identify new therapies for spasms has led to the generation of a number of rodent models of infantile spasms. These include acute and chronic models of infantile spasms, with cryptogenic or symptomatic origin, many of which are based on specific etiologies. In this review, we summarize the clinical experience with treating infantile spasms and the main features of the new animal models of infantile spasms and discuss their utility in the preclinical development of new therapies for infantile spasms.
Topics: Adrenocorticotropic Hormone; Animals; Anticonvulsants; Disease Models, Animal; Humans; Infant; Mice; Rats; Receptors, GABA; Sirolimus; Spasms, Infantile; Vigabatrin
PubMed: 20618396
DOI: 10.1111/j.1528-1167.2010.02605.x -
Pharmacology & Therapeutics Aug 2020Infantile spasms (IS or epileptic spasms during infancy) were first described by Dr. William James West (aka West syndrome) in his own son in 1841. While rare by... (Review)
Review
Infantile spasms (IS or epileptic spasms during infancy) were first described by Dr. William James West (aka West syndrome) in his own son in 1841. While rare by definition (occurring in 1 per 3200-3400 live births), IS represent a major social and treatment burden. The etiology of IS varies - there are many (>200) different known pathologies resulting in IS and still in about one third of cases there is no obvious reason. With the advancement of genetic analysis, role of certain genes (such as ARX or CDKL5 and others) in IS appears to be important. Current treatment strategies with incomplete efficacy and serious potential adverse effects include adrenocorticotropin (ACTH), corticosteroids (prednisone, prednisolone) and vigabatrin, more recently also a combination of hormones and vigabatrin. Second line treatments include pyridoxine (vitamin B6) and ketogenic diet. Additional treatment approaches use rapamycin, cannabidiol, valproic acid and other anti-seizure medications. Efficacy of these second line medications is variable but usually inferior to hormonal treatments and vigabatrin. Thus, new and effective models of this devastating condition are required for the search of additional treatment options as well as for better understanding the mechanisms of IS. Currently, eight models of IS are reviewed along with the ideas and mechanisms behind these models, drugs tested using the models and their efficacy and usefulness. Etiological variety of IS is somewhat reflected in the variety of the models. However, it seems that for finding precise personalized approaches, this variety is necessary as there is no "one-size-fits-all" approach possible for both IS in particular and epilepsy in general.
Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Animals; Diet, Ketogenic; Disease Models, Animal; Drug Therapy, Combination; Humans; Infant; Spasms, Infantile
PubMed: 32417271
DOI: 10.1016/j.pharmthera.2020.107578