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Neurological Sciences : Official... Dec 2020Since its first clinical description (on his son) by William James West (1793-1848) in 1841, and the definition of the classical triad of (1) infantile spasms; (2)... (Review)
Review
Since its first clinical description (on his son) by William James West (1793-1848) in 1841, and the definition of the classical triad of (1) infantile spasms; (2) hypsarrhythmia, and (3) developmental arrest or regression as "West syndrome", new and relevant advances have been recorded in this uncommon disorder. New approaches include terminology of clinical spasms (e.g., infantile (IS) vs. epileptic spasms (ES)), variety of clinical and electroencephalographic (EEG) features (e.g., typical ictal phenomena without EEG abnormalities), burden of developmental delay, spectrum of associated genetic abnormalities, pathogenesis, treatment options, and related outcome and prognosis. Aside the classical manifestations, IS or ES may present with atypical electroclinical phenotypes (e.g., subtle spasms; modified hypsarrhythmia) and may have their onset outside infancy. An increasing number of genes, proteins, and signaling pathways play crucial roles in the pathogenesis. This condition is currently regarded as a spectrum of disorders: the so-called infantile spasm syndrome (ISs), in association with other causal factors, including structural, infectious, metabolic, syndromic, and immunologic events, all acting on a genetic predisposing background. Hormonal therapy and ketogenic diet are widely used also in combination with (classical and recent) pharmacological drugs. Biologically targeted and gene therapies are increasingly studied. The present narrative review searched in seven electronic databases (primary MeSH terms/keywords included West syndrome, infantile spasms and infantile spasms syndrome and were coupled to 25 secondary clinical, EEG, therapeutic, outcomes, and associated conditions terms) including MEDLINE, Embase, Cochrane Central, Web of Sciences, Pubmed, Scopus, and OMIM to highlight the past knowledge and more recent advances.
Topics: Electroencephalography; Humans; Infant; Prognosis; Spasms, Infantile
PubMed: 32827285
DOI: 10.1007/s10072-020-04600-5 -
Brain : a Journal of Neurology Jun 2022Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders...
Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.
Topics: Electroencephalography; Epilepsy; Humans; Infant; Munc18 Proteins; Retrospective Studies; Seizures; Spasms, Infantile
PubMed: 35190816
DOI: 10.1093/brain/awab327 -
CNS Drugs Jun 2022Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD... (Review)
Review
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD develop refractory epilepsy with multiple seizure types. Management of seizures in CDD remains challenging for clinicians given the highly refractory nature of seizures and the limited number of disease-specific studies that offer a high level of evidence. Epileptic spasms are the most common seizure type in CDD and are more often refractory to standard first-line treatment than are spasms of other etiologies. In other seizure types, the effectiveness of antiseizure medications is limited and wanes over time. Ketogenic diet and palliative surgical treatments have both had mixed results in observational studies. When treating refractory seizures in CDD, we recommend carefully balancing seizure control and treatment-related side effects to optimize each individual's overall quality of life. Clinical trials of medications targeting epilepsy in CDD have been conducted, and additional investigational small molecules, gene therapy, and other disease-modifying therapies are in development for CDD.
Topics: Epilepsy; Epileptic Syndromes; Humans; Protein Serine-Threonine Kinases; Quality of Life; Seizures; Spasm; Spasms, Infantile
PubMed: 35633486
DOI: 10.1007/s40263-022-00921-5 -
Neurology Jan 2019To delineate the epileptology, a key part of the phenotypic spectrum, in a large patient cohort.
OBJECTIVE
To delineate the epileptology, a key part of the phenotypic spectrum, in a large patient cohort.
METHODS
Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic variants or chromosome 6p21.32 microdeletions incorporating . We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos.
RESULTS
We included 57 patients (53% male, median age 8 years) with mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%).
CONCLUSIONS
mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.
Topics: Adolescent; Adult; Anticonvulsants; Brain; Brain Diseases; Child; Child, Preschool; Cohort Studies; Developmental Disabilities; Electroencephalography; Female; Genetic Association Studies; Humans; Infant; Male; Mutation; Spasms, Infantile; Young Adult; ras GTPase-Activating Proteins
PubMed: 30541864
DOI: 10.1212/WNL.0000000000006729 -
Annals of Neurology Dec 2019Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and...
OBJECTIVE
Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe developmental and epileptic encephalopathies. We delineate the genetic causes and genotype-phenotype correlations of a large EIMFS cohort.
METHODS
Phenotypic and molecular data were analyzed on patients recruited through an international collaborative study.
RESULTS
We ascertained 135 patients from 128 unrelated families. Ninety-three of 135 (69%) had causative variants (42/55 previously reported) across 23 genes, including 9 novel EIMFS genes: de novo dominant GABRA1, GABRB1, ATP1A3; X-linked CDKL5, PIGA; and recessive ITPA, AIMP1, KARS, WWOX. The most frequently implicated genes were KCNT1 (36/135, 27%) and SCN2A (10/135, 7%). Mosaicism occurred in 2 probands (SCN2A, GABRB3) and 3 unaffected mothers (KCNT1). Median age at seizure onset was 4 weeks, with earlier onset in the SCN2A, KCNQ2, and BRAT1 groups. Epileptic spasms occurred in 22% patients. A total of 127 patients had severe to profound developmental impairment. All but 7 patients had ongoing seizures. Additional features included microcephaly, movement disorders, spasticity, and scoliosis. Mortality occurred in 33% at median age 2 years 7 months.
INTERPRETATION
We identified a genetic cause in 69% of patients with EIMFS. We highlight the genetic heterogeneity of EIMFS with 9 newly implicated genes, bringing the total number to 33. Mosaicism was observed in probands and parents, carrying critical implications for recurrence risk. EIMFS pathophysiology involves diverse molecular processes from gene and protein regulation to ion channel function and solute trafficking. ANN NEUROL 2019;86:821-831.
Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Female; Genetic Predisposition to Disease; Humans; Infant; Male; Seizures; Spasms, Infantile
PubMed: 31618474
DOI: 10.1002/ana.25619 -
Epilepsy Research Jul 2021To develop an improved interictal electroencephalogram (EEG) grading scale for children with infantile spasms founded on elements with adequate inter-rater reliability...
OBJECTIVE
To develop an improved interictal electroencephalogram (EEG) grading scale for children with infantile spasms founded on elements with adequate inter-rater reliability (IRR) to justify its further study for clinical and research purposes.
METHODS
Three blinded reviewers assessed five-minute sleep epochs in 93 EEGs from 62 children (31 consecutive controls, 31 consecutive infantile spasms [pretreatment and posttreatment studies]) using a longitudinal bipolar montage. We determined the IRR of background amplitude, epileptiform discharges, >3 spike foci (including <50 % or >50 %), grouped multifocal spikes, paroxysmal voltage attenuations, and symmetry of sleep spindles. Data were used to finalize the 2021 BASED (Burden of AmplitudeS and Epileptiform Discharges) score.
RESULTS
All elements included in the 2021 BASED score had moderate to near perfect IRR. Among controls, >200 μv background waves occurred commonly in the bilateral posterior temporal (T3-T5, T4-T6) and midline (Fz-Cz, Cz-Pz) regions. Excluding midline and occipital channels (which have normal high amplitude background waves), we designated abnormal high amplitude background waves as >200 μv for most channels, but >300 μv for T3-T5 and T4-T6. The IRR was moderate to near perfect for <50 % >3 spike foci, >50 % >3 spike foci, paroxysmal voltage attenuations, grouped multifocal spikes (GMFS), and symmetric sleep spindles. Paroxysmal voltage attenuations, GMFS, and >50 % >3 spike foci all significantly distinguished pretreatment from posttreatment studies whereas symmetric sleep spindles did not (as planned, the latter was not included in the 2021 BASED score). When the 2021 BASED score was applied to the 22 children with infantile spasms achieving clinical remission with treatment, 19 met criteria for electroclinical remission and three did not.
SIGNIFICANCE
The 2021 BASED score includes elements with high levels of IRR and correlates well with the presence or absence of infantile spasms.
Topics: Child; Electroencephalography; Humans; Infant; Reproducibility of Results; Sleep; Spasm; Spasms, Infantile
PubMed: 33839516
DOI: 10.1016/j.eplepsyres.2021.106631 -
Developmental Medicine and Child... Apr 2023To explore the phenotypic spectrum and refine the genotype-phenotype correlation of DYNC1H1-related epilepsy.
AIM
To explore the phenotypic spectrum and refine the genotype-phenotype correlation of DYNC1H1-related epilepsy.
METHOD
The clinical data of 15 patients with epilepsy in our cohort and 50 patients with epilepsy from 24 published studies with the DYNC1H1 variants were evaluated.
RESULTS
In our cohort, 13 variants were identified from 15 patients (seven males, eight females). Twelve variants were de novo and seven were new. Age at seizure onset ranged from 3 months to 4 years 5 months (median age 1 year). Common seizure types were epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. Mild-to-severe developmental delay was present in all patients. Six patients were diagnosed with West syndrome and one was diagnosed with epileptic encephalopathy with continuous spikes and waves during slow sleep (CSWS). Collectively, in our cohort and published studies, 17% had ophthalmic diseases, 31% of variants were located in the stalk domain, and 92% patients with epilepsy had a malformation of cortical development (MCD).
INTERPRETATION
The phenotypes of DYNC1H1-related epilepsy included multiple seizure types; the most common epileptic syndrome was West syndrome. CSWS is a new phenotype of DYNC1H1-related epilepsy. One-third of the variants in patients with epilepsy were located in the stalk domain. Most patients had a MCD and developmental delay.
WHAT THIS PAPER ADDS
Nearly 40% of patients with DYNC1H1 variants had epilepsy. Ninety-two percent of patients with DYNC1H1-related epilepsy had malformation of cortical development. More than 10% of patients with DYNC1H1-related epilepsy were diagnosed with West syndrome. Continuous spikes and waves during slow sleep could be a new phenotype of DYNC1H1 variants. One-third of the variants in patients with epilepsy were located in the stalk domain.
Topics: Male; Female; Humans; Spasms, Infantile; Mutation; Epilepsy; Seizures; Genetic Association Studies; Electroencephalography; Cytoplasmic Dyneins
PubMed: 36175372
DOI: 10.1111/dmcn.15414 -
Advances in Protein Chemistry and... 2017West syndrome (WS) is an infantile epileptic encephalopathy that manifests with infantile spasms (IS), hypsarrhythmia (in ~60% of infants), and poor neurodevelopmental... (Review)
Review
West syndrome (WS) is an infantile epileptic encephalopathy that manifests with infantile spasms (IS), hypsarrhythmia (in ~60% of infants), and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12%-15%), or of unknown origin. The current treatment options include hormonal treatment (adrenocorticotropic hormone and high-dose steroids) and the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate proinflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review, we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of WS? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?
Topics: Animals; Brain; Cytokines; Epilepsy; Humans; Infant; Inflammation; Lennox Gastaut Syndrome; Neurosecretory Systems; Seizures; Spasms, Infantile
PubMed: 28427564
DOI: 10.1016/bs.apcsb.2017.01.005 -
Ugeskrift For Laeger Apr 2020Infantile spasms (IS) is a severe developmental and epileptic encephalopathy, occurring mainly in children aged 3-18 months. IS have multiple aetiologies, and the... (Review)
Review
Infantile spasms (IS) is a severe developmental and epileptic encephalopathy, occurring mainly in children aged 3-18 months. IS have multiple aetiologies, and the treatment differs accordingly. Early diagnosis and treatment may improve the outcome, but many patients are initially misdiagnosed. Evaluation includes seizure semiology, electroencephalography, cerebral magnetic resonance imaging and genetic and metabolic testing. Treatment varies among centres, and initial treatment may include vigabatrin and/or corticosteroids. In recent years, as summarised in this review, knowledge has substantially increased regarding genetic aetiologies and treatment regimens.
Topics: Anticonvulsants; Child; Electroencephalography; Humans; Infant; Magnetic Resonance Imaging; Spasms, Infantile; Vigabatrin
PubMed: 32286217
DOI: No ID Found -
BMC Pediatrics Sep 2021West syndrome is a convulsive disorder of infancy with unique seizures and a characteristic background electroencephalograph pattern. Adrenocorticotropic hormone (ACTH)... (Observational Study)
Observational Study
BACKGROUND
West syndrome is a convulsive disorder of infancy with unique seizures and a characteristic background electroencephalograph pattern. Adrenocorticotropic hormone (ACTH) is effective in spasm cessation, yet metabolic consequences of this therapeutic agent in childhood have not been published.
METHODS
In this observational study we explored the cardiometabolic outcomes of 117 children with West syndrome (78 ACTH-treated and 39 non-ACTH-treated) monitored at a single medical center from 1995 to 2019 (median follow-up 7.2 years). Outcomes included the prevalence of cardiometabolic derangements (obesity, hypertension, and dyslipidemia) during infancy (< 2 years), early childhood (2-6 years), and childhood/adolescence (6-18 years).
RESULTS
The rates of metabolic derangements during infancy in the West syndrome cohort were high compared to childhood/adolescence (obesity 27.3 % vs. 3.3 %, [p = 0.010], diastolic hypertension 48.8 % vs. 5.1 % [p < 0.001], hypertriglyceridemia 71 % vs. 40 % [p = 0.008], low high-density lipoprotein cholesterol [HDL-c] 54.2 % vs. 12.9 % [p = 0.001], and elevated triglycerides/HDL-c ratios 62.5 % vs. 12.9 % [p < 0.001]). The proportion of systolic and/or diastolic blood pressure levels categorized as hypertensive was 58.5 % during infancy, 48.1 % during early childhood, and 26.3 % during childhood/adolescence. ACTH-treated patients had higher weight and weight-to-length z-scores and higher triglyceride levels during infancy compared to non-ACTH-treated patients (p = 0.008, p = 0.001, and p = 0.037, respectively), and higher triglyceride levels during early childhood (p = 0.050), with no significant group differences during childhood/adolescence.
CONCLUSIONS
Children with West syndrome apparently have an increased prevalence of cardiometabolic derangements more pronounced in infants and in ACTH-treated patients. These findings highlight the need to monitor these children for cardiometabolic derangements, even though these cardiometabolic abnormalities are transitory and tend to decrease with time. The health implications of cardiometabolic derangements during critical windows of growth and development warrant further investigation.
Topics: Adolescent; Child; Child, Preschool; Humans; Hypertension; Infant; Metabolic Syndrome; Obesity; Overweight; Risk Factors; Spasms, Infantile
PubMed: 34537045
DOI: 10.1186/s12887-021-02871-1