Fifteen years of real-world data on the use of vigabatrin in individuals with infantile epileptic spasms syndrome.

OBJECTIVE: This study was undertaken to evaluate our treatment algorithm for infantile epileptic spasms syndrome (IESS) used between 2000 and 2018. We initiated vigabatrin (VGB), and steroids were added if the electroclinical response (spasms and electroencephalogram [EEG]) to VGB was not obtained or incomplete. METHODS: Individuals with IESS treated with VGB were recruited from our hospital clinical data warehouse based on electronic health records (EHRs) generated since 2009 and containing relevant keywords. We confirmed the diagnosis of IESS. Clinical, EEG, imaging, and biological data were extracted from the EHRs. We analyzed factors associated with short-term response, time to response, relapse, time to relapse of spasms, and the presence of spasms at last follow-up. RESULTS: We collected data from 198 individuals (female: 46.5%, IESS onset: 6 [4.5-10.3] months, follow-up: 4.6 [2.5-7.6] years, median [Q1-Q3]) including 129 (65.2%) with identifiable etiology. VGB was started 17 (5-57.5) days after IESS diagnosis. A total of 113 individuals were responders (57.1% of the cohort), 64 with VGB alone and 38 with VGB further combined with steroids (56.6% and 33.6% of responders, respectively). Among responders, 33 (29%) experienced relapses of spasms, mostly those with later onset of spasms (p = .002) and those who received VGB for <24 months after spasms cessation compared to a longer duration on VGB (45% vs. 12.8%, p = .003). At follow-up, 92 individuals were seizure-free (46.5% of the whole cohort), including 26 free of therapy (13.1%). One hundred twelve individuals (56.6%) were still receiving VGB, with a duration of 3.2 (1.75-5.7) years. SIGNIFICANCE: Our sequential protocol introducing VGB then adding steroids is an effective alternative to a combined VGB-steroids approach in IESS. It avoids steroid-related adverse events, as well as those from VGB-steroid combination. According to our data, a period of 7 days seems sufficient to assess VGB response and enables the addition of steroids rapidly if needed. Continuing VGB for 2 years may balance the risk of relapse and treatment-induced adverse events.

Electrographic screening for infantile epileptic spasms syndrome in a single sleep-wake cycle.

OBJECTIVE: Infantile epileptic spasms syndrome (IESS) is a common and urgent diagnosis with seizure and nonseizure mimics. Evaluation with prolonged video-electroencephalography (EEG) can be time-consuming and costly. This study investigated the use of EEG review of a single sleep-wake cycle to exclude IESS. METHODS: We retrospectively reviewed video-EEG studies to rule out IESS in children between the ages of 2 months and 2 years in the period from January 2019 through June 2020. EEG studies were reviewed from the start of the recording through the first sleep-wake cycle and scored as "normal," "consistent with IESS," or "abnormal but not diagnostic of IESS." Scores were compared to the clinical report created by analysis of the entire video-EEG. RESULTS: Inclusion criteria were met in 238 EEG studies. The mean patient age was 7.6 months. The median duration of the full study was 908 min, compared to 107.5 min for the first sleep-wake cycle only. The median difference in recording time was 801 min, p-value < .01. Scored outcomes were similar. Sixty-eight percent of EEG studies were scored as "normal" on first sleep-wake cycle review as compared to 63% on full study review, 13% scored as "consistent with IESS" compared to 16% and 19% scored as "abnormal but not diagnostic of IESS" compared to 21%. Sensitivity and specificity of the first sleep-wake cycle review for studies "consistent with IESS" was 84% and 100%, respectively. No cases of IESS were scored as normal on first sleep-wake cycle review. SIGNIFICANCE: A single sleep-wake cycle captured on EEG can triage studies when IESS is suspected. A normal first sleep-wake cycle did not miss cases of IESS and could result in reduced EEG recording time. Because most of these cases presented to an emergency department, a normal first sleep-wake cycle may help providers determine the acuity, or necessity, of further testing.

Treatment modalities for infantile spasms: current considerations and evolving strategies in clinical practice.

Infantile spasms, newly classified as infantile epileptic spasm syndrome (IESS), occur in children under 2 years of age and present as an occur as brief, symmetrical, contractions of the musculature of the neck, trunk, and extremities. When infantile spasms occur with a concomitant hypsarrhythmia on electroencephalogram (EEG) and developmental regression, it is known as West Syndrome. There is no universally accepted mainstay of treatment for this condition, but some options include synthetic adrenocorticotropic hormone (ACTH), repository corticotropin injection (RCI/Acthar Gel), corticosteroids, valproic acid, vigabatrin, and surgery. Without effective treatment, infantile spasms can cause an impairment of psychomotor development and/or cognitive and behavioral functions. The first-line treatment in the USA is ACTH related to high efficacy for cessation of infantile spasms long-term and low-cost profile. Acthar Gel is a repository corticotropin intramuscular injection that became FDA-approved for the treatment of IESS in 2010. Though it is believed that ACTH, Acthar Gel, and corticosteroids all work via a negative feedback pathway to decrease corticotropin-releasing hormone (CRH) release, their safety and efficacy profiles all vary. Vigabatrin and valproic acid are both anti-seizure medications that work by increasing GABA concentrations in the CNS and decreasing excitatory activity. Acthar Gel has been shown to have superior efficacy and a diminished side effect profile when compared with other treatment modalities.

Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.

De Novo Variants in CDK19 Are Associated with a Syndrome Involving Intellectual Disability and Epileptic Encephalopathy.

We identified three unrelated individuals with de novo missense variants in CDK19, encoding a cyclin-dependent kinase protein family member that predominantly regulates gene transcription. These individuals presented with hypotonia, global developmental delay, epileptic encephalopathy, and dysmorphic features. CDK19 is conserved between vertebrate and invertebrate model organisms, but currently abnormalities in CDK19 are not known to be associated with a human disorder. Loss of Cdk8, the fly homolog of CDK19, causes larval lethality, which is suppressed by expression of human CDK19 reference cDNA. In contrast, the CDK19 p.Tyr32His and p.Thr196Ala variants identified in the affected individuals fail to rescue the loss of Cdk8 and behave as null alleles. Additionally, neuronal RNAi-mediated knockdown of Cdk8 in flies results in semi-lethality. The few eclosing flies exhibit severe seizures and a reduced lifespan. Both phenotypes are fully suppressed by moderate expression of the CDK19 reference cDNA but not by expression of the two variants. Finally, loss of Cdk8 causes an obvious loss of boutons and synapses at larval neuromuscular junctions (NMJs). Together, our findings demonstrate that human CDK19 fully replaces the function of Cdk8 in the fly, the human disease-associated CDK19 variants behave as strong loss-of-function variants, and deleterious CDK19 variants underlie a syndromic neurodevelopmental disorder.

Hypsarrhythmia paroxysm intensities that initiate and render physical and mental retardation irreversible in West syndrome.

PURPOSE: The present study would like to investigate the effect of hypsarrhythmia paroxysms on neurological examination findings. MATERIAL AND METHOD: This study enrolled 48 children with normal cranial magnetic resonance imaging (cMRI) findings who were previously untreated with adrenocorticotropic hormone (ACTH) and had no history of asphyxia or anoxia at birth, no underlying disease, and no history of head trauma or central nervous system infection. In these children, duration of treatment delay (DTD) was calculated, HPs in NREM sleep were counted, and neurological examination findings were identified. During the study, sometimes the 'countable hypsarrhythmia paroxysms index' (cHPI) and sometimes the 'durational hypsarrhythmia paroxysm index (dHPI)' was estimated. The onset of neurological examination findings, the onset of physical and mental retardation and the time when physical and mental retardation became irreversible were investigated. The children were stratified into 5 groups based on DTD and attempts were made to prevent the recurrence of aborted ISs by ACTH treatment. RESULTS: I- When 'cHPI = 4/min'; mild growth retardation may be noticed. II- When 'cHPI = 6/min' and 'dHPI = 25%'; reduced eye tracking and reduced movement may be observed. III- When 'cHPI = 8/min' and 'dHPI >32%'; reduced eye tracking and reduced movement become evident, and neurological examination findings are reversible. IV- When 'dHPI = 45%'; partially permanent, mild motor and psychiatric sequelae develop. V- When 'dHPI >49%'; neurological examination findings become irreversible. VI- No relationship was found between neurological examination findings the early onset of ISs. CONCLUSION: WS cannot be treated unless DCHP is elucidated.

Neurobehavioral deficits and a progressive ictogenesis in the tetrodotoxin model of epileptic spasms.

OBJECTIVE: Our goal was to determine whether animals with a history of epileptic spasms have learning and memory deficits. We also used continuous (24/7) long-term electroencephalographic (EEG) recordings to evaluate the evolution of epileptiform activity in the same animals over time. METHODS: Object recognition memory and object location memory tests were undertaken, as well as a matching to place water maze test that evaluated working memory. A retrospective analysis was undertaken of long-term video/EEG recordings from rats with epileptic spasms. The frequency and duration of the ictal events of spasms were quantified. RESULTS: Rats with a history of epileptic spasms showed impairment on the three behavioral tests, and their scores on the object recognition memory and matching to place water maze tests indicated neocortical involvement in the observed impaired cognition. Analysis of EEG recordings unexpectedly showed that the ictal events of spasms and their accompanying behaviors progressively increased in duration over a 2-week period soon after onset, after which spasm duration plateaued. At the same time, spasm frequency remained unchanged. Soon after spasm onset, ictal events were variable in wave form but became more stereotyped as the syndrome evolved. SIGNIFICANCE: Our EEG findings are the first to demonstrate progressive ictogenesis for epileptic spasms. Furthermore, in demonstrating cognitive deficits in the tetrodotoxin model, we have met a criterion for an animal model of West syndrome. Animal models will allow in-depth studies of spasm progression's potential role in cognitive regression and may elucidate why early treatment is considered essential for improved neurodevelopmental outcomes in children.

Vigabatrin-associated brain abnormalities on MRI and other neurological symptoms in patients with West syndrome.

OBJECTIVES: Report a series of children with West syndrome (WS) treated with vigabatrin (VGB) who developed characteristic MRI alterations. In the majority, these adverse events were asymptomatic; however, some of the patients developed movement disorders and acute encephalopathy. METHODS: This is a retrospective analysis of our epilepsy clinical and EEG database of 288 patients with WS seen between 2014 and 2020. All patients who received VGB alone or with concomitant therapies, such as adrenocorticotropic hormone (ACTH), high-dose oral corticosteroids, ketogenic diet, valproate, levetiracetam, or topiramate, were evaluated. RESULTS: In 44 of 288 patients with WS receiving VGB, MRI findings compatible with VGB-associated brain abnormalities were identified; median age at diagnosis was 6.29 months (range, 2 weeks to 11 months). The etiology of WS with vigabatrin-associated brain abnormalities on MRI (VABAM) was unknown in 22 (52.27%), genetic in seven (15.9%), genetic-structural in three (6.8%), structural malformative in three others (6.8%), and structural acquired in eight patients (18.2%). Vigabatrin-associated brain abnormalities on MRI was asymptomatic in 25 of 44 patients. Ten of 44 (22.7%) infants were reported to have had a movement disorder (choreoathetosis, dystonic posturing). Nine of 42 infants exhibited progressive psychomotor deterioration associated with signs and symptoms of encephalopathy. CONCLUSION: MRI abnormalities were observed in infants treated with VGB and they appeared to be dose dependent. In our study common locations for MRI abnormalities included globi pallidi and brainstem, followed by thalami and dentate nuclei. Risk factors for the development of VABAM may include age younger than 11 months and higher VGB dose of VGB (>165 mg/kg/day). Vigabatrin-associated brain abnormalities on MRI usually resolved following VGB discontinuation, probably after a period of 3 months.

Adjunctive perampanel therapy for patients with epileptic spasms.

BACKGROUND: Perampanel is an antiepileptic drug. Some studies have documented the efficacy of perampanel in epileptic spasms. We aimed to evaluate the efficacy and safety of adjunctive perampanel therapy (PT) in patients with epileptic spasms. METHODS: We retrospectively surveyed the efficacy and safety of adjunctive PT in 14 patients with epileptic spasms at the Saitama Children's Medical Center between June 2016 and September 2021. Seizure outcomes and safety were evaluated 12 months after commencing PT. Response to perampanel was defined as complete remission of epileptic spasms for more than 3 months. RESULTS: The median age at onset of epileptic spasms was 0.4 years (range, 0.1-1.3 years). The etiology was structural in 11 patients, genetic in two, and unknown in one. The median age at the commencement of PT was 3.2 years (1.5-10.3 years). The initial and maintenance doses of perampanel were administered at 0.04 (range, 0.02-0.05) mg/kg/day and 0.12 (range, 0.03-0.24) mg/kg/day, respectively. Five of the 14 patients (35.7%) showed remission of epileptic spasms for more than 3 months at 12 months after PT; these patients had a structural etiology. The median duration between commencement of perampanel and spasm remission was 2 months (range, 1-6 months). No serious adverse effects occurred. CONCLUSIONS: This is the first case series evaluating adjunctive PT for epileptic spasms. PT is worth investigating to treat epileptic spasms in patients with structural etiologies. As our study population primarily comprised children aged 2 years and older, PT may be useful for epileptic spasms beyond infancy.

Adrenocorticotropic Hormone Induced Status Dystonicus in a Child with West Syndrome.

Dystonia is a movement disorder characterized by involuntary sustained or intermittent muscle contraction causing repetitive twisting movements and abnormal postures. Status dystonicus (SD) is an enigmatic disease of cryptic etiology. We hereby report a child with West syndrome (WS) who went on to develop SD following intramuscular adrenocorticotropic hormone (ACTH) injection. An 11-month-old male child presented with complaints of flexor spasms for 2 months. The diagnosis of WS was confirmed by electroencephalography (EEG), which showed hypsarrhythmia. Intramuscular ACTH was added, and oral trihexyphenidyl was started for dystonia. On day 7 of ACTH, the child developed frequent opisthotonic posturing. Management protocol for grade IV SD was initiated. Administration of N-terminal of ACTH in rat locus coeruleus has been shown to produce human dystonia-like movement and abnormal posturing. How to cite this article: Singh J, Aulakh R. Adrenocorticotropic Hormone Induced Status Dystonicus in a Child with West Syndrome. Indian J Crit Care Med 2022;26(8):961-962.

Biallelic Variants in CNPY3, Encoding an Endoplasmic Reticulum Chaperone, Cause Early-Onset Epileptic Encephalopathy.

Early-onset epileptic encephalopathies, including West syndrome (WS), are a group of neurological disorders characterized by developmental impairments and intractable seizures from early infancy. We have now identified biallelic CNPY3 variants in three individuals with WS; these include compound-heterozygous missense and frameshift variants in a family with two affected siblings (individuals 1 and 2) and a homozygous splicing variant in a consanguineous family (individual 3). All three individuals showed hippocampal malrotation. In individuals 1 and 2, electroencephalography (EEG) revealed characteristic fast waves and diffuse sharp- and slow-wave complexes. The fast waves were clinically associated with seizures. CNPY3 encodes a co-chaperone in the endoplasmic reticulum and regulates the subcellular distribution and responses of multiple Toll-like receptors. The amount of CNPY3 in lymphoblastoid cells derived from individuals 1 and 2 was severely lower than that in control cells. Cnpy3-knockout mice exhibited spastic or dystonic features under resting conditions and hyperactivity and anxiolytic behavior during the open field test. Also, their resting EEG showed enhanced activity in the fast beta frequency band (20-35 Hz), which could mimic the fast waves in individuals 1 and 2. These data suggest that CNPY3 and Cnpy3 perform essential roles in brain function in addition to known Toll-like receptor-dependent immune responses.

Decreased abundance of Akkermansia after adrenocorticotropic hormone therapy in patients with West syndrome.

BACKGROUND: Infants suffer from a severe epileptic encephalopathy known as West syndrome (WS). Treatment with adrenocorticotropic hormone (ACTH) indicates the involvement of the gut-brain axis in WS. Several pieces of evidence show the communication of the gut microbiota (GM) with the brain via the hypothalamic-pituitary-adrenal axis (HPA axis) and blood cytokines. This study aimed at (1) determining the GM diversity in infants having WS and (2) comparing the results of infants having WS with those of the healthy infants and also in the patients with WS before and after the ACTH therapy. RESULTS: In this study, 29 infants with WS and 29 healthy infants aged 3-13 months were recruited. Fecal samples were collected, and DNA was extracted and sequenced on the Illumina MiSeq platform. Kruskal-Wallis rank-sum test was used to analyze the between-group differences in the Chao1 index, Shannon index, and the abundances of GM at different taxonomy levels. R software was used to plot the graphs. The top five dominant GM genera between patients with WS and healthy infants showed no significant differences. However, the relative abundance of genus Akkermansia was observed to be significantly (P = 0.011) higher in the BT group than in the HC group and AT group. After 2 weeks of ACTH therapy, the relative abundance of Akkermansia significantly (P = 0.003) decreased. CONCLUSION: The relative abundance of Akkermansia was observed to be significantly higher in patients with WS than that in healthy infants. However, the relationship between Akkermansia and WS pathogenesis needs to be clarified in further studies.

Antiepileptogenic effects of rapamycin in a model of infantile spasms due to structural lesions.

OBJECTIVE: Infantile spasms may evolve into persistent epilepsies including Lennox-Gastaut syndrome. We compared adult epilepsy outcomes in models of infantile spasms due to structural etiology (multiple-hit model) or focal cortical inflammation and determined the anti-epileptogenic effects of pulse-rapamycin, previously shown to stop spasms in multiple-hit rats. METHODS: Spasms were induced in 3-day-old male rats via right intracerebral doxorubicin/lipopolysaccharide (multiple-hit model) infusions. Controls and sham rats were used. Separate multiple-hit rats received pulse-rapamycin or vehicle intraperitoneally between postnatal days 4 and 6. In adult mice, video-EEG (electroencephalography) scoring for seizures and sleep and histology were done blinded to treatment. RESULTS: Motor-type seizures developed in 66.7% of multiple-hit rats, usually from sleep, but were reduced in the pulse-rapamycin-treated group (20%, p = .043 vs multiple-hit) and rare in other groups (0-9.1%, p < .05 vs multiple-hit). Spike-and-wave bursts had a slower frequency in multiple-hit rats (5.4-5.8Hz) than in the other groups (7.6-8.3Hz) (p < .05); pulse rapamycin had no effect on the hourly spike-and-wave burst rates in adulthood. Rapamycin, however, reduced the time spent in slow-wave-sleep (17.2%), which was increased in multiple-hit rats (71.6%, p = .003). Sham rats spent more time in wakefulness (43.7%) compared to controls (30.6%, p = .043). Multiple-hit rats, with or without rapamycin treatment, had right more than left corticohippocampal, basal ganglia lesions. There was no macroscopic pathology in the other groups. SIGNIFICANCE: Structural corticohippocampal/basal ganglia lesions increase the risk for post-infantile spasms epilepsy, Lennox-Gastaut syndrome features, and sleep dysregulation. Pulse rapamycin treatment for infantile spasms has anti-epileptogenic effects, despite the structural lesions, and decreases the time spent in slow wave sleep.

The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy.

OBJECTIVE: Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. METHODS: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. RESULTS: The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one-half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one-third of all cases paroxysms of fast activity with electrodecrement. ALG13-related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one-third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. SIGNIFICANCE: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Disparate effects of hormones and vigabatrin on sleep slow waves in patients with West syndrome - An indication of their mode of action?

Synaptic downscaling during sleep, a physiological process to restore synaptic homeostasis and maintain learning efficiency and healthy brain development, has been related to a reduction of the slope of sleep slow waves (SSW). However, such synaptic downscaling seems not to be reflected in high-amplitude SSW. Recently we have shown reduced SSW slopes during hormonal treatment (adrenocorticotrophic hormone, prednisolone) in patients with West syndrome (WS). Yet, whether this reduction was related to successful treatment or reflects a specific effect of hormone therapy is unknown. Thus, we retrospectively analysed nap electroencephalograms of 61 patients with WS successfully treated with hormones, vigabatrin (VGB), or both. The slope of SSW during treatment (T1) and 2-7 months later (T2) when hormonal treatment was tapered off were compared between the treatment groups and healthy, age-matched controls. At T1 hormone treatment reduced the slope of low-amplitude SSW, whereas VGB increased the slope of high-amplitude SSW (linear mixed effect model: FGroup  = 7.04, p < 0.001; FAmplitude  = 1,646.68, p < 0.001; FGroup*Amplitude  = 3.38, p < 0.001). At T2, untreated patients did not differ anymore from healthy controls, whereas those still under VGB showed the same alterations as those with VGB at T1. This result indicates a disparate effect of VGB and hormone on the SSW slope. In particular, hormones seem to reduce the slope of cortical generated low-amplitude SSW, similar to the physiological synaptic downscaling during sleep. Thus, a loss of functional neuronal connectivity might be an alternative explanation of the antiepileptic effect of hormonal treatment.

Potential induction of epileptic spasms by nonselective voltage-gated sodium channel blockade: Interaction with etiology.

PURPOSE: Epileptic spasms are often preceded by focal (or multifocal) seizures. Based on a series of case reports suggesting that carbamazepine and oxcarbazepine may induce epileptic spasms, we set out to rigorously evaluate the potential association between exposure to voltage-gated sodium channel blockade and latency to epileptic spasms. METHODS: We identified 50 cases (children with focal seizures and evolution to epileptic spasms) and 50 controls (children with focal seizures without evolution to epileptic spasms). For each patient, we reviewed all sequential neurology encounters between onset of epilepsy and emergence of epileptic spasms. For each encounter we recorded seizure-frequency and all anti-seizure therapy exposures. Using multivariable Cox proportional hazards regression, we evaluated the association between voltage-gated sodium channel exposure (carbamazepine, oxcarbazepine, lacosamide, or phenytoin) and latency to epileptic spasms onset, with adjustment for etiology and seizure-frequency. RESULTS: Latency to epileptic spasms onset was independently associated with exposure to sodium channel blockade (hazard ratio = 2.4; 95% CI 1.1-5.2; P = 0.03) and high-risk etiology (hazard ratio = 2.8; 95% CI 1.5-5.1; P = 0.001). With assessment for interaction between sodium channel blockade and etiology, we identified an estimated 7-fold increased risk of epileptic spasms with the combination of sodium channel blockade and high-risk etiology (hazard ratio = 7.0, 95% CI 2.5-19.8; P < 0.001). CONCLUSION: This study suggests that voltage-gated sodium channel blockade may induce epileptic spasms among children at risk on the basis of etiology. Further study is warranted to replicate these findings, ascertain possible drug- and dose-specific risks, and identify potential mechanisms of harm.

Quality of life at 6 years in children treated for West syndrome with hormonal therapy.

INTRODUCTION: West syndrome is a severe epileptic encephalopathy occurring in infancy. Majority of affected children suffer from poor epilepsy control in later life and are dependent on care-givers for daily living. There is no previous study evaluating the Quality of Life (QOL) in children suffered from WS. METHOD: A prospective cohort study was performed at six years in a group of children with West syndrome, followed up in the Sri Lanka Infantile Spasm Study (SLISS). The quality of life was evaluated using Sri Lankan Health-Related Quality-of-Life Index for school children (SLHRQ-S), an age-specific, primary caregiver proxy-rated, validated questionnaire for Sri Lankan children with epilepsy. Information on epilepsy, medication, and daily activities was obtained from the parents. RESULTS: Fifty parents of initial 97 children treated for WS participated. The majority had no ongoing epilepsy (56%) at time of evaluation. The mean QOL was 67.22 (SD 15.68). Mean QOL scores for individual domains showed that physical domain was the worst affected (58.51 (SD = 22.11)). Psychological and social function domains were 68.73 (SD = 17.74) and 75.2 (SD = 14.87), respectively. Male sex (0.02), using multiple anti-seizure medications (0.00) and lower ILAE epilepsy control scale (0.02) were significantly associated with a poor quality of life. Age at onset, delay in treatment, and early spasm control were among the factors that did not influence quality of life. CONCLUSION: Despite having control of their epilepsy in the majority, these children suffered from poor quality of life. The greater impact on the physical domain possibly is related to the effect of underlying pathologies.

West syndrome: A study of 26 patients receiving short-term therapy.

OBJECTIVE: We describe the electroclinical characteristics of a series of 26 patients with idiopathic West syndrome (WS), who had an excellent response to treatment with vigabatrin (VGB) and corticosteroids alone or in combination. METHODS: Evaluating the records of 178 patients with WS studied at Garrahan Hospital, Niño Jesús Hospital, and Clínica San Lucas between January 2005 and June 2017, we selected 26 patients that met the inclusion criteria of idiopathic WS. The inclusion criteria for idiopathic WS were (1) no personal history of disease, (2) normal neurological examination and neurodevelopment, (3) symmetric spasms in clusters not preceded by any other type of seizure, (d) symmetric hypsarrhythmia, (e) normal electroencephalogram (EEG) background, e.g., normal sleep EEG pattern, (f) normal magnetic resonance imaging (MRI) recording, (g) normal neurometabolic and genetic studies, and (h) at least 2 years of follow-up. RESULTS: Fifteen boys and 11 girls met the inclusion criteria of idiopathic WS. The current age of the children ranges between 2 years 10 months and 12 years 10 months. Age at first epileptic spasms (ES) ranged from 4 to 11 months, with a mean age of 7 and a median of 7.5 months, respectively; ES were in clusters, bilateral and symmetrical in all cases. Spasms were flexor in nine (34.7%), mixed flexor-extensor in 15 (57.7%), and extensor in three (7.6%). In all patients the EEG showed typical pattern of hypsarrhythmia. CONCLUSION: These patients with idiopathic WS who have an excellent response to initial treatment should be treated for a short period of time with adrenocorticotropic hormone (ACTH) and VGB alone or in combination.

Acthar® Gel (repository corticotropin injection) dose-response relationships in an animal model of epileptic spasms.

Studies were undertaken to evaluate the effectiveness of Acthar® Gel (repository corticotropin injection [RCI]) in the tetrodotoxin (TTX) model of early-life-induced epileptic spasms. Repository corticotropin injection (RCI) is widely used in the United States to treat infantile spasms. A major component of RCI is N25 deamidated ACTH. Additionally, we hoped to provide some insight into the possible role circulating corticosteroids play in spasm cessation by comparing the RCI dose-response relationships for spasm suppression to RCI-induced corticosterone release from the adrenal gland. Spasms were induced by chronic TTX infusion into the neocortex beginning on postnatal day 11. Repository corticotropin injection (RCI) dosages were between 8 and 32 IU/kg/day. Drug titration protocols were used, and comparisons were made to injections of a vehicle gel. Video/EEG recordings (24/7) monitored the drug's effects continuously for up to 2 months. Tetrodotoxin (TTX)-infused control rats were monitored for the same period of time. In separate experiments, the same dosages of RCI were given to rats and 1 h later plasma was collected and assayed for corticosterone. A parallel study compared the effects of 1-day and 10-day RCI treatments on circulating corticosterone. Results showed that RCI was ineffective at dosages of 8, 12, and 16 IU/kg/day but eliminated spasms in 66% of animals treated with 24 or 32 IU/kg/day. Treating animals with 32 IU/kg/day alone produced the same degree of spasms suppression as observed during the titration protocols. In rats that had hypsarrhythmia-like activity, RCI eliminated this abnormal interictal EEG pattern in all rats that became seizure-free. In terms of plasma corticosterone, 1- and 10-day treatments with RCI produced similar increases in this hormone and the levels increased linearly with increasing dosages of RCI. This stood in sharp contrast to the sigmoid-like dose-response curve for decreases in spasm counts. Our results further validate the TTX model as relevant for the study of infantile spasms. The model should be useful for investigating how RCI acts to eliminate seizures and hypsarrhythmia. Dose-response results suggest that either very high concentrations of circulating corticosteroids are required to abolish spasms or RCI acts through a different mechanism.