Early Response, Long-Term Seizure Outcome, and Very-Low-Dose Adrenocorticotrophic Hormone Therapy for Infantile Epileptic Spasms Syndrome With Down Syndrome.

BACKGROUND: Infantile epileptic spasms syndrome (IESS) with Down syndrome has good treatment response and good seizure outcomes with high-dose adrenocorticotrophic hormone (ACTH) therapy. We investigated the early treatment response of epileptic spasms (ES), long-term seizure outcome, and efficacy of very-low-dose ACTH therapy for IESS with Down syndrome. METHODS: We retrospectively investigated patients with Down syndrome and IESS between April 1983 and January 2023. We defined response to treatment as clinical remission and electrographic resolution of hypsarrhythmia after treatment for more than one month and early treatment as any treatment for ES within three months of initiation of treatment. Long-term seizure outcomes were determined by the presence of any type of seizure within one year of the last visit. We investigated the dosage and efficacy of very-low-dose ACTH therapy. RESULTS: Thirty patients were enrolled with a median follow-up period of 7.7 years (range: 1.3 to 19.1). The response and relapse rates in the early treatment were 83.3% and 16.0%, respectively. The seizure-free rate of long-term seizure outcomes was 80.0%. Long-term seizure outcomes correlated with early treatment response to ES. The response rate of very-low-dose ACTH therapy was 59.3%. The efficacy of ACTH therapy tended to be dose-dependent (P = 0.055). CONCLUSIONS: Early treatment response to ES may be useful in predicting long-term seizure outcomes of IESS with Down syndrome. Very-low-dose ACTH therapy was the most effective treatment for ES and could exhibit dose-dependent efficacy. Depending on the IESS etiology, the ACTH dose could be reduced to minimize its side effects.

Computational EEG attributes predict response to therapy for epileptic spasms.

OBJECTIVE: We set out to evaluate whether response to treatment for epileptic spasms is associated with specific candidate computational EEG biomarkers, independent of clinical attributes. METHODS: We identified 50 children with epileptic spasms, with pre- and post-treatment overnight video-EEG. After EEG samples were preprocessed in an automated fashion to remove artifacts, we calculated amplitude, power spectrum, functional connectivity, entropy, and long-range temporal correlations (LRTCs). To evaluate the extent to which each feature is independently associated with response and relapse, we conducted logistic and proportional hazards regression, respectively. RESULTS: After statistical adjustment for the duration of epileptic spasms prior to treatment, we observed an association between response and stronger baseline and post-treatment LRTCs (P = 0.042 and P = 0.004, respectively), and higher post-treatment entropy (P = 0.003). On an exploratory basis, freedom from relapse was associated with stronger post-treatment LRTCs (P = 0.006) and higher post-treatment entropy (P = 0.044). CONCLUSION: This study suggests that multiple EEG features-especially LRTCs and entropy-may predict response and relapse. SIGNIFICANCE: This study represents a step toward a more precise approach to measure and predict response to treatment for epileptic spasms.

Epileptic spasms relapse is associated with response latency but not conventional attributes of post-treatment EEG.

OBJECTIVE: Relapse of epileptic spasms after initial treatment of infantile epileptic spasms syndrome (IESS) is common. However, past studies of small cohorts have inconsistently linked relapse risk to etiology, treatment modality, and EEG features upon response. Using a large single-center IESS cohort, we set out to quantify the risk of epileptic spasms relapse and identify specific risk factors. METHODS: We identified all children with epileptic spasms at our center using a clinical EEG database. Using the electronic medical record, we confirmed IESS syndrome classification and ascertained treatment, response, time to relapse, etiology, EEG features, and other demographic factors. Relapse-free survival analysis was carried out using Cox proportional hazards regression. RESULTS: Among 599 children with IESS, 197 specifically responded to hormonal therapy and/or vigabatrin (as opposed to surgery or other second-line treatments). In this study, 41 (21%) subjects exhibited relapse of epileptic spasms within 12 months of response. Longer duration of IESS prior to response (>3 months) was strongly associated with shorter latency to relapse (hazard ratio = 3.11; 95% CI 1.59-6.10; p = 0.001). Relapse was not associated with etiology, developmental status, or any post-treatment EEG feature. SIGNIFICANCE: This study suggests that long duration of IESS before response is the single largest clinical predictor of relapse risk, and therefore underscores the importance of prompt and successful initial treatment. Further study is needed to evaluate candidate biomarkers of epileptic spasms relapse and identify treatments to mitigate this risk. PLAIN LANGUAGE SUMMARY: Relapse of infantile spasms is common after initially successful treatment. With study of a large group of children with infantile spasms, we determined that relapse is linked to long duration of infantile spasms. In contrast, relapse was not associated with the cause of infantile spasms, developmental measures, or EEG features at the time of initial response. Further study is needed to identify tools to predict impending relapse of infantile spasms.

Modulation index predicts the effect of ethosuximide on developmental and epileptic encephalopathy with spike-and-wave activation in sleep.

PURPOSE: In developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis. METHODS: We retrospectively enrolled children with DEE-SWAS who had an electroencephalogram (EEG) recorded between January 2009 and September 2022 and were prescribed ESM at Okayama University Hospital. Only patients whose EEG showed continuous spike-and-wave during sleep were included. We extracted 5-min non-rapid eye movement sleep stage N2 segments from EEG recorded before starting ESM. We calculated the modulation index (MI) as the measure of PAC in pair combination comprising one of two fast oscillation types (gamma, 40-80 Hz; ripples, 80-150 Hz) and one of five slow-wave bands (delta, 0.5-1, 1-2, 2-3, and 3-4 Hz; theta, 4-8 Hz), and compared it between ESM responders and non-responders. RESULTS: We identified 20 children with a diagnosis of DEE-SWAS who took ESM. Fifteen were ESM responders. Regarding gamma oscillations, significant differences were seen only in MI with 0.5-1 Hz slow waves in the frontal pole and occipital regions. Regarding ripples, ESM responders had significantly higher MI in coupling with all slow waves in the frontal pole region, 0.5-1, 3-4, and 4-8 Hz slow waves in the frontal region, 3-4 Hz slow waves in the parietal region, 0.5-1, 2-3, 3-4, and 4-8 Hz slow waves in the occipital region, and 3-4 Hz slow waves in the anterior-temporal region. SIGNIFICANCE: High MI in a wider area of the brain may represent the epileptic network mediated by the thalamus in DEE-SWAS and may be a predictor of ESM effectiveness.

ATP1A2-related epileptic encephalopathy and movement disorder: Clinical features of three novel patients.

OBJECTIVE: Variants in the ATP1A2 gene exhibit a wide clinical spectrum, ranging from familial hemiplegic migraine to childhood epilepsies and early infantile developmental epileptic encephalopathy (EIDEE) with movement disorders. This study aims to describe the epileptology of three unpublished cases and summarize epilepsy features of the other 17 published cases with ATP1A2 variants and EIDEE. METHODS: Medical records of three novel patients with pathogenic ATP1A2 variants were retrospectively reviewed. Additionally, the PUBMED, EMBASE, and Cochrane databases were searched until December 2023 for articles on EIDEE with ATP1A2 variants, without language or publication year restrictions. RESULTS: Three female patients, aged 6 months-10 years, were investigated. Epilepsy onset occurred between 5 days and 2 years, accompanied by severe developmental delay, intellectual disability, drug-resistant epilepsy, severe movement disorder, and recurrent status epilepticus. All individuals had pathogenic variants of the ATP1A2 gene (ATP1A2 c.720_721del (p.Ile240MetfsTer9), ATP1A2c.3022C > T (p.Arg1008Trp), ATP1A2 c.1096G > T (p.Gly366Cys), according to ACMG criteria. Memantine was p) rescribed to three patients, one with a reduction in ictal frequency, one with improvement in gait pattern, coordination, and attention span, and another one in alertness without significant side effects. SIGNIFICANCE: This study reinforces the association between ATP1A2 variants and a severe phenotype. All patients had de novo variants, focal motor seizures with impaired awareness as the primary type of seizure; of the 11 EEGs recorded, 10 presented a slow background rhythm, 7 multifocal interictal epileptiform discharges (IED), predominantly temporal IEDs, followed by frontal IED, as well as ten ictal recordings, which showed ictal onset from the same regions mentioned above. Treatment with antiseizure medication was generally ineffective, but memantine showed moderate improvement. Prospective studies are needed to enlarge the phenotype and assess the efficacy of NMDA receptor antagonist therapies in reducing seizure frequency and improving quality of life.

Identification of a novel splice-site WWOX variant with paternal uniparental isodisomy in a patient with infantile epileptic encephalopathy.

WOREE syndrome is an early infantile epileptic encephalopathy characterized by drug-resistant seizures and severe psychomotor developmental delays. We report a case of a WWOX splice-site mutation with uniparental isodisomy. A 1-year and 7-month-old girl presented with nystagmus and epileptic seizures from early infancy, with no fixation or pursuit of vision. Physical examination revealed small deformities, such as swelling of both cheeks, folded fingers, rocking feet, and scoliosis. Brain imaging revealed slight hypoplasia of the cerebrum. Electroencephalogram showed focal paroxysmal discharges during the interictal phase of seizures. Vitamin B6 and zonisamide were administered for early infantile epileptic encephalopathy; however, the seizures were not relieved. Despite altering the type and dosage of antiepileptic drugs and ACTH therapy, the seizures were intractable. Whole-exome analysis revealed the homozygosity of WWOX(NM_016373.4):c.516+1G>A. The WWOX mRNA sequencing using peripheral blood RNA confirmed that exon 5 was homozygously deleted. Based on these results, the patient was diagnosed with WOREE syndrome at 5 months. The WWOX variant found in this study is novel and has never been reported before. WOREE syndrome being extremely rare, further case series and analyses of its pathophysiology are warranted.

Timing the clinical onset of epileptic spasms in infantile epileptic spasms syndrome: A tertiary health center's experience.

OBJECTIVE: Lead time to treatment (clinical onset of epileptic spasms [ES] to initiation of appropriate treatment) is known to predict outcomes in infantile epileptic spasms syndrome (IESS). Timing the clinical onset of ES is crucial to establish lead time. We investigated how often ES onset could be established to the nearest week. We aimed to (1) ascertain the exact date or estimate the nearest week of ES onset and (2) compare clinical/demographic factors between patients where date of ES onset was determined or estimated to the nearest week and patients whose date of ES onset could not be estimated to the nearest week. Reasons for difficulties in estimating date of ES onset were explored. METHODS: Retrospective chart review of new onset IESS patients (January 2019-May 2022) extracted the date or week of the clinical onset of ES. Predictors of difficulty in date of ES onset estimation to the nearest week were examined by regression analysis. Sources contributing to difficulties determining date of ES onset were assessed after grouping into categories (provider-, caregiver-, disease-related). RESULTS: Among 100 patients, date of ES onset was estimated to the nearest week in 47%. On univariable analysis, age at diagnosis (p = .021), development delay (p = .007), developmental regression/stagnation (p = .021), ES intermixed with other seizures (p = .011), and nonclustered ES at onset (p = .005) were associated with difficulties estimating date of ES onset. On multivariable analysis, failure to establish date of ES onset was related to ES intermixed with other seizures (p = .004) and nonclustered ES at onset (p = .003). Sources contributing to difficulties determining date of ES onset included disease-related factors (ES characteristics, challenges interpreting electroencephalograms) and provider/caregiver-related factors (delayed diagnosis). SIGNIFICANCE: Difficulties with estimation of lead time (due to difficulties timing ES onset) can impact clinical care (prognostication), as even small increments in lead time duration can have adverse developmental consequences.

Efficacy and safety of corticosteroids and ACTH in epileptic syndromes beyond Infantile Epileptic Spasms Syndrome (IESS): A systematic review and meta-analysis.

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and "symptomatic" etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.

Purified cannabidiol as add-on therapy in children with treatment-resistant infantile epileptic spasms syndrome.

OBJECTIVE: The aim of this study was to assess efficacy, safety, and tolerability of highly purified cannabidiol oil (CBD) as add-on therapy for the treatment of a series of patients with infantile epileptic spasms syndrome (IESS) who were resistant to antiseizure medications and ketogenic dietary therapy. MATERIAL AND METHODS: We conducted a retrospective analysis of the medical records of 28 infants with treatment-resistant IESS aged 6 to 21 months who received highly purified CBD between July 2021 and June 2023. Data were collected on neurological examinations, EEG, Video-EEG and polygraphic recordings, imaging studies, laboratory testing, and seizure frequency, type, and duration, and adverse effects. As the primary outcome, a reduction of frequency of epileptic spasms (ES) was assessed. ES freedom was considered after a minimal time of 1 month without ES. RESULTS: Sixteen male and 12 female patients, aged 6-21 months, who received CBD for treatment-resistant IESS were included. The etiology was structural in 10, Down syndrome in seven, genetic in nine, and unknown in two. Initial CBD dose was 2 mg/kg/day, which was uptitrated to a median dose of 25 mg/kg/day (range, 2-50). Prior to CBD initiation, patients had a median of 69 ES in clusters per day (range, 41-75) and of 10 focal seizures per week (range, 7-13). After a mean and median follow-up of 15 and 12.5 months (range, 6-26 months), seven patients were ES free and 12 had a >50 % ES reduction. Five of seven patients (71 %) with Down syndrome and 3/5 (60 %) with cerebral palsy responded well. Adverse effects were mild. EEG improvements correlated with ES reductions. CONCLUSION: In this study evaluating the use of CBD in children with IESS, 19/28 (67.8 %) had a more than 50 % ES reduction with good tolerability.

Early life seizures and epileptic spasms in STXBP1-related disorders.

OBJECTIVE: Individuals with disease-causing variants in STXBP1 frequently have epilepsy onset in the first year of life with a variety of seizure types, including epileptic spasms. However, the impact of early onset seizures and antiseizure medication (ASM) on the risk of developing epileptic spasms and impact on their trajectory are poorly understood, limiting informed and anticipatory treatment, as well as trial design. METHODS: We retrospectively reconstructed seizure and medication histories in weekly intervals for individuals with STXBP1 developmental and epileptic encephalopathy (DEE) with epilepsy onset in the first year of life and quantitatively analyzed longitudinal seizure histories and medication response. RESULTS: We included 61 individuals with early onset seizures, 29 of whom had epileptic spasms. Individuals with neonatal seizures were likely to have continued seizures after the neonatal period (25/26). The risk of developing epileptic spasms was not increased in individuals with neonatal seizures or early infantile seizures (21/41 vs. 8/16, odds ratio [OR] = 1, 95% confidence interval [CI] = .3-3.9, p = 1). We did not find any ASM associated with the development of epileptic spasms following prior seizures. Individuals with prior seizures (n = 16/21, 76%) had a higher risk of developing refractory epileptic spasms (n = 5/8, 63%, OR = 1.9, 95% CI = .2-14.6, p = .6). Individuals with refractory epileptic spasms had a later onset of epileptic spasms (n = 20, median = 20 weeks) compared to individuals with nonrefractory epileptic spasms (n = 8, median = 13 weeks, p = .08). SIGNIFICANCE: We provide a comprehensive assessment of early onset seizures in STXBP1-DEE and show that the risk of epileptic spasms is not increased following a prior history of early life seizures, nor by certain ASMs. Our study provides baseline information for targeted treatment and prognostication in early life seizures in STXBP1-DEE.

The vigabatrin-associated brain abnormalities on MRI and their differential diagnosis.

Vigabatrin is an anti-epileptic drug that inhibits the enzyme γ-aminobutyric acid (GABA)-transaminase. The anticonvulsant effect of vigabatrin involves increasing GABA levels and attenuating glutamate-glutamine cycling. Vigabatrin indications include infantile spasms and refractory focal seizures. Despite having a significant role in paediatric epileptology, vigabatrin has adverse effects, such as retinal toxicity, in up to 30% of patients after 1 year of use and brain abnormalities on magnetic resonance imaging (MRI). The percentage of patients with brain abnormalities on MRI varies between 22-32% of children using vigabatrin to treat infantile spasms. Risk factors for presenting these imaging abnormalities are cryptogenic infantile spasms, age <12 months old, high dosage, and possible concomitant hormonal therapy. Clinically, these abnormalities are usually asymptomatic. Histopathological analysis reveals white matter vacuolation and intramyelinic oedema. The typical findings of vigabatrin-associated brain abnormalities on MRI are bilateral and have a symmetrical hyperintense signal on T2-weighted imaging, with diffusion restriction, that often compromise the globi pallidi, thalami, subthalamic nuclei, cerebral peduncles, midbrain, dorsal brainstem, including the medial longitudinal fasciculi, and dentate nuclei of the cerebellum. In this article, the authors intend to review the clinical manifestations, histopathological features, imaging aspects, and differential diagnosis of vigabatrin-associated brain abnormalities on MRI.

Delays to care in infantile epileptic spasms syndrome: Racial and ethnic inequities.

OBJECTIVE: Non-Hispanic (NH) Black children are less likely to receive a standard treatment course for infantile epileptic spasms syndrome (IESS) than White/NH children at pediatric tertiary care epilepsy centers in the United States. However, if inequities exist in time to diagnosis is unknown. Diagnostic delays as little as 1 week can be associated with worse developmental outcomes. METHODS: Diagnostic delays were evaluated in a retrospective cohort of 100 children with new onset IESS between January 2019 and May 2022. RESULTS: Children with Black, Indigenous, and People of Color (BIPOC) caregivers were more likely to experience clinically significant delays in referral from first provider to neurologist, when compared to White/NH children, even after controlling for other demographic and clinical variables (odds ratio = 4.98, confidence interval = 1.24-19.94, p = .023). SIGNIFICANCE: Disproportionate diagnostic delays place BIPOC children at risk of adverse developmental and epilepsy outcomes. Further interventional prospective and qualitative studies are needed to address inequities in care.

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.

Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?

The devastating developmental and epileptic encephalopathy of infantile epileptic spasms syndrome (IESS) has numerous causes, including, but not limited to, brain injury, metabolic, and genetic conditions. Given the stereotyped electrophysiologic, age-dependent, and clinical findings, there likely exists one or more final common pathways in the development of IESS. The identity of this final common pathway is unknown, but it may represent a novel therapeutic target for infantile spasms. Previous research on IESS has focused largely on identifying the neuroanatomic substrate using specialized neuroimaging techniques and cerebrospinal fluid analysis in human patients. Over the past three decades, several animal models of IESS were created with an aim to interrogate the underlying pathogenesis of IESS, to identify novel therapeutic targets, and to test various treatments. Each of these models have been successful at recapitulating multiple aspects of the human IESS condition. These animal models have implicated several different molecular pathways in the development of infantile spasms. In this review we outline the progress that has been made thus far using these animal models and discuss future directions to help researchers identify novel treatments for drug-resistant IESS.

Real-life data comparing the efficacy of vigabatrin and oral steroids given sequentially or combined for infantile epileptic spasms syndrome.

AIMS: The prognosis of Infantile epileptic spasm syndrome (IESS), relates to the underlying etiology and delay in controlling epileptic spasms. Based on the spasm-free rate, a randomized controlled trial has demonstrated the superiority of combining oral steroids and vigabatrin over oral steroids alone but confirmation in real-life conditions is mandatory. METHODS: We compared two real-life IESS cohorts: a multicenter, retrospective cohort of 40 infants treated with vigabatrin followed by a sequential (ST) addition of steroids, and a prospective, single-center cohort of 58 infants treated with an immediate combination of vigabatrin and steroids (CT). RESULTS: The two cohorts were similar. When the rate of spasm-free infants in the two cohorts was compared on day 14, a significant difference was observed between the ST (27,5 %) and CT cohorts (64 %) (p < 0.0004). This difference remained significant on day 30, with 55 % spasm-free patients in the ST cohort compared to 76 % in the CT cohort (p = 0.03). After the infants had received both vigabatrin and steroids, without taking into account the time point after treatment initiation, no significant difference was observed in the spasm-free rate between the two cohorts (p = 0.38). INTERPRETATION: Real-life data confirm the interest of combination therapy as a first-line treatment for IESS.

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.

Societal costs of illness for infantile epileptic spasms syndrome and evolutionary cost prediction in the era of WHO's IGAP.

BACKGROUND: To achieve the goal of improving the quality of life for persons with epilepsy within the framework of the WHO's Intersectoral Global Action Plan (IGAP), our study aimed to assess the societal financial burden linked to infantile epileptic spasms syndrome (IESS), ensuring that children afflicted with IESS receive high-quality healthcare without enduring substantial financial constraints. METHODS: Between August 2022 and March 2023, 92 children with IESS (male: female: 2:1), recently diagnosed or previously followed-up, were recruited. We gathered costs for drugs, tests, and medical services, along with legal guardians' monthly income. Total expenditure was determined by multiplying unit costs by the yearly service usage commencing from the onset. Time series analysis was utilised to forecast the financial burden from 2022 to 2032. RESULTS: Clinicians' first choice of treatment was ACTH (n = 60, 65·2%), prednisolone (n = 25, 27·2%), and vigabatrin (n = 7, 7·6%) and the median cost of treatment during the initial year was INR 39,010 [USD 479·2]. The median direct medical, direct non-medical, and indirect cost were INR 31,650 [USD 388·4], INR 6581 [USD 80·8], and INR 10,100 [USD 124·07], respectively. Families lost a median of 12 days of work annually. Drug costs and loss of wages were the key factors in the financial burden. The projected and adjusted figures exhibited an incremental growth rate of 2·6% tri-annually. INTERPRETATION: This pioneering study in developing countries, the first of its kind, evaluates the societal cost, financial hardship, and trajectory of incremental cost in IESS. The primary drivers of the financial burden were pharmacological treatment and family work adjustments. The government shoulders 62% of the financial burden, and projected a triannual growth of 2·6% from 2022 to 2032. Our results rationalize policymakers' focus on incorporating IESS into social security programs, particularly in developing countries.

Predicting Antiseizure Medication Treatment in Children with Rare Tuberous Sclerosis Complex-Related Epilepsy Using Deep Learning.

BACKGROUND AND PURPOSE: Tuberous sclerosis complex disease is a rare, multisystem genetic disease, but appropriate drug treatment allows many pediatric patients to have positive outcomes. The purpose of this study was to predict the effectiveness of antiseizure medication treatment in children with tuberous sclerosis complex-related epilepsy. MATERIALS AND METHODS: We conducted a retrospective study involving 300 children with tuberous sclerosis complex-related epilepsy. The study included the analysis of clinical data and T2WI and FLAIR images. The clinical data consisted of sex, age of onset, age at imaging, infantile spasms, and antiseizure medication numbers. To forecast antiseizure medication treatment, we developed a multitechnique deep learning method called WAE-Net. This method used multicontrast MR imaging and clinical data. The T2WI and FLAIR images were combined as FLAIR3 to enhance the contrast between tuberous sclerosis complex lesions and normal brain tissues. We trained a clinical data-based model using a fully connected network with the above-mentioned variables. After that, a weighted-average ensemble network built from the ResNet3D architecture was created as the final model. RESULTS: The experiments had shown that age of onset, age at imaging, infantile spasms, and antiseizure medication numbers were significantly different between the 2 drug-treatment outcomes (P < .05). The hybrid technique of FLAIR3 could accurately localize tuberous sclerosis complex lesions, and the proposed method achieved the best performance (area under the curve = 0.908 and accuracy of 0.847) in the testing cohort among the compared methods. CONCLUSIONS: The proposed method could predict antiseizure medication treatment of children with rare tuberous sclerosis complex-related epilepsy and could be a strong baseline for future studies.