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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.

Purpose: Infantile epileptic spasms syndrome (IESS) is associated with abnormal neuronal networks during a critical period of synaptogenesis and brain plasticity. Hypsarrhythmia is a visual EEG biomarker used to diagnose IESS, assess response to treatment, and monitor relapse. Computational EEG biomarkers hold promise in providing unbiased, reliable, and objective criteria for clinical management. We hypothesized that computational and visual EEG biomarkers of IESS would correlate after treatment with vigabatrin and that these responses might differ between responders and non-responders. Methods: A retrospective analysis was conducted at a single center, involving children with IESS at initial diagnosis and following first-line treatment with vigabatrin. Visual EEG biomarkers of hypsarrhythmia were compared with computational EEG biomarkers, including spike and spike fast-oscillation source coherence, spectral power, and mean global field power, using retrospective analysis of EEG recorded at initial diagnosis and after vigabatrin treatment. Responders and non-responders were compared based on the characteristics of their follow-up EEGs. Results: In this pilot study, we observed a reduction in the EEG biomarker of hypsarrhythmia/modified hypsarrhythmia from 20/20 (100%) cases at the initial diagnosis to 9/20 (45%) cases after treatment with vigabatrin, indicating a 55% (11/20) responder rate. No significant difference in spike frequency was observed after treatment (p = 0.104). We observed no significant differences after treatment with vigabatrin in the computational EEG biomarkers that we assessed, including spike source coherence at 90% (p = 0.983), spike source coherence lag range (p > 0.999), spike gamma source coherence at 90% (p = 0.177), spike gamma source coherence lag range (p > 0.999), spectral power (0.642), or mean global field power (0.932). However, when follow-up EEGs were compared, there was a significant difference in mean global field power (p = 0.038) between vigabatrin responders and non-responders. In contrast, no such difference was observed for spike source coherence at 90% (p = 0.285), spike course coherence lag range (p = 0.819), spike gamma source coherence at 90% (p = 0.205), spike gamma source coherence lag range (p > 0.999), or spectral power (p = 0.445). Finally, our treated group did not differ significantly from healthy controls at initial diagnosis or follow-up in terms of spectral power (p = 0.420) or mean global field power (0.127). Conclusion: In this pilot study, we show that mean global field power is a computational EEG biomarker that is significantly reduced in IESS after treatment with vigabatrin. Although computational EEG biomarkers of network connectivity using spike source coherence appear to be a promising tool, future studies should further explore their potential for assessing treatment responses in IESS. [ABSTRACT FROM AUTHOR]

Background: Developing anti-obesity interventions targeting appetite or food intake, the primary driver of obesity, remains challenging. Here, we demonstrated that dietary γ-aminobutyric acid (GABA) with GABA-degradation inhibitory drugs could be an anti-obesity intervention possessing strong food intake-suppressive and weight-loss effects. Methods: High-fat (HF)-diet-induced obese mice were divided into six groups receiving either the HF diet or the 2% GABA-HF diet with daily administration of PBS or the GABA-degradation inhibitory drugs, vigabatrin and ethanolamine-O-sulfate (EOS). In 24-h fast-induced refeeding, lean mice with a basal diet were used, and food intake was measured from 0.5 to 24 h after refeeding. Results: Coadministration of the 2% GABA-HF diet with vigabatrin or EOS significantly decreased food intake (−53%, −35%) and body weight (−22%, −16%) within 11 days in obese mice, along with a marked increase in plasma GABA levels. Mice receiving dietary GABA alone or the drugs alone exhibited no such effects. Hypothalamic GABA levels increased in drug-treated mice, regardless of diet. At 0.5 h after refeeding, food intake was similar in all groups. However, at 0.5 h, plasma GABA levels were markedly increased only in mice receiving coadministration of dietary GABA and the drugs, and their food intake was completely inhibited for over 6 h, while mice in other groups gradually increased their food intake. Conclusion: Combining dietary GABA with GABA-degradation inhibitory drugs effectively suppresses food intake and promotes weight loss in obese mice, primarily through increased plasma GABA availability. These findings may advance the development of food intake-controlling strategies for obesity management. [ABSTRACT FROM AUTHOR]

Background: Developing anti-obesity interventions targeting appetite or food intake, the primary driver of obesity, remains challenging. Here, we demonstrated that dietary γ-aminobutyric acid (GABA) with GABA-degradation inhibitory drugs could be an anti-obesity intervention possessing strong food intake-suppressive and weight-loss effects. Methods: High-fat (HF)-diet-induced obese mice were divided into six groups receiving either the HF diet or the 2% GABA-HF diet with daily administration of PBS or the GABA-degradation inhibitory drugs, vigabatrin and ethanolamine-Osulfate (EOS). In 24-h fast-induced refeeding, lean mice with a basal diet were used, and food intake was measured from 0.5 to 24 h after refeeding. Results: Coadministration of the 2% GABA-HF diet with vigabatrin or EOS significantly decreased food intake (-53%, -35%) and body weight (-22%, -16%) within 11 days in obese mice, along with a marked increase in plasma GABA levels. Mice receiving dietary GABA alone or the drugs alone exhibited no such effects. Hypothalamic GABA levels increased in drugtreated mice, regardless of diet. At 0.5 h after refeeding, food intake was similar in all groups. However, at 0.5 h, plasma GABA levels were markedly increased only in mice receiving coadministration of dietary GABA and the drugs, and their food intake was completely inhibited for over 6 h, while mice in other groups gradually increased their food intake. Conclusion: Combining dietary GABA with GABA-degradation inhibitory drugs effectively suppresses food intake and promotes weight loss in obese mice, primarily through increased plasma GABA availability. These findings may advance the development of food intake-controlling strategies for obesity management. [ABSTRACT FROM AUTHOR]

Background: Inborn errors of glutathione metabolism may cause high anion gap metabolic acidosis due to pyroglutamic acid accumulation. Since 1988, cases of this acidosis have been reported in individuals without these defects. Methods: Given the poorly characterized predisposing factors, presentation, management, and prognosis of acquired pyroglutamic acidosis, we conducted a systematic review using the National Library of Medicine, Excerpta Medica, Web of Science, and Google Scholar databases. Results: A total of 131 cases were found. Most patients were females (79%), adults (92%) aged 51 years or older (66%) with pre-existing conditions (74%) such as undernutrition, alcohol-use disorder, or kidney disease, and had an ongoing infection (69%). The clinical features included diminished consciousness (60%), Kussmaul breathing (56%), and nausea or vomiting (27%). At least 92% of patients were on paracetamol therapy for >10 days at an appropriate dose, 32% on a β-lactamase-resistant penicillin, and 2.3% on vigabatrin. Besides severe anion gap acidosis, patients also presented with hypokalemia (24%) and kidney function deterioration (41%). Management involved discontinuing the offending drug (100%), bicarbonate (63%), acetylcysteine (42%), and acute kidney replacement therapy (18%). The fatality rate was 18%, which was higher without acetylcysteine (24%) compared to with it (11%). Conclusions: Acquired pyroglutamic acidosis is a rare, potentially fatal metabolic derangement, which usually occurs after paracetamol use, frequently combined with a β-lactamase-resistant penicillin or vigabatrin. This condition predominantly affects adults, especially women with factors like undernutrition, alcohol-use disorder, or kidney disease, often during infection. Increased awareness of this rare condition is necessary. [ABSTRACT FROM AUTHOR]

Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE. The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models. Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes. Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively. Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, which is crucial for cell proliferation, growth, and differentiation, and is stimulated by various energy sources and hormonal signaling pathways. Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC. Brain tumours, sudden unexpected death from epilepsy, and respiratory conditions are the three leading causes of morbidity and mortality. Even though several therapeutic options are available for the treatment of TSC, there is further need for a better understanding of the pathophysiological basis of the neurologic and other manifestations seen in TSC, and for novel therapeutic approaches. This review provides an overview of the main current therapies for TSC and discusses recent studies highlighting the repurposing of approved drugs and the emerging role of novel targets for future drug design. [ABSTRACT FROM AUTHOR]

Background: The goal of this study was to develop and validate a UPLC-MS/MS method for simultaneous measurement of 13 AEDs, including carbamazepine, oxcarbazepine, lamotrigine, levetiracetam, topiramate, primidone, zonisamide, gabapentin, lacosamide, perampanel, pregabalin, rufinamide, and vigabatrin, in whole blood samples. Methods: A UPLC-MS/MS method for simultaneous determination of 13 AEDs in whole blood was developed, and validation was conducted for accuracy, precision, limit of quantification (LOQ), matrix effect, and stability. Our method was compared to two different hospitals using UPLC-MS/MS. Results: All AEDs exhibited linearity across the AMR (analytical measurement range), with R² values ranging from 0.994 to 1.000. The imprecision and inaccuracy for low and high quality control (QC) levels were within an acceptable range, with the coefficient of variation (CV) < 15%. The LOQ was 0.62 μg/mL for carbamazepine, 1.61 μg/mL for oxcarbazepine, 1.30 μg/mL for lamotrigine, 13.20 μg/mL for levetiracetam, 1.26 μg/mL for topiramate, 1.01 μg/mL for primidone, 1.59 μg/mL for zonisamide, 1.09 μg/mL for lacosamide, 1.61 μg/mL for gabapentin, 0.50 μg/mL for pregabalin, 0.07 ng/mL for perampanel, 3.00 μg/mL for rufinamide, and 2.06 μg/mL for vigabatrin. All AEDs demonstrated acceptable assay parameters for carryover, stability, and matrix effects. Moreover, the assay showed satisfactory results compared to two different hospitals with a bias of less than 15%. Conclusions: We successfully developed and validated a fast and robust UPLC-MS/MS method for routine therapeutic drug monitoring of thirteen antiepileptic drugs simultaneously. [ABSTRACT FROM AUTHOR]

Abstract 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.

Aims: Vigabatrin is an antiepileptic drug used to treat some forms of severe epilepsy in children. The main adverse effect is ocular toxicity, which is related to the cumulative dose. The aim of the study is to identify an acceptable exposure range, both through the development of a population pharmacokinetic model of vigabatrin in children enabling us to calculate patient exposure and through the study of therapeutic response. Methods: We performed a retrospective study including children with epilepsy followed at Necker‐Enfants Malades hospital who had a vigabatrin assay between January 2019 and January 2022. The population pharmacokinetic study was performed on Monolix2021 using a nonlinear mixed‐effects modelling approach. Children treated for epileptic spasms were classified into responder and nonresponder groups according to whether the spasms resolved, in order to identify an effective plasma exposure range. Results: We included 79 patients and analysed 159 samples. The median age was 4.2 years (range 0.3–18). A 2‐compartment model with allometry and creatinine clearance on clearance best fit our data. Exposure analysis was performed on 61 patients with epileptic spasms. Of the 22 patients who responded (36%), 95% had an AUC0–24 between 264 and 549 mg.h.L−1. Conclusions: The population pharmacokinetic model allowed us to identify bodyweight and creatinine clearance as the 2 main factors explaining the observed interindividual variability of vigabatrin. An acceptable exposure range was defined in this study. A target concentration intervention approach using this pharmacokinetic model could be used to avoid overexposure in responder patients. [ABSTRACT FROM AUTHOR]

• Vigabatrin is first choice for infantile spasms in Denmark. • A cohort of 326 children with infantile spasms was followed to a mean age of 8.2 years. • Vigabatrin alone led to spasm control in 44.7 %. • At end of follow-up 44.2 % had a severe neurodevelopmental delay and 76.4 % still had epilepsy. • In this national cohort incidence of infantile spasms was 0.22 per 1.000 live births. To investigate the treatment of infantile epileptic spasm syndrome (IESS) in Denmark. National retrospective cohort study of all patients born 1996–2019 who had a diagnosis of IESS in the National Patient Registry. Medical records were reviewed to evaluate the diagnosis. Patients were included if semiology was compatible with IESS, or if unclear semiology if there was an abnormal EEG or EEG with hypsarrhythmia. Number of cases with a register based IESS diagnosis was 538. Medical records were unavailable in 48 and 164 did not fulfil the inclusion criteria. Thereby the cohort consisted of 326 children. Mean age at onset of IESS was 5.9 months and mean lead time to treatment was 26.6 days (SD= 63.5). Consistent with the Danish treatment guidelines most patients received vigabatrin as first treatment. In the cohort 44.7 % of patients solely received vigabatrin, whereas combined vigabatrin and corticosteroid was given to 28.3 % (either hydrocortisone or prednisolone). Other anti-seizure medication was given to 28.4 % within 90 days of IESS onset. Aetiology was prenatal (40.3 %), perinatal (10.5 %), postnatal (3.7 %), with unknown timing (10.2 %) or with unknown aetiology (33.5 %). The cohort was followed to a mean age of 8.2 years. At latest follow-up severe neurodevelopmental outcome was seen in 44.2 % and 76.4 % still had epilepsy. The incidence of IESS was 22 per 100.000 live births. In Denmark treatment algorithm is based on start of treatment with vigabatrin. A total of 44.7 % became seizure free by vigabatrin. Neurodevelopmental outcome was severe. A national incidence could be established. [ABSTRACT FROM AUTHOR]

PurposeInfantile epileptic spasms syndrome (IESS) is associated with abnormal neuronal networks during a critical period of synaptogenesis and brain plasticity. Hypsarrhythmia is a visual EEG biomarker used to diagnose IESS, assess response to treatment, and monitor relapse. Computational EEG biomarkers hold promise in providing unbiased, reliable, and objective criteria for clinical management. We hypothesized that computational and visual EEG biomarkers of IESS would correlate after treatment with vigabatrin and that these responses might differ between responders and non-responders.MethodsA retrospective analysis was conducted at a single center, involving children with IESS at initial diagnosis and following first-line treatment with vigabatrin. Visual EEG biomarkers of hypsarrhythmia were compared with computational EEG biomarkers, including spike and spike fast-oscillation source coherence, spectral power, and mean global field power, using retrospective analysis of EEG recorded at initial diagnosis and after vigabatrin treatment. Responders and non-responders were compared based on the characteristics of their follow-up EEGs.ResultsIn this pilot study, we observed a reduction in the EEG biomarker of hypsarrhythmia/modified hypsarrhythmia from 20/20 (100%) cases at the initial diagnosis to 9/20 (45%) cases after treatment with vigabatrin, indicating a 55% (11/20) responder rate. No significant difference in spike frequency was observed after treatment (p = 0.104). We observed no significant differences after treatment with vigabatrin in the computational EEG biomarkers that we assessed, including spike source coherence at 90% (p = 0.983), spike source coherence lag range (p > 0.999), spike gamma source coherence at 90% (p = 0.177), spike gamma source coherence lag range (p > 0.999), spectral power (0.642), or mean global field power (0.932). However, when follow-up EEGs were compared, there was a significant difference in mean global field power (p = 0.038) between vigabatrin responders and non-responders. In contrast, no such difference was observed for spike source coherence at 90% (p = 0.285), spike course coherence lag range (p = 0.819), spike gamma source coherence at 90% (p = 0.205), spike gamma source coherence lag range (p > 0.999), or spectral power (p = 0.445). Finally, our treated group did not differ significantly from healthy controls at initial diagnosis or follow-up in terms of spectral power (p = 0.420) or mean global field power (0.127).ConclusionIn this pilot study, we show that mean global field power is a computational EEG biomarker that is significantly reduced in IESS after treatment with vigabatrin. Although computational EEG biomarkers of network connectivity using spike source coherence appear to be a promising tool, future studies should further explore their potential for assessing treatment responses in IESS.

Vigabatrin (VGB) is a gammaaminobutyric acid-ergic (GABA-ergic) antiepileptic drug (AED) and is one of 2 approved drugs available to treat infantile spasms (IS). The aim of this study is to elucidate conflicting data on the toxic effects of VGB and to obtain detailed information about its possible cytogenotoxic effects in human lymphocytes. For this purpose, in vitro Chromosomal Aberration (CA), Sister Chromatid Exchange (SCE), Micronucleus (MN) tests, and Comet Assay were performed to determine possible genotoxic and cytotoxic effects of VGB. In addition, the binding energy level of VGB to DNA was determined in silico by molecular docking. The highest concentration (80 μg/ml) of VGB increased the SCE, CA, MN and micronucleated binuclear cell (BNMN) frequency significantly compared to the control after 24 and 48 hours of treatment. In the tail density and tail length parameters, the dose-dependent increase was found to be statistically significant compared to the control. At the 40 and 80 μg/ml concentrations of VGB for 48 hours caused a statistically significant increase in both CA/Cell and AC percentages, while MI and NDI decreased only significantly at the highest concentration (80 µg/ml) causing. In the Comet Assay head density, tail density and tail length parameters, the dose-dependent increase was found to be statistically significant compared to the control. Also, the in silico molecular docking analysis showed that VGB interacts with B-DNA close to the threshold binding energy. The lowest negative free binding energy (ΔG binding) was found as −5.13 kcal/mol. In conclusion, all results are evaluated together, it has been determined that VGB has cytogenotoxic effects in vitro and binds to DNA in silico with significant free binding energy. [ABSTRACT FROM AUTHOR]

This review concerns the rare, acquired, usually iatrogenic, high-anion-gap metabolic acidosis, pyroglutamic acidosis. Pyroglutamate is a derivative of the amino acid glutamate, and is an intermediate in the 'glutathione cycle', by which glutathione is continuously synthesized and broken down. The vast majority of pyroglutamic acidosis cases occur in patients on regular, therapeutic doses of paracetamol. In about a third of cases, flucloxacillin is co-prescribed. In addition, the patients are almost always seriously unwell in other ways, typically with undernourishment of some form. Paracetamol, with underlying disorders, conspires to divert the glutathione cycle, leading to the overproduction of pyroglutamate. Hypokalaemia is seen in about a third of cases. Once the diagnosis is suspected, it is simple to stop the paracetamol and change the antibiotic (if flucloxacillin is present), pending biochemistry. N-acetyl-cysteine can be given, but while the biochemical justification is compelling, the clinical evidence base is anecdotal. [ABSTRACT FROM AUTHOR]

Background and objectivesStandard therapies (adrenocorticotropic hormone [ACTH], oral steroids, or vigabatrin) fail to control infantile spasms in almost half of children. Early identification of nonresponders could enable rapid initiation of sequential therapy. We aimed to determine the time to clinical remission after appropriate infantile spasms treatment initiation and identify predictors of the time to infantile spasms treatment response.MethodsThe National Infantile Spasms Consortium prospectively followed children aged 2-24 months with new-onset infantile spasms at 23 US centers (2012-2018). We included children treated with standard therapy (ACTH, oral steroids, or vigabatrin). Sustained treatment response was defined as having the last clinically recognized infantile spasms on or before treatment day 14, absence of hypsarrhythmia on EEG 2-4 weeks after treatment, and persistence of remission to day 30. We analyzed the time to treatment response and assessed clinical characteristics to predict sustained treatment response.ResultsAmong 395 infants, clinical infantile spasms remission occurred in 43% (n = 171) within the first 2 weeks of treatment, of which 81% (138/171) responded within the first week of treatment. There was no difference in the median time to response across standard therapies (ACTH: median 4 days, interquartile range [IQR] 3-7; oral steroids: median 3 days, IQR 2-5; vigabatrin: median 3 days, IQR 1-6). Individuals without hypsarrhythmia on the pretreatment EEG (i.e., abnormal but not hypsarrhythmia) were more likely to have early treatment response than infants with hypsarrhythmia at infantile spasms onset (hazard ratio 2.23, 95% CI 1.39-3.57). No other clinical factors predicted early responders to therapy.DiscussionRemission after first infantile spasms treatment can be identified by treatment day 7 in most children. Given the importance of early and effective treatment, these data suggest that children who do not respond to standard infantile spasms therapy within 1 week should be reassessed immediately for additional standard treatment. This approach could optimize outcomes by facilitating early sequential therapy for children with infantile spasms.

Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively. Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, which is crucial for cell proliferation, growth, and differentiation, and is stimulated by various energy sources and hormonal signaling pathways. Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC. Brain tumours, sudden unexpected death from epilepsy, and respiratory conditions are the three leading causes of morbidity and mortality. Even though several therapeutic options are available for the treatment of TSC, there is further need for a better understanding of the pathophysiological basis of the neurologic and other manifestations seen in TSC, and for novel therapeutic approaches. This review provides an overview of the main current therapies for TSC and discusses recent studies highlighting the repurposing of approved drugs and the emerging role of novel targets for future drug design.

BackgroundThe antiepileptic medication vigabatrin has been associated with ocular toxicity, and close ophthalmic monitoring has been recommended; however, there is no clear consensus regarding the value and feasibility of such monitoring in children. We describe ophthalmic assessments in children in a real-world clinical setting, the incidence of vigabatrin-related ocular toxicity, and the utility of regular screening or ancillary testing in children taking vigabatrin.MethodsThe medical records of children taking vigabatrin with one or more ophthalmic assessments at Children's Hospital of Philadelphia or University of California, San Francisco, between May 2010 and May 2021, were reviewed retrospectively. Abnormalities on ophthalmic examination, visual field (VF), electroretinogram (ERG), and optical coherence tomography (OCT) were reviewed and categorized as attributable to vigabatrin, possibly attributable to vigabatrin, or not attributable to vigabatrin.ResultsA total of 1,281 assessments of 284 children (mean age, 2.09 years) were included. Of these, 283 (99.6%) had funduscopic examination(s), 37 (13.0%) had ERG, 19 (6.7%) had OCT, and 6 (2.1%) had formal VF. Rate of examinations and ERGs per child decreased over the 10-year study period. Two children (0.7%) had definite vigabatrin-related ocular toxicity, both identified on ERG. An additional 4 children (1.4%) had optic atrophy of unclear relation to vigabatrin, categorized as possible toxicity. The remaining 278 children did not have abnormal examination or testing findings attributable to vigabatrin.ConclusionsThe incidence of vigabatrin-related ocular toxicity in children was low in our cohort. Ocular and neurologic comorbidities and limited examinations in children make identification of such toxicity challenging and the value of screening is unclear.

OBJECTIVE: The aim of this study was to determine whether selection of treatment for children with infantile spasms (IS) varies by race/ethnicity. METHODS: The prospective US National Infantile Spasms Consortium database includes children with IS treated from 2012 to 2018. We examined the relationship between race/ethnicity and receipt of standard IS therapy (prednisolone, adrenocorticotropic hormone, vigabatrin), adjusting for demographic and clinical variables using logistic regression. Our primary outcome was treatment course, which considered therapy prescribed for the first and, when needed, the second IS treatment together. RESULTS: Of 555 children, 324 (58%) were non-Hispanic white, 55 (10%) non-Hispanic Black, 24 (4%) non-Hispanic Asian, 80 (14%) Hispanic, and 72 (13%) other/unknown. Most (398, 72%) received a standard treatment course. Insurance type, geographic location, history of prematurity, prior seizures, developmental delay or regression, abnormal head circumference, hypsarrhythmia, and IS etiologies were associated with standard therapy. In adjusted models, non-Hispanic Black children had lower odds of receiving a standard treatment course compared with non-Hispanic white children (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.20-0.89; p = 0.02). Adjusted models also showed that children with public (vs. private) insurance had lower odds of receiving standard therapy for treatment 1 (OR, 0.42; CI, 0.21-0.84; p = 0.01). INTERPRETATION: Non-Hispanic Black children were more often treated with non-standard IS therapies than non-Hispanic white children. Likewise, children with public (vs. private) insurance were less likely to receive standard therapies. Investigating drivers of inequities, and understanding the impact of racism on treatment decisions, are critical next steps to improve care for patients with IS. ANN NEUROL 2022;92:32-44.

This article provides information on the synthesis of (S)-(+)-vigabatrin, an antiseizure medication used for epilepsy. It explains that GABA, an inhibitory transmitter, is ineffective in preventing seizures due to the blood-brain barrier. Vigabatrin, an analogue of GABA, can cross the barrier and increase GABA concentration in the brain, preventing seizures. The article presents a new synthesis method for (S)-(+)-vigabatrin using Meldrum's acid, which eliminates the use of hazardous reagents. The document also details the synthesis and characterization of two chemical compounds, (R)-2-tert-Butoxycarbonylamino-4-thiomethylbutanoic Acid (8) and (5S)-5-(2-Methylthioethyl)-2-pyrrolidone (6), and acknowledges the support of Emcure Pharmaceuticals Ltd. [Extracted from the article]

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. 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). 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). Real-life data confirm the interest of combination therapy as a first-line treatment for IESS. • Combination of VGB and steroids was more effective at day 14 • Combination of VGB and steroids is more effective in achieving seizure freedom than sequential treatment on the spasm-free rate at one month. [ABSTRACT FROM AUTHOR]

Abstract Vigabatrin is the medication used for the treatment of infantile spasms and refractory complex partial seizures, but its usage has always been contradictory due to its effect on vision. This review focuses on the registry, mechanism of injury, animal study, pharmacokinetics, risk factors, efficacy, safety and precautions of vigabatrin. The first visual defect with vigabatrin use was detected in 1997. This led to initiation of many trials including compulsory registration of patients in Sabril registry. The site of toxicity is found to be inner retina where vigabatrin tends to inhibit densely gamma amino butyric acid-C (GABA-C) receptors resulting in intoxication of visual field and also genetic variations held responsible for the injury. The toxicological studies of vigabatrin on various animals reveal different physiology, deficiency of taurine and light can effect on visual field and its related cells. Only thing need to be monitored with use of vigabatrin is visual field because it is well absorbed, with zero protein binding and no necessary dosage adjustment. The effect of vigabatrin is seen to vary with age, duration of therapy, cumulative dose and gender. The efficacy differs in various studies for different forms of epilepsy and so does the safety. Precautions are needed to be followed regarding use of vigabatrin by considering the risk versus benefit ratio for each and every individual and also discussing with the patient’s caregivers. The ultimate goal in treating with vigabatrin for any form of epilepsy is the good clinical response.

Abstract This systematic review and meta‐analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta‐analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR = 0.37, 95% CI = 0.20‐0.67) for patients with new‐onset IESS. Meta‐analysis of the nine OSs agrees with the result from RCTs (OR = 0.61, 95% CI = 0.43‐0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR = 5.59, 95% CI = 2.17‐14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR = 0.75, 95% CI = 0.09‐6.45). Hormonal monotherapy is better than VGB monotherapy for non‐TSC‐associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy.

Purpose: To investigate the pharmacokinetics and tissue distribution of VGB racemate and its single enantiomers, and explore the potential of clinic development for single enantiomer S-VGB. Methods: In the pharmacokinetics study, male Sprague-Dawley rats were gavaged with VGB racemate or its single enantiomers dosing 50, 100 or 200 mg/kg, and the blood samples were collected during 12 h at regular intervals. In the experiment of tissue distribution, VGB and its single enantiomers were administered intravenously dosing 200 mg/kg, and the tissues including heart, liver, spleen, lung and kidney, eyes, hippocampus, and prefrontal cortex were separated at different times. The concentrations of R-VGB and S-VGB in the plasma and tissues were measured using HPLC. Results: Both S-VGB and R-VGB could be detected in the plasma of rats administered with VGB racemate, reaching Cmax at approximately 0.5 h with t1/2 2–3 h. There was no significant pharmacokinetic difference between the two enantiomers when VGB racemate was given 200 mg/kg and 100 mg/kg. However, when given at the dose of 50 mg/kg, S-VGB presented a shorter t1/2 and a higher Cl/F than R-VGB, indicating a faster metabolism of S-VGB. Furthermore, when single enantiomer was administered respectively, S-VGB presented a slower metabolism than R-VGB, as indicated by a longer t1/2 and MRT but a lower Cmax. Moreover, compared with the VGB racemate, the single enantiomers S-VGB and R-VGB had shorter t1/2 and MRT, higher Cmax and AUC/D, and lower Vz/F and Cl/F, indicating the stronger oral absorption and faster metabolism of single enantiomer. In addition, regardless of VGB racemate administration or single enantiomer administration, S-VGB and R-VGB had similar characteristics in tissue distribution, and the content of S-VGB in hippocampus, prefrontal cortex and liver was much higher than that of R-VGB. Conclusions: Although there is no transformation between S-VGB and R-VGB in vivo, those two enantiomers display certain disparities in the pharmacokinetics and tissue distribution, and interact with each other. These findings might be a possible interpretation for the pharmacological and toxic effects of VGB and a potential direction for the development and optimization of the single enantiomer S-VGB.

We aimed to systematically characterize the magnetic resonance imaging (MRI) findings in vigabatrin-related neurotoxicity in children and determine the reversibility of lesions based on follow-up images. We evaluated children with a history of refractory seizures who had a brain MRI while on vigabatrin therapy. We included available brain MRI studies before vigabatrin therapy initiation, during vigabatrin treatment, and after vigabatrin was discontinued. A pediatric neuroradiologist systematically assessed images on T2/fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging /apparent diffusion coefficient sequences to identify hyperintense lesions and/or restricted diffusion. The frequency of abnormal signal at each location was determined, as well as the reversibility of these after vigabatrin discontinuation. MRIs of 43 patients were reviewed: 13 before vigabatrin initiation, 18 during treatment, and 12 after vigabatrin discontinuation. In the MRIs acquired during vigabatrin treatment, most lesions on T2/FLAIR occurred in the globus pallidi, thalami, and midbrain. Correspondingly, the most common locations for restricted diffusion were the globus pallidi, thalami, and subthalamic nuclei. On MRI after vigabatrin discontinuation, complete resolution of lesions on T2/FLAIR in all patients was seen in the midbrain, dentate nuclei, subthalamic nuclei, and hypothalami. Complete resolution of restricted diffusion was observed in the globus pallidi, midbrain, dentate nuclei, hippocampi, anterior commissure, and hypothalami. Globus pallidi and thalami are the most commonly affected structures in vigabatrin-related toxicity, and most vigabatrin-related neuroimaging findings are reversible. [ABSTRACT FROM AUTHOR]

Avantika Singh,1,&ast; Aristides Hadjinicolaou,1,&ast; Jurriaan M Peters,1 Catherine L Salussolia1,2 1Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA; 2F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA&ast;These authors contributed equally to this workCorrespondence: Catherine L Salussolia, 3 Blackfan Circle, Center for Life Sciences 14060, Boston, MA, 02115, USA, Tel +617-355-7970, Email catherine.salussolia@childrens.harvard.eduAbstract: Tuberous sclerosis complex (TSC) is a neurogenetic disorder that affects multiple organ systems, including the heart, kidneys, eyes, skin, and central nervous system. The neurologic manifestations have the highest morbidity and mortality, in particular in children. Clinically, patients with TSC often present with new-onset seizures within the first year of life. TSC-associated epilepsy is often difficult to treat and refractory to multiple antiseizure medications. Refractory TSC-associated epilepsy is associated with increased risk of neurodevelopmental comorbidities, including developmental delay, intellectual disability, autism spectrum disorder, and attention hyperactivity disorder. An increasing body of research suggests that early, effective treatment of TSC-associated epilepsy during critical neurodevelopmental periods can potentially improve cognitive outcomes. Therefore, it is important to treat TSC-associated epilepsy aggressively, whether it be with pharmacological therapy, surgical intervention, and/or neuromodulation. This review discusses current and future pharmacological treatments for TSC-associated epilepsy, as well as the importance of early surgical evaluation for refractory epilepsy in children with TSC and consideration of neuromodulatory interventions in young adults.Keywords: neurodevelopment, infantile spasms, vigabatrin, epilepsy surgery

Presentamos una revisión respecto a Vigabatrin en el tratamiento de epilepsia en niños, haciendo énfasis en Sindrome de West y epilepsia focal. En el primer caso la evidencia es comparable con la descrita para esteroides, sin embargo la incidencia de efectos colaterales es menor. Es de elección, con adecuado nivel de evidencia, en el manejo de epilepsia causada por esclerosis tuberosa. Se puede recomendar en el manejo de epilepsia focal, vigilando la aparición de crisis paradójicas.

Introducción. Se presenta una serie de pacientes que recibieron vigabatrín como tratamiento farmacológico para manejo de epilepsia causada por trastornos del desarrollo cortical. Objetivos. Evaluar la efectividad en cuanto a control de crisis en estos pacientes, teniendo en cuenta los hallazgos previos de la semejanza histológica y funcional de los trastornos del desarrollo cortical con las lesiones de la esclerosis tuberosa. Material y métodos. Se revisaron las historias de los pacientes con diagnóstico de trastorno del desarrollo cortical que recibieron este tratamiento como pacientes de la Liga Central Contra la Epilepsia, en el periodo comprendido entre los años 2005 a 2008. Se registraron datos sobre tipo de trastorno del desarrollo cortical, clasificación de la epilepsia, control de crisis antes y después del tratamiento con vigabatrín y presencia de efectos adversos. Resultados. Se revisaron 14 historias, el 57,11 % varones, con edades comprendidas entre 4 y 28 años. La forma de epilepsia más común fue la focal de diferente localización, y el tipo de malformación cortical más común fue la displasia cortical focal. El 50% de los pacientes mostró control superior al 90% respecto a las crisis registradas antes del inicio de tratamiento con Vigabatrin. Sólo un paciente mostró clínicamente disminución del campo visual y mejoró con la suspensión del tratamiento. Conclusión. En nuestra experiencia en pacientes pediátricos y adultos Vigabatrín es un tratamiento efectivo y seguro para el manejo de pacientes con epilepsia secundaria a trastornos del desarrollo cortical. Debe vigilarse estrechamente la posible aparición de los efectos adversos.

El Vigabatrin (VGB) es un medicamento anticonvulsivante cuyo uso en epilepsia se conoce desde hace tres décadas, está indicado en el control de crisis parciales complejas en epilepsias focales refractarias y en espasmos infantiles, especialmente los asociados a Esclerosis tuberosa, pero la descripción de efectos secundarios con la parición de defectos de los campos visuales (DCV) comenzó a limitar su uso en particular en Estados Unidos y otros países; sin embargo, en Europa, especialmente en el Reino Unido y Francia y en Asia principalmente en Japón, asi como en Latinoamérica, se continuó con su formulación, con buenos resultados en cuanto a control de crisis y manejo farmacocinético y se continuó acumulando experiencia en la aparición de efectos adversos especialmente el DCV. En Agosto de 2009, la Food and Drug Administration (FDA) aprueba su uso en Estados Unidos, como terapia adjunta para el tratamiento de crisis parciales complejas en adultos y en espasmos infantiles. La FDA implementa y recomienda métodos y estrategias de evaluación y control por los posibles efectos secundarios. En este artículo se revisan generalidades sobre las propiedades farmacológicas y farmacocinéticas, modo de acción, indicaciones en epilepsia y la relevancia de la limitación de su uso por los efectos colaterales en particular en los trastornos de la visión.

Se presenta una revisión de la literatura acerca de la presencia de alteración del campo visual asociada al uso de vigabatrín como antiepiléptico. Considerando las precauciones de prescripción derivadas de los efectos visuales de vigabatrin, presentamos una revisión no sistemática que muestra los principales datos respecto a prevalencia, factores de riesgo, fisiopatología y seguimiento de esta alteración. La prevalencia de aparición de la retinopatía es variable según las series revisadas, y los factores de riesgo como uso de dosis máxima, dosis acumulada y edad no están claramente demostrados, por lo que se considera a éste un efecto idiosincrático. Se recomienda la vigilancia oftalmológica y campimétrica periódica.

Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the presence of benign tumors in many organs. The pathogenic mutation is found in either the TSC1 or TSC2 tumor suppressor genes. The presence of cortical or subcortical tubers is associated with focal epileptiform discharges on the electroencephalogram and subclinical seizures prior to the onset of clinical seizures. It is known that epileptic seizures in tuberous sclerosis are very resistant to the treatment, therefore, developmental delay usually occurs. In the last decade, more attention has been paid to early recognition and control of seizures (with vigabatrin or everolimus) in tuberous sclerosis complex, as this is highly correlated with improved developmental and neurological outcomes. The article reviews epilepsy and preventive antiepileptic treatment for tuberous sclerosis complex.

Vigabatrin is the medication used for the treatment of infantile spasms and refractory complex partial seizures, but its usage has always been contradictory due to its effect on vision. This review focuses on the registry, mechanism of injury, animal study, pharmacokinetics, risk factors, efficacy, safety and precautions of vigabatrin. The first visual defect with vigabatrin use was detected in 1997. This led to initiation of many trials including compulsory registration of patients in Sabril registry. The site of toxicity is found to be inner retina where vigabatrin tends to inhibit densely gamma amino butyric acid-C (GABA-C) receptors resulting in intoxication of visual field and also genetic variations held responsible for the injury. The toxicological studies of vigabatrin on various animals reveal different physiology, deficiency of taurine and light can effect on visual field and its related cells. Only thing need to be monitored with use of vigabatrin is visual field because it is well absorbed, with zero protein binding and no necessary dosage adjustment. The effect of vigabatrin is seen to vary with age, duration of therapy, cumulative dose and gender. The efficacy differs in various studies for different forms of epilepsy and so does the safety. Precautions are needed to be followed regarding use of vigabatrin by considering the risk versus benefit ratio for each and every individual and also discussing with the patient's caregivers. The ultimate goal in treating with vigabatrin for any form of epilepsy is the good clinical response. [ABSTRACT FROM AUTHOR]

Objective: We aimed to assess the treatment response of infantile‐onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. Methods: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. Results: We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p <.0001). Fourteen‐day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p =.0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p <.0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD. Significance: Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed. [ABSTRACT FROM AUTHOR]

Tuberous sclerosis complex (TSC) is a common genetic cause of epilepsy. Infantile epileptic spasm syndrome (IESS) is often the presenting neurologic feature, progressively evolving into refractory epilepsy. Vigabatrin (VGB) is often used in clinical practice as a first-line therapy in TSC with IESS. This systematic review aims to collect and analyze the efficacy data about VGB in TSC cases with IESS, in order to evaluate the strength of evidence in the literature. A systematic search of trials, observational studies, and case series involving patients with TSC and IESS treated with VGB was performed using MEDLINE, CENTRAL, and the US NIH Clinical Trials Registry. Single case studies, animal and non-English language studies were excluded. Seventeen studies were selected, of which 3 were RCTs and 14 were observational studies. An overall response rate of 67% (231/343 responders) resulted from the analysis, with a spasm-free rate restricted to RCTs of 88% (29/33 subjects). Although all the studies analyzed reported beneficial effects of VGB in TSC patients with IESS, with higher response rates in comparison to non-TSC subjects with IESS, a low level of evidence and high heterogeneity do not guarantee sufficient strength for therapeutic recommendations. [ABSTRACT FROM AUTHOR]

This systematic review and meta‐analysis aimed to evaluate the efficacy of vigabatrin (VGB) in treating infantile epileptic spasms syndrome (IESS). Databases of PubMed, Embase, Web of Science, MEDLINE, and Cochrane Library were systematically searched. All the relevant randomized controlled trials (RCTs) and observational studies (OSs) of VGB for IESS were included and analyzed separately. The primary outcome was the cessation of epileptic spasms (ES). Five RCTs and nine OSs compared the efficacy of VGB vs hormonal monotherapy for IESS. Meta‐analysis of the five RCTs showed that hormonal monotherapy was significantly better than VGB monotherapy (OR = 0.37, 95% CI = 0.20‐0.67) for patients with new‐onset IESS. Meta‐analysis of the nine OSs agrees with the result from RCTs (OR = 0.61, 95% CI = 0.43‐0.85). VGB was more effective in patients with TSC than in those with other etiologies (five OSs, OR = 5.59, 95% CI = 2.17‐14.41). There was no significant difference in the efficiency of VGB combined with hormonal therapy vs hormonal monotherapy for IESS (two RCTs, OR = 0.75, 95% CI = 0.09‐6.45). Hormonal monotherapy is better than VGB monotherapy for non‐TSC‐associated IESS. But for patients with IESS due to TSC, VGB is the first choice. VGB combined with hormone therapy does not definitely increase ES control rates compared with that of hormonal monotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Epileptic spasms are a devastating form of early infantile epileptic encephalopathy (EIEE) with various etiologies. Early diagnosis and a shorter lead time to treatment are crucial to stop the seizures and optimize the neurodevelopmental outcome. Genetic testing has become an integral part of epilepsy care that directly guides management and family planning and discovers new targeted treatments. Neuronal differentiation Factor 2 (NEUROD2) variants have recently been a cause of neurodevelopmental disorders (NDDs) and EIEEs with distinctive features. However, there is limited information about the clinical and electroencephalographic response of epileptic spasm treatment in NEUROD2-related NDD syndrome. Case presentation We report a female patient of Southeast Asian ethnicity with global developmental delay and epileptic spasms commencing in the first few months of life. A novel de novo heterozygous pathogenic NEUROD2 variant, p. E130Q, was subsequently identified by whole-exome sequencing. Electroencephalogram before treatment showed multifocal independent spikes predominantly in both posterior head regions and demonstrated marked improvement following combined vigabatrin and high-dose prednisolone treatment. However, multiple courses of relapse occurred after weaning off the antiseizure medication. Conclusions We propose that epileptic spasms related to de novo NEUROD2 pathogenic variant respond well to combined vigabatrin and high-dose prednisolone therapy. These findings may imply the benefit of using combination therapy to treat epileptic spasms in NEUROD2-related NDD syndrome.

Objective: To compare efficacy and safety of corticosteroids and combined therapy with corticosteroids and vigabatrin in infantile spasm. Study Design: Randomized Controlled Trial. Setting: Department of Neurology, Children’s Hospital and the Institute of Child Health Multan, Pakistan. Period: November 2020 to November 2022. Material & Methods: A total of 320 children of either gender aged 1-24 month with clinical diagnosis of infantile spasm were included. Infants were randomized into either receiving prednisolone (Group-A) or vigabatrin plus prednisolone (Group-B). Demographical information along with treatment outcomes and adverse effects were noted. Final outcomes were labeled at day-180. Results: In a total of 320 children, 170 (53.1%) were male. Overall, the mean age was 1.3±0.5 years while 166 (51.9%) children were aged between 1 to 2 years. A total of 166 (51.9%) children responded to allocated treatment. The response rate was significantly better in Group-B (n=118, 73.8%) versus Group-A (n=48, 30.0%), p<0.0001. Significantly more children in Group-A missed follow-ups in comparison to those in Group-B (11.8% vs. 1.9%, p=0.0006). Mortality was statistically similar in both study groups (2.5% vs. 1.9%, p=0.7023). The most treatment related adverse effect was noted to be increased appetite and/or weight, gastrointestinal symptoms and sleep disturbance in 253 (79.1%), 121 (37.8%) and 117 (36.6%) respectively. Increased appetite and/or weight gain was significantly more in Group-A (p<0.0001). Conclusion: The findings of this study are in support of using combination therapy of prednisolone and vigabatrin instead of monotherapy for patients with infantile spasm as reflected by higher number of responders to therapy. [ABSTRACT FROM AUTHOR]