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In this study, we assessed the toxicity and toxicokinetics of racemic vigabatrin and its S- and R-enantiomers (vigabatrin consists of 50:50% of the two enantiomers) by administering doses of the three test articles to male Long Evans rats via oral gavage. The animals were housed under high-intensity light conditions and the study consisted of an escalating dose phase and a 21-day fixed-dose phase. Systemic toxicity of vigabatrin appears to be due to the Vig-S-enantiomer only, as increasing doses of Vig-S or Vig-RS caused body weight loss, decreased food consumption, and affected activity. Administration of the Vig-R-enantiomer did not cause any such effects. Systemic exposure to R- and S-enantiomers was approximately linear with dose. Compared to administration of the racemate, there appeared to be a tendency for animals to take up higher amounts of Vig-R and lower amounts of Vig-S when administered as enantiomer. Bilateral retinal atrophy was observed in the fixed-dose phase in rats receiving Vig-S (either alone or as part of Vig-RS) and was characterized by irregular thinning and disorganization of the outer nuclear layer and thinning of the photoreceptor layer. The administration of the R-enantiomer alone did not cause any microscopic retinal change. [ABSTRACT FROM AUTHOR]

After initially successful treatment of infantile spasms, the long-term cumulative risk of relapse approaches 50%, and there is no established protocol to mitigate this risk. Although vigabatrin may be an effective means to prevent relapse, there is little guidance as to ideal duration and dosage. Using a cohort of children with infantile spasms and tuberous sclerosis complex (TSC), we evaluated the potential association of post-response VGB treatment and the rate of infantile spasms relapse. Patients with infantile spasms and clinical response to vigabatrin were identified among a multicenter prospective observational cohort of children with TSC. For each patient we recorded dates of infantile spasms onset, response to vigabatrin, relapse (if any), and quantified duration and dosage of vigabatrin after response. Time to relapse as a function of vigabatrin exposure was evaluated using survival analyses. We identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3-22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1-9.6). Relapse occurred after VGB discontinuation in four patients, and during continued VGB treatment in the remaining eight cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01-28.4, P =  0.61), but weighted-average dosage was associated with marked reduction in relapse risk: Each 50 mg/kg/d increment in dosage was associated with 61% reduction in risk (HR 0.39, 95%CI 0.17 - 0.90, P =  0.026). This study suggests that the risk of infantile spasms relapse in TSC may be reduced by high-dose vigabatrin treatment.

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. [ABSTRACT FROM AUTHOR]

Aim: To report response to first treatment in infants with infantile spasms (IS), including incremental benefit of prednisolone 60 mg/day and vigabatrin following prednisolone 40 mg/day failure in infants commenced on the United Kingdom Infantile Spasms Study (UKISS) treatment sequence. Methods: In this retrospective analysis, we compared effectiveness of prednisolone, vigabatrin and nonstandard treatments as first treatment for IS. In infants who commenced the UKISS treatment sequence, we evaluated response to each step. Primary outcome was spasm cessation after 42 days. Secondary outcomes were severe side effects and spasm relapse after 42 days. Results: Treatment response data were available for 151 infants. First treatment was prednisolone in 99 infants, vigabatrin in 18 and nonstandard treatment in 34. The rate of spasm cessation with first treatment was significantly higher with prednisolone (62/99, 63%) than vigabatrin (5/18, 28%, P = 0.01) or nonstandard treatment (2/34, 5.9%, P < 0.01). Of 112 infants who commenced the UKISS treatment sequence, 71/112 (63%) responded to prednisolone 40 mg/day. Among non‐responders, 12/29 (41%) subsequently responded to prednisolone 60 mg/day, and 10/22 (45%) to vigabatrin. Severe side effects and spasm relapse were not significantly different between each treatment. Conclusion: We confirm higher rates of spasm cessation with initial treatment with prednisolone than vigabatrin and nonstandard therapy. Non‐use of prednisolone as first treatment in over one third of infants highlights a concerning treatment gap. The UKISS treatment sequence has high overall treatment response (total 93/112; 83%), with similar benefit of subsequent prednisolone 60 mg/day and vigabatrin in prednisolone 40 mg/day non‐responders. [ABSTRACT FROM AUTHOR]

γ-Aminobutyric acid (GABA) plays an important role in regulating neuronal excitability. Four structurally related drugs to GABA including pregabalin (PGB), gabapentin (GBP), vigabatrin (VGB), and baclofen are used for the treatment of central nervous system disorders. These drugs are small aliphatic molecules having neither fluorescent nor strong absorbance in the ultraviolet/visible region; therefore, direct determination of these analytes by optical methods is difficult. Additionally, their high boiling point makes gas chromatography impossible. Accordingly, the amine or acid moiety in these drugs is derivatized in order to improve their selectivity and sensitivity during determination in the biological samples. This review focuses on derivatization based methods and their different reactions for determination of PGB, GBP, VGB, and baclofen in the biological samples and pharmaceutical preparations reported between 1980 and 2020. High-performance liquid chromatography methods coupled with different detectors are a commonly used methods for determination of GABA analogs after derivatization. These methods cover 38.89% of all developed methods for determination of GABA analogs. [ABSTRACT FROM AUTHOR]

• Outcomes in post-anoxic status epilepticus are dismal despite advances in resuscitation. • Effective therapies targeting hyperexcitability from cardiac arrest are urgently needed. • Early GABA-transaminase inhibition with vigabatrin may be an effective adjunctive therapy for PASE. • Halted GABA catabolism promotes synergistic augmentation of GABAergic pathway. The outcomes of patients who experience status epilepticus during the post-cardiac arrest period, or post-anoxic status epilepticus (PASE), remain dismal despite advances in resuscitation. The combination of therapeutic nihilism and the refractoriness of seizures in a setting where pessimistic prognostic impressions prevail is likely the main driver of such poor outcomes. The resulting pervasive vicious cycle perpetuates this knowledge gap, whereby hypoxic-ischemic insults as the etiology for seizures remain a ubiquitous exclusion criterion for clinal trials in status epilepticus. Effective therapies targeting hyperexcitability resulting from hypoxic-ischemic brain injury are urgently needed. Early inhibition of gamma-aminobutyric acid (GABA) transaminase with vigabatrin holds potential as an effective adjunctive therapy for PASE. This scientific premise is based on the resulting halted GABA catabolism thereby promoting synergistic augmentation of GABAergic pathway when used in combination with positive GABAergic allosteric modulators. This paper is based on a lecture presented at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures, in London 8–10 April 2024. [ABSTRACT FROM AUTHOR]

[Display omitted] • Investigated differences in pharmacological and toxicological effects of Vigabatrin (VGB) and its enantiomers S-VGB and R-VGB. • Analysis of effects on synaptic plasticity and the Wnt/β-catenin/GSK 3β signaling pathway. • S-VGB showed stronger antiepileptic and neuroprotective effects with lower toxicity compared to VGB raceme. • S-VGB and VGB may modulate neuronal damage and synaptic plasticity related to epilepsy through the Wnt/β-catenin/GSK 3β signaling pathway. The study aimed to investigate the potential pharmacological and toxicological differences between Vigabatrin (VGB) and its enantiomers S-VGB and R-VGB. The researchers focused on the toxic effects and antiepileptic activity of these compounds in a rat model. The epileptic rat model was established by intraperitoneal injection of kainic acid, and the antiepileptic activity of VGB, S-VGB, and VGB was observed, focusing on the improvements in seizure latency, seizure frequency and sensory, motor, learning and memory deficits in epileptic rats, as well as the hippocampal expression of key molecular associated with synaptic plasticity and the Wnt/β-catenin/GSK 3β signaling pathway. The acute toxic test was carried out and the LD50 was calculated, and tretinal damages in epileptic rats were also evaluated. The results showed that S-VGB exhibited stronger antiepileptic and neuroprotective effects with lower toxicity compared to VGB raceme. These findings suggest that S-VGB and VGB may modulate neuronal damage, glial cell activation, and synaptic plasticity related to epilepsy through the Wnt/β-catenin/GSK 3β signaling pathway. The study provides valuable insights into the potential differential effects of VGB enantiomers, highlighting the potential of S-VGB as an antiepileptic drug with reduced side effects. S-VGB has the highest antiepileptic effect and lowest toxicity compared to VGB and R-VGB. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is a ubiquitous cellular pathway. mTORopathies, a group of disorders characterized by hyperactivity of the mTORC1 pathway, illustrate the prominent role of the mTOR pathway in disease pathology, often profoundly affecting the central nervous system. One of the most debilitating symptoms of mTORopathies is drug-resistant epilepsy, emphasizing the urgent need for a deeper understanding of disease mechanisms to develop novel anti-epileptic drugs. In this study, we explored the multiwell Multi-electrode array (MEA) system as a tool to identify robust network activity parameters in an approach to model mTORopathy-related epilepsy in vitro. To this extent, we cultured mouse primary hippocampal neurons on the multiwell MEA to identify robust network activity phenotypes in mTORC1-hyperactive neuronal networks. mTOR-hyperactivity was induced either through deletion of Tsc1 or overexpression of a constitutively active RHEB variant identified in patients, RHEBp.P37L. mTORC1 dependency of the phenotypes was assessed using rapamycin, and vigabatrin was applied to treat epilepsy-like phenotypes. We show that hyperactivity of the mTORC1 pathway leads to aberrant network activity. In both the Tsc1 -KO and RHEB-p.P37L models, we identified changes in network synchronicity, rhythmicity, and burst characteristics. The presence of these phenotypes is prevented upon early treatment with the mTORC1-inhibitor rapamycin. Application of rapamycin in mature neuronal cultures could only partially rescue the network activity phenotypes. Additionally, treatment with the anti-epileptic drug vigabatrin reduced network activity and restored burst characteristics. Taken together, we showed that mTORC1-hyperactive neuronal cultures on the multiwell MEA system present reliable network activity phenotypes that can be used as an assay to explore the potency of new drug treatments targeting epilepsy in mTORopathy patients and may give more insights into the pathophysiological mechanisms underlying epilepsy in these patients. • mTORC1 hyperactivity results in marked network activity phenotypes on the MEA. • Early but not late rapamycin treatment can restore mTORC1 hyperactivity phentoypes. • Vigabatrin treatment reduces neuronal network activity and restores reverberations. [ABSTRACT FROM AUTHOR]

Abstract Background Nearly one in three unconscious cardiac arrest survivors experience post-anoxic status epilepticus (PASE). Historically, PASE has been deemed untreatable resulting in its exclusion from status epilepticus clinical trials. However, emerging reports of survivors achieving functional independence following early and aggressive treatment of PASE challenged this widespread therapeutic nihilism. In the absence of proven therapies specific to PASE, standard of care treatment leans on general management strategies for status epilepticus. Vigabatrin—an approved therapy for refractory focal-onset seizures in adults—inhibits the enzyme responsible for GABA catabolism, increases brain GABA levels and may act synergistically with anesthetic agents to abort seizures. Our central hypothesis is that early inhibition of GABA breakdown is possible in the post-cardiac arrest period and may be an effective adjunctive treatment in PASE. Methods This is a phase IIa, single-center, open-label, pilot clinical trial with blinded outcome assessment, of a single dose of vigabatrin in 12 consecutive PASE subjects. Subjects will receive a single loading dose of 4500 mg of vigabatrin (or dose adjusted in moderate and severe renal impairment) via enteric tube within 48 h of PASE onset. Vigabatrin levels will be monitored at 0- (baseline), 0.5-, 1-, 2-, 3-, 6-, 12-, 24-, 48-, 72- and 168-h (7 days) post-vigabatrin. Serum biomarkers of neuronal injury will be measured at 0-, 24-, 48-, 72- and 96-h post-vigabatrin. The primary feasibility endpoint is the proportion of enrolled subjects among identified eligible subjects receiving vigabatrin within 48 h of PASE onset. The primary pharmacokinetic endpoint is the measured vigabatrin level at 3 h post-administration. Descriptive statistics with rates and proportions will be obtained regarding feasibility outcomes, along with the noncompartmental method for pharmacokinetic analyses. The area under the vigabatrin concentration-time curve in plasma from zero to the time of the last quantifiable concentration (AUC0-tlqc) will be calculated to estimate dose-linear pharmacokinetics. Perspective Vigabatrin demonstrates high potential for synergism with current standard of care therapies. Demonstration of the feasibility of vigabatrin administration and preliminary safety in PASE will pave the way for future efficacy and safety trials of this pharmacotherapeutic. Trial Registration NCT04772547.

OBJECTIVE:Epileptic spasms (ES) are associated with pathological neuronal networks, which may underlie characteristic EEG patterns such as hypsarrhythmia. Here we evaluate EEG functional connectivity as a quantitative marker of treatment response, in comparison to classic visual EEG features. METHODS:We retrospectively identified 21 ES patients and 21 healthy controls. EEG data recorded before treatment and after ≥10 days of treatment underwent blinded visual assessment, and functional connectivity was measured using cross-correlation techniques. Short-term treatment response and long-term outcome data were collected. RESULTS:Subjects with ES had stronger, more stable functional networks than controls. After treatment initiation, all responders (defined by cessation of spasms) exhibited decreases in functional connectivity strength, while an increase in connectivity strength occurred only in non-responders. There were six subjects with unusually strong pre-treatment functional connectivity, and all were responders. Visually assessed EEG features were not predictive of treatment response. CONCLUSIONS:Changes in network connectivity and stability correlate to treatment response for ES, and high pre-treatment connectivity may predict favorable short-term treatment response. Quantitative measures outperform visual analysis of the EEG. SIGNIFICANCE:Functional networks may have value as objective markers of treatment response in ES, with potential to facilitate rapid identification of personalized, effective treatments.

Background: West syndrome (WS) is a frequent epileptic encephalopathy associated with Down syndrome (DS). This study evaluated an outpatient protocol for WS in patients with DS who received vigabatrin (VGB) or VGB plus adrenocorticotrophic hormone. Methods: We analyzed infants treated in two neuropediatric centers from 2001–2021. We reviewed perinatal and familial history of epilepsy, spasm onset, treatment lag, electroencephalogram, neuroimaging, progression to epilepsy, and other neurological conditions. The outcomes were electroclinical resolution (ECR), relapses, and epilepsy progression. Results: Nineteen infants were included; 57.8% were male. The average spasm onset, follow-up, and treatment lag were 6.4 months, 8.15 years, and 2.33 months, respectively. Almost 74% had ECR after protocol intervention and minor epilepsy progression. Relapses occurred during combined therapy. Conclusions: The treatment protocol, especially combined therapy, was effective for WS in DS, impacting epilepsy progression and indicating the effectiveness of combined therapy to treat WS in patients with trisomy 21. [ABSTRACT FROM AUTHOR]

In our present work, some novel substituted 4-phenyl-5-vinylpyrrolidin-2-one derivatives were designed, synthesized, and evaluated for their γ-aminobutyric acid-aminotransferase (GABA-AT) inhibition and in-vivo anticonvulsant activity. Among all the synthesized derivatives, compound 7f was observed as the most potent and competitive inhibitor of GABA-AT (IC50 = 46.29 ± 3.19 µM, Ki = 0.106 ± 0.004 μM). The in-vivo anticonvulsant activity against maximum electroshock (MES) and PTZ, induced seizures test of compound 7f, was observed very significantly (P < 0.05) in comparison with standard Vigabatrin and have shown an increase in the level of GABA in the cortex region of the brain. The ex-vivo studies have also suggested reduced tissue necrosis. Finally, In-silico molecular docking and dynamics studies of compound 7f have shown that it forms desired amino acid residue interactions with the GABA-AT and was stable for 50 ns in the active site pocket of the enzyme. [ABSTRACT FROM AUTHOR]

Vigabatrin-associated brain abnormalities on MRI (VABAM) are observed in approximately 20% of children who receive vigabatrin for treatment of infantile epileptic spasms syndrome. Although usually reversible and asymptomatic, VABAM is occasionally symptomatic. Whereas asymptomatic VABAM appears to be dose-dependent, symptomatic VABAM is possibly associated with co-administration of vigabatrin and hormonal therapy (i.e., corticosteroids or adrenocorticotropic hormone). With retrospective study of a cohort of vigabatrin-treated children, we evaluated candidate risk factors for VABAM. Among 108 children with detailed vigabatrin exposure data, we identified VABAM in 17 children (11 symptomatic). Symptomatic VABAM was strongly associated with simultaneous exposure to hormonal therapy (p = 0.001). Neither symptomatic nor asymptomatic VABAM were associated with peak vigabatrin dose. Although these data support the hypothesis that symptomatic VABAM risk is higher with coadministration of vigabatrin and hormonal therapy, this study does not establish a causal link. Further study is warranted to better understand the pathogenesis of VABAM and devise strategies to mitigate risk. Clinicians should carefully weigh the potential risk of symptomatic vigabatrin toxicity against the known benefit of vigabatrin and hormonal therapy coadministration. PLAIN LANGUAGE SUMMARY: Several case reports suggest that the combination of vigabatrin and hormonal therapy for treatment of infantile spasms may provoke an adverse reaction known as symptomatic vigabatrin MRI toxicity (sVABAM, which includes characteristic changes on MRI images and associated symptoms). In response to these reports, we studied a large single-center cohort of children with infantile spasms and determined that combination therapy is indeed statistically associated with sVABAM. However, we have not proven that combination therapy actually causes sVABAM. Further study is needed to clarify the nature of sVABAM and risk factors thereof., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Clobazam (CLB) and Vigabatrin (VGB) are commonly used antiepileptic drugs (AEDs) in the treatment of epilepsy. Here, we have examined the genotoxic effect of these AEDs in Drosophila melanogaster . The Drosophila larvae were exposed to different concentrations of CLB and VGB containing food media. The assessment encompassed oxidative stress, DNA damage, protein levels, and gene expression profiles. In the CLB-treated group, a reduction in reactive oxygen species (ROS) and lipid peroxidation (LPO) levels was observed, alongside increased levels of superoxide dismutase (SOD), catalase (CAT), and nitric oxide (NO). Conversely, the VGB-treated group displayed contrasting results, with increased ROS and LPO and decreased SOD, CAT, and NO levels. However, both CLB and VGB induced DNA damage in Drosophila. Proteomic analysis (SDS-PAGE and OHRLCMS) in the CLB and VGB groups identified numerous proteins, including Acyl-CoA synthetase long-chain, NADH-ubiquinone oxidoreductase 75 kDa subunit, V-type proton ATPase subunit E, ADP/ATP carrier protein, malic enzyme, and DNA-binding protein modulo. These proteins were found to be associated with pathways like growth promotion, notch signaling, Wnt signaling, neuromuscular junction (NMJ) signaling, bone morphogenetic protein (BMP) signaling, and other GABAergic mechanisms. Furthermore, mRNA levels of ACSL, ND75, Vha26, sesB, and Men genes were upregulated in both CLB and VGB-treated groups. These findings suggest that CLB and VGB could have the potential to induce genotoxicity and post-transcriptional modifications in humans, highlighting the importance of monitoring their effects when used as AEDs., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Tuberous sclerosis Complex (TSC) is a genetic disorder characterized by multisystem involvement, with epilepsy affecting 80-90% of patients, often beginning in infancy. Early-life seizures in TSC are associated with poor neurodevelopmental outcomes, underscoring the importance of timely and effective management. This review explores the evolving treatment landscape for TSC-associated seizures in young children, focusing on three recently approved or license-expanded therapies: vigabatrin, everolimus, and cannabidiol. The efficacy and safety profiles of these treatments are examined based on clinical trials and real-world evidence, with a focus on their use in treating seizures in young children. The preemptive use of vigabatrin in clinical studies has also been carefully reviewed. A treatment algorithm is proposed, emphasizing early diagnosis, prompt initiation of appropriate therapy, and a stepwise approach to managing both infantile spasms and focal seizures. The algorithm incorporates these newer therapies alongside traditional antiseizure medications and non-pharmacological approaches. Challenges in optimizing treatment strategies, minimizing side effects, and improving long-term outcomes are discussed. This review aims to guide clinicians in navigating the complex landscape of early-life seizures associated with TSC, ultimately striving for improved seizure control and better developmental outcomes in this vulnerable population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Debopam Samanta collected the data, analyzed and interpreted them, and drafted and revised the manuscript for intellectual content.He declares no potential conflicts of interest with respect to this article's research, authorship, and/or publication.]., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction. Vigabatrin (VGB) is an antiepileptic drug that acts to irreversibly inhibit the γ-aminobutyric acid (GABA) transaminase enzyme, elevating GABA levels. Broad studies have established that long-term treatment and/or high doses of VGB lead to variable visual defects. However, little attention has been paid to its other side effects, especially those demonstrating cerebellar involvement. Sodium glucose-linked co-transporter 2 (SGLT2) inhibitors are antidiabetic agents with protective effects far greater than expected based on their anti-hyperglycemic effect. Method. Our study herein was designed to investigate the possible ameliorative effect of empagliflozin, the SGLT2 inhibitors, in VGB-induced cerebellar toxicity. A total of 40 male Wistar rats were allocated equally into 4 groups: Group I: control group; Group II: VGB group; Group III empagliflozin treated VGB group; and Group IV: empagliflozin treated group. All groups were subjected to the detection of cerebellar messenger RNA gene expression of silent mating type information regulation 2 homolog 1 (SIRT1) and Nucleoporin p62 (P62). Mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and beclin1 levels were assessed by the ELISA technique while malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected spectrophotometrically. Immuno-histochemical studies, focusing on glial fibrillary acidic protein (GFAP) and S100 were performed, and the optical color density and the mean area percentage of GFAP positive astrocytes and the number of S 100 positive cells were also counted. Results. Following empagliflozin treatment, we documented significant upregulation of both SIRT1 and P62 mRNA gene expression. Additionally, AMPK, Beclin1 levels, and SOD activity were significantly improved, while both mTOR and MDA levels were significantly reduced. Conclusions. We concluded for the first time that empagliflozin efficiently ameliorated the VGB-induced disrupted mTOR/AMPK/SIRT-1 signaling axis with subsequent improvement of the autophagy machinery and mitigation of the oxidative and inflammatory cellular environment, paving the way for an innovative therapeutic potential in managing VGB-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Recurrent and profound hypoglycemia is a leading cause of neonatal brain injury. Small-for-gestational-age infants are at risk of hypoglycemia due to substrate deficiency and hyperinsulinism. Inappropriate insulin secretion by the β-cells of the pancreas results in hypoglycemia, neuronal energy deprivation, and parieto-occipital brain injury. Hypoglycemic neuronal injury is increasingly being identified as a trigger for infantile spasms, even though the underlying pathophysiological mechanisms remain elusive. A term, small-for-gestational-age male infant developed severe symptomatic hypoglycemia on day 3 of life. He required a high glucose infusion rate (14 mg/kg/min) to maintain normoglycemia. Critical blood samples showed inappropriate insulin levels while hypoglycemic and hypoketonemic, consistent with a diagnosis of hyperinsulinemic hypoglycemia. Blood glucose levels normalized with a diazoxide dose of 5 mg/kg/day. Gradually, glucose infusion was weaned with increasing oral feeds while maintaining prefeed capillary blood glucose levels. While at home, his glucose profile remained stable on the self-weaning dose of diazoxide. He passed a resolution fasting study at 4 months of age after weaning off diazoxide. He developed left gaze preference at 2.5 months of age while on treatment for hyperinsulinemic hypoglycemia but developed infantile spasms at 5 months that was confirmed with an electroencephalogram (EEG). Gaze preference may be epileptic, even in the absence of seizures. Spasms were well controlled with high-dose prednisolone therapy. At the age of 6 years, he has a mild fine motor delay and learning disabilities. Early diagnosis and treatment of infantile spasms have a better prognosis. Identifying gaze preference as a predating sign of occipital lobe epilepsy, EEG monitoring, and, if required, treatment could have possibly averted the genesis of infantile spasms. [ABSTRACT FROM AUTHOR]

ObjectiveAlthough the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible-and largely asymptomatic-signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena.MethodsChildren with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure.ResultsWe identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the limited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumulative) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039).SignificanceWe have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy.

Tuberous sclerosis com plex (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 dis charges on the electroencephalogram and subclinical seizures prior to the on set of clinical seizures. It is known that epileptic seizures in tuberous sclerosis are very resistant to the treatment, there fore, develop mental de - lay usually occurs. In the last de cade, more attention has been paid to early recognition and control of seizures (with vigabatrin or everolimus) in tuberous sclerosis com plex, as this is highly correlated with improved developmental and neurological out - comes. The article re views epilepsy and preventive antiepileptic treatment for tuberous sclerosis complex [ABSTRACT FROM AUTHOR]

We evaluated the efficacy and safety of vigabatrin in focal epilepsy associated with tuberous sclerosis complex by retrospectively reviewing patients with focal epilepsy and tuberous sclerosis complex treated with vigabatrin at a pediatric epilepsy center over an 8-year period. Of 85 patients, 20 (23.5%) were seizure-free for >12 months, 45 (52.9%) were responders (≥50% seizure reduction), and 20 (23.5%) were nonresponders. The median age (in months) at seizure onset in the seizure-free group (median, 15; interquartile range [IQR], 6-23.3) was higher than that of responders (median, 5; IQR, 3-14) and nonresponders (median, 6; IQR, 2-12). Fewer patients in the seizure-free group had calcification in their largest tubers, but the presence of tuber calcification did not differ among groups. Vigabatrin is more likely to result in seizure freedom in children with tuberous sclerosis complex who have later infantile onset of focal seizures and no calcification in their largest tuber. [ABSTRACT FROM AUTHOR]

Abstract Background Vigabatrin (VGB) is an approved non-traditional antiepileptic drug that has been revealed to have potential for treating brain tumors; however, its effect on ionic channels in glioma cells remains largely unclear. Methods With the aid of patch-clamp technology, we investigated the effects of VGB on various ionic currents in the glioblastoma multiforme cell line 13–06-MG. Results In cell-attached configuration, VGB concentration-dependently reduced the activity of intermediate-conductance Ca2+-activated K+ (IKCa) channels, while DCEBIO (5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one) counteracted the VGB-induced inhibition of IKCa channels. However, the activity of neither large-conductance Ca2+-activated (BKCa) nor inwardly rectifying K+ (KIR) channels were affected by the presence of VGB in human 13–06-MG cells. However, in the continued presence of VGB, the addition of GAL-021 or BaCl2 effectively suppressed BKCa and KIR channels. Conclusions The inhibitory effect of VGB on IKCa channels demonstrated in the current study could be an important underlying mechanism of VGB-induced antineoplastic (e.g., anti-glioma) actions.

Many studies have focussed on modulating the activity of γ-aminobutyric acid transaminase (GABA-T), a GABA-catabolizing enzyme, for treating neurological diseases, such as epilepsy and drug addiction. Nevertheless, human GABA-T synthesis and purification have not been established. Thus, biochemical and drug design studies on GABA-T have been performed by using porcine GABA-T mostly and even bacterial GABA-T. Here we report an optimised protocol for overexpression of 6xHis-tagged human GABA-T in human cells followed by a two-step protein purification. Then, we established an optimised human GABA-T (0.5 U/mg) activity assay. Finally, we compared the difference between human and bacterial GABA-T in sensitivity to two irreversible GABA-T inhibitors, gabaculine and vigabatrin. Human GABA-T in homodimeric form showed 70-fold higher sensitivity to vigabatrin than bacterial GABA-T in multimeric form, indicating the importance of using human GABA-T. In summary, our newly developed protocol can be an important first step in developing more effective human GABA-T modulators.

ObjectiveInfantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first-line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome.MethodsThe National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ACTH] or oral corticosteroids), vigabatrin, or "other." Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi-square tests and multivariable logistic regression models.ResultsOne hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040).SignificanceGreater than one third of children with IS will respond to a second medication. Choosing a standard medication (ACTH, oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.

Background: Nearly one in three unconscious cardiac arrest survivors experience post-anoxic status epilepticus (PASE). Historically, PASE has been deemed untreatable resulting in its exclusion from status epilepticus clinical trials. However, emerging reports of survivors achieving functional independence following early and aggressive treatment of PASE challenged this widespread therapeutic nihilism. In the absence of proven therapies specifc to PASE, standard of care treatment leans on general management strategies for status epilepticus. Vigabatrin--an approved therapy for refractory focal-onset seizures in adults--inhibits the enzyme responsible for GABA catabolism, increases brain GABA levels and may act synergistically with anesthetic agents to abort seizures. Our central hypothesis is that early inhibi- tion of GABA breakdown is possible in the post-cardiac arrest period and may be an efective adjunctive treatment in PASE. Methods: This is a phase IIa, single-center, open-label, pilot clinical trial with blinded outcome assessment, of a single dose of vigabatrin in 12 consecutive PASE subjects. Subjects will receive a single loading dose of 4500 mg of vigaba- trin (or dose adjusted in moderate and severe renal impairment) via enteric tube within 48 h of PASE onset. Vigabatrin levels will be monitored at 0- (baseline), 0.5-, 1-, 2-, 3-, 6-, 12-, 24-, 48-, 72- and 168-h (7 days) post-vigabatrin. Serum biomarkers of neuronal injury will be measured at 0-, 24-, 48-, 72- and 96-h post-vigabatrin. The primary feasibility endpoint is the proportion of enrolled subjects among identifed eligible subjects receiving vigabatrin within 48 h of PASE onset. The primary pharmacokinetic endpoint is the measured vigabatrin level at 3 h post-administration. Descriptive statistics with rates and proportions will be obtained regarding feasibility outcomes, along with the noncompartmental method for pharmacokinetic analyses. The area under the vigabatrin concentration-time curve in plasma from zero to the time of the last quantifable concentration (AUC0-tlqc) will be calculated to estimate dose-linear pharmacokinetics. Perspective: Vigabatrin demonstrates high potential for synergism with current standard of care therapies. Demonstration of the feasibility of vigabatrin administration and preliminary safety in PASE will pave the way for future efcacy and safety trials of this pharmacotherapeutic. Trial Registration NCT04772547. [ABSTRACT FROM AUTHOR]

OBJECTIVE Early treatment of infantile spasms (IS) may be imperative for improvement of neurodevelopmental outcomes. Existing studies have led to inconclusive recommendations with variation in treatment. Our objective was to determine the national average cost, initial diagnostic workup, treatments, and hospital length of stay for patients with IS. METHODS This retrospective cohort study was designed to review data of patients < 2 years from 43 non-profit institutions. Data obtained included patient demographics, length of stay, admission cost, and treatments used from 2004 to 2014. Cost data were collected and adjusted to 2014 dollars, the year data were analyzed. RESULTS A total of 6183 patients met study criteria (n = 3382, 55% male). Three-quarters of patients (n = 4684, 76%) had an electroencephalogram, 56.4% had brain imaging (n = 3487), and 17% (n = 1050) underwent a lumbar puncture. Medication for IS was initiated during inpatient hospital stay in two-thirds of all patients (n = 4139, 67%). Most patients were initiated on corticotropin (n = 2066, 33%) or topiramate (n = 1804, 29%). Average length of stay was 5.8 days with an average adjusted cost of $18,348. Over time there was an 86.6% increase in cost from an average $12,534.54 (2004) to $23,391.20 (2014), a significant change (p < 0.01). This correlated with an increase in average length of stay. CONCLUSIONS Variability exists in diagnostic workup and pharmacotherapy initiated for IS, which may lead to differences in the cost of hospital stay. Further studies may help determine contributing factors to increased cost and improve health care utilization for IS patients. [ABSTRACT FROM AUTHOR]

Summary: Objective: Vigabatrin (VGB) is the first‐line treatment for infantile spasms (IS). Previous studies have shown that VGB exposure may cause vigabatrin‐associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM). Based on previous studies, this study aimed to go further to explore the possible risk factors and the incidence of VABAM. In addition, diffusion‐weighted imaging (DWI) and T2‐weighted imaging (T2WI) were compared to explore whether DWI should be used as a routine examination sequence when MRI is performed in children receiving VGB. Methods: Children with IS receiving VGB were selected as the study subjects. Whether VABAM occurred or not was categorized as the VABAM group and the non‐VABAM group, respectively. Their general clinical data and medication exposure were collected. The possible risk factors of VABAM and different MRI sequences were compared and statistically analyzed. Results: A total of 77 children with IS were enrolled in the study, of which 25 (32.5%) developed VABAM. Twenty‐three of the 25 VABAM cases have a peak dosage of VGB between 50 and 150 mg/kg/day. The earliest observation time of VABAM was 30 days. Regression analysis of relevant risk factors showed that the peak dosage of VGB was the risk factor for VABAM. Comparison between different MRI sequences showed that DWI is more sensitive than T2WI to the evaluation of VABAM. Significance: In our study, the occurrence of VABAM was 32.5%, indicating a higher incidence than in most previous reports. In addition, we once again verified that the peak dosage of VGB was the risk factor of VABAM. Caution should be exercised that our data also suggest that VABAM may occur even using the conventional dosage of VGB (ie, 50–150 mg/kg/day). Therefore, even when using the conventional dosage of VGB, regular MRI examination should be required. Furthermore, DWI sequence should be used as a routine examination sequence when MRI is performed in children with IS who are receiving VGB. [ABSTRACT FROM AUTHOR]

Many studies have focussed on modulating the activity of γ-aminobutyric acid transaminase (GABA-T), a GABA-catabolizing enzyme, for treating neurological diseases, such as epilepsy and drug addiction. Nevertheless, human GABA-T synthesis and purification have not been established. Thus, biochemical and drug design studies on GABA-T have been performed by using porcine GABA-T mostly and even bacterial GABA-T. Here we report an optimised protocol for overexpression of 6xHis-tagged human GABA-T in human cells followed by a two-step protein purification. Then, we established an optimised human GABA-T (0.5 U/mg) activity assay. Finally, we compared the difference between human and bacterial GABA-T in sensitivity to two irreversible GABA-T inhibitors, gabaculine and vigabatrin. Human GABA-T in homodimeric form showed 70-fold higher sensitivity to vigabatrin than bacterial GABA-T in multimeric form, indicating the importance of using human GABA-T. In summary, our newly developed protocol can be an important first step in developing more effective human GABA-T modulators. [ABSTRACT FROM AUTHOR]

Summary: Objective: An attractive target to interfere with epileptic brain hyperexcitability is the enhancement of γ‐aminobutyric acidergic (GABAergic) inhibition by inactivation of the GABA‐metabolizing enzyme GABA aminotransferase (GABA‐AT). GABA‐AT inactivators were designed to control seizures by raising brain GABA levels. OV329, a novel drug candidate for the treatment of epilepsy and addiction, has been shown in vitro to be substantially more potent as a GABA‐AT inactivator than vigabatrin, an antiseizure drug approved as an add‐on therapy for adult patients with refractory complex partial seizures and monotherapy for pediatric patients with infantile spasms. Thus, we hypothesized that OV329 should produce pronounced anticonvulsant effects in two different rat seizure models. Methods: We therefore examined the effects of OV329 (5, 20, and 40 mg/kg ip) on the seizure threshold of female Wistar Unilever rats, using the timed intravenous pentylenetetrazole (ivPTZ) seizure threshold model as a seizure test particularly sensitive to GABA‐potentiating manipulations, and amygdala‐kindled rats as a model of difficult‐to‐treat temporal lobe epilepsy. Results: GABA‐AT inactivation by OV329 clearly increased the threshold of both ivPTZ‐induced and amygdala‐kindled seizures. OV329 further showed a 30‐fold greater anticonvulsant potency on ivPTZ‐induced myoclonic jerks and clonic seizures compared to vigabatrin investigated previously. Notably, all rats were responsive to OV329 in both seizure models. Significance: These results reveal an anticonvulsant profile of OV329 that appears to be superior in both potency and efficacy to vigabatrin and highlight OV329 as a highly promising candidate for the treatment of seizures and pharmacoresistant epilepsies. [ABSTRACT FROM AUTHOR]

Abstract Epilepsy can occur in individuals with Down syndrome (DS), with epileptic spasms representing the most frequent seizure type in this population. Epileptic spasms can have devastating consequences on the development of individuals with the condition. This review sought to explore the lifetime prevalence and underlying mechanism of epileptic spasms in this population. We also aimed to review the response rate to various treatments, the relapse rate, and the development of subsequent epilepsy or autism in this population. A comprehensive literature search was conducted for articles discussing the lifetime prevalence, diagnosis, treatment, outcomes, or underlying etiology of epileptic spasms in animal models or individuals with DS. According to available literature, the global clinic‐based lifetime prevalence of epilepsy in individuals with DS ranged from 1.6% to 23.1%, with epileptic spasms representing 6.7%‐66.7% of these cases. Response rate to treatment with adrenocorticotropic hormone/corticosteroids was highest (81%) and has the most literature supporting its use, with other regimens, including vigabatrin and other antiepileptic drugs, having lower response rates. Epileptic spasms occur more frequently in children with DS than in the general population, though more studies are needed to determine the true lifetime prevalence of epileptic spasms in this population. Generally, children with DS and epileptic spasms tend to be more responsive to treatment and have better outcomes than children with epileptic spasms of unknown etiology (ie, without DS), in terms of response and relapse rates as well as the development of intractable epilepsy (eg, Lennox‐Gastaut syndrome).

Purpose Vigabatrin has proven efficacy in the treatment of infantile spasms, but it carries the risk of irreversible visual field constriction. The incidence of vigabatrin-induced visual field constriction seems to depend on the extent of vigabatrin exposure. The aim of this study was to evaluate whether the therapeutic effect of vigabatrin is maintained in patients with infantile spasms receiving a short vigabatrin course followed by switching to another antiepileptic drug. Methods Patients with infantile spasms responsive to initial vigabatrin treatment were divided into a vigabatrin switch group (n=25) and a vigabatrin maintenance group (n=41). In the former group, vigabatrin was switched to other drugs within 6 months of spasm remission. The rate of seizure recurrence at 6 and 12 months from spasm remission was compared between the two groups. Results No statistically significant differences were found between the vigabatrin switch and maintenance groups in the age of onset, presence of concomitant seizures, time from spasm onset to vigabatrin treatment, time from vigabatrin treatment initiation to spasm remission, or vigabatrin dose at spasm remission. The number of patients with seizure recurrence at 12 months after spasm remission was 3 (3/25, 12%) in the vigabatrin switch group and 10 (10/41, 24.4%) in the vigabatrin maintenance group. The seizure recurrence rate at 12 months from spasm remission was not significantly different between groups. Conclusion A short course of vigabatrin could be considered in patients with infantile spasms who are responsive to initial vigabatrin treatment, since spasm remission was maintained after switching to other drugs.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of gamma-aminobutyric acid metabolism. Children with SSADH deficiency usually manifest with developmental delay, behavioral symptoms, language dysfunction, seizures, hypotonia, extrapyramidal symptoms, and ataxia. Diagnosis of SSADH deficiency is established by an abnormal urine organic acid pattern, including increased excretion of 4-hydroxybutyric acid and the identification of biallelic pathogenic variants in aldehyde dehydrogenase 5 family, member A 1 (ALDH5A1) gene. Here, we describe a 15-month-old girl with SSADH deficiency presenting with developmental delay, language deficits, and acute-onset right hemiparesis, following recovery from a diarrheal illness. Brain magnetic resonance imaging revealed hyperintense signal changes involving the left globus pallidus in T2-weighted images with restriction of diffusion in the diffusion-weighted images. Increased excretion of 4-hydroxybutyric acid, threo-4,5-dihydroxyhexanoic acid lactone and erythro-4,5-dihydroxyhexanoic acid lactone was detected by urine organic acid analysis and a diagnosis of SSADH deficiency was confirmed by the identification of homozygous pathogenic variant in ALDH5A1. Stroke mimic is a novel presentation in our patient with SSADH deficiency. She was initiated on treatment with vigabatrin and has shown developmental gains with the recovery of right hemiparesis. Follow-up neuroimaging shows near complete resolution of signal changes in the left globus pallidus, while there was subtle hyperintensity in the right globus pallidus. The phenotypic spectrum of SSADH deficiency is widely expanding, and this disorder should be considered in the differential diagnosis of children with metabolic stroke.