Approach to Preventive Epilepsy Treatment in Tuberous Sclerosis Complex and Current Clinical Practice in 23 Countries.

Tuberous sclerosis complex (TSC) is associated with a high risk of early-onset epilepsy and developmental delay. Recently, EEG monitoring in infants with TSC and preventive antiepileptogenic treatment have been proposed to improve epilepsy and neurodevelopmental outcome. We explored how recent studies and recommendations regarding EEG monitoring and preventive epilepsy treatment have influenced the clinical practice of epilepsy management among children with TSC. METHODS: A survey on the epilepsy management approach in infants with TSC was sent by e-mail to 165 clinicians who actively participated in TSC international research conferences in years 2016 - 2019. Additionally, the e-mail addresses of TSC referral centers were collected from national TSC organizations. The survey was also distributed in the American Epilepsy Society newsletter. Only responses from centers providing neurological care for children with TSC were included in the study. RESULTS: Sixty-one responses from 23 countries were analyzed. Sixty respondents answered questions concerning infants, and 57 of 60 respondents (95%) perform at least one EEG study before epilepsy onset and 42 (70.0%) conduct regular EEG monitoring. Most of the clinicians perform video EEG (42/61, 68.8%). Overall, 51.7% of respondents, mostly from Europe, Australia, and South America, endorse preventive antiepileptic treatment in infants with TSC. Vigabatrin is a preferred drug in patients younger than two years old for both focal (61.7%) and generalized (56.7%) seizures. CONCLUSIONS: Despite the lack of published results of randomized trials, the concepts of preseizure EEG monitoring and epilepsy prevention are already being implemented in the majority of surveyed centers.

Fulminant vigabatrin toxicity during combination therapy with adrenocorticotropic hormone for infantile spasms: Three cases and review of the literature.

Vigabatrin (VGB), adrenocorticotropic hormone (ACTH), and prednisone are first-line treatments for infantile spasms (IS). A recent study reported benefits from the use of combination VGB and hormonal therapy over hormonal treatment alone in IS. We describe three patients with IS who developed acute encephalopathy with extrapyramidal symptoms, vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), and death in one patient shortly after initiation of therapy with VGB and ACTH. A literature review supports increased risk of fulminant, symptomatic VABAM in patients receiving VGB in association with hormonal therapy, raising concerns regarding its safety in IS.

Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?

OBJECTIVE: To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80-150 mg/kg/day). METHODS: Infants with TSC, aged ≤4 months and without previous seizures were enrolled in a prospective study and closely followed with monthly video EEG and serial standardized neurodevelopmental testing (Bayley Scales of Infant Development and Autism Diagnostic Observation Schedule). RESULTS: Eighty infants were enrolled. At the age of 24 months testing identified risk of Autism Spectrum Disorder (ASD) in 24/80 children (30.0%), and developmental delay (DD) in 26/80 (32.5%). Children with epilepsy (51/80; 63.8%) had a higher risk of ASD (P = 0.02) and DD (P = 0.001). Overall, no child presented with moderate or severe DD at 24 months (developmental quotient < 55). In 20% of children abnormal developmental trajectories were detected before the onset of seizures. Furthermore, 21% of all children with risk of ASD at 24 months had not developed seizures at that timepoint. There was no significant difference between early and conventional treatment with respect to rate of risk of ASD (P = 0.8) or DD (P = 0.9) at 24 months. INTERPRETATION: This study confirms a relationship between epilepsy and risk of ASD/DD. However, in this combined randomized/open label study, early treatment with vigabatrin did not alter the risk of ASD or DD at age 2 years.

Are Epileptic Spasms a Seizure Type for the Insular Region?

Two patients with insular and striatal postnatal scar had epileptic spasms (ES) that were asymmetrical and the only seizure type, whereas none of the usual ictal symptoms of insular seizures occurred. Ictal electroencephalography (EEG) showed the high-amplitude slow-wave characteristic of ES. Vigabatrin remained efficient for over 4 years for one patient and right into the third decade for the other one. Such ES are distinct from infantile and late onset spasms. Furthermore, these observations suggest that in ES insular epilepsy triggers paroxysmal activation of the striatum, and that vigabatrin inhibits the striatal startle motor program, thus interrupting the corticostriatal loop.

Long-term vigabatrin treatment modifies pentylenetetrazole-induced seizures in mice: focused on GABA brain concentration.

BACKGROUND: The goal of our study was to examine the long-term effect of vigabatrin (VGB), a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor on clonazepam (CLO), ethosuximide (ETX) and valproate (VPA) anticonvulsive activity against pentylenetetrazole (PTZ)-induced seizures in mice. METHODS: VGB was administered for 3 and 7 days. Convulsions were evoked by PTZ at its CD97 (99 mg/kg). The influence of CLO, ETX and VPA alone or in combination with VGB on motor performance and long-term memory was analyzed. γ-aminobutyric acid (GABA) concentration in mice brain and plasma as well as glutamate decarboxylase (GAD) activity was measured. RESULTS: After 3 days of treatment, VGB in doses up to 500 mg/kg increased PTZ-induced seizure threshold, whereas after 7 days VGB (at the dose of 125 mg/kg) inhibited clonic seizures in experimental mice. 7 days of VGB administration did not change the protective effect of CLO, ETX and VPA against PTZ-induced seizures. 7 days of VGB treatment at a subthreshold dose of 75 mg/kg decreased TD50 of ETX and CLO in the chimney test, but did not affect TD50 value for VPA. 7 days of VGB administration in combination with AEDs did not affect long-term memory in mice. VGB after 3 days or 7 days of administration increased brain GABA concentration. GAD activity was decreased after 3 and 7 days of VGB administration. CONCLUSIONS: The presented results confirm anticonvulsive activity of VGB through GABA metabolism alteration and suggest care when combining VGB with ETX or CLO in the therapy.

Compliance With Standard Therapies and Remission Rates After Implementation of an Infantile Spasms Management Guideline.

BACKGROUND: We implemented an infantile spasms management guideline recommending standard therapies and, early start of next treatment. After six years, we determined (1) our compliance with standard therapies, (2) time to next treatment, and (3) rate of initial and three-month electroclinical remission with first, second, and third treatments. METHODS: This is a retrospective record review of newly diagnosed spasms from September 2012 to September 2018, with the onset age of two months to two years. RESULTS: Standard therapies (hormone or vigabatrin) were the first treatments in 114 of 115 consecutive patients. The second and third treatments were started within 14 days of failed treatment in only 21% and 24%, respectively. Remission with the first and second treatments was similar (41% and 40%). Remission was lower for the third treatment (15%), although higher if standard therapy was used (36%). Initial and three-month remission by the first treatment was significantly higher for adrenocorticotropic hormone (ACTH, 66% and 79%, respectively) and prednisolone (53% and 83%, respectively) than for vigabatrin (19% and 40%, respectively). There were no significant differences in patient characteristics or rates of remission between ACTH and prednisolone. CONCLUSIONS: Although we achieved excellent compliance with standard therapies as initial treatment, a next treatment often started after two weeks. Given the superiority of hormone therapies over vigabatrin and standard therapies over nonstandard therapies, as well as the potentially negative impact of delays in effective treatment, future interventions need to focus on increasing the use of hormone over vigabatrin (for patients without tuberous sclerosis complex), use of standard therapies as second and third treatments, and reducing delays to next treatment.

The Topographical Relationship between Visual Field Loss and Peripapillary Retinal Nerve Fibre Layer Thinning Arising from Long-Term Exposure to Vigabatrin.

BACKGROUND: The antiepileptic drug vigabatrin is associated with characteristic visual field loss (VAVFL) and thinning of the peripapillary retinal nerve fibre layer (PPRNFL); however, the relationship is equivocal. OBJECTIVE: The aim of this study was to determine the function-structure relationship associated with long-term exposure to vigabatrin, thereby improving the risk/benefit analysis of the drug. METHODS: A cross-sectional observational design identified 40 adults who had received long-term vigabatrin for refractory seizures, who had no evidence of co-existing retino-geniculo-cortical visual pathway abnormality, and who had undergone a standardized protocol of perimetry and of optical coherence tomography (OCT) of the PPRNFL. Vigabatrin toxicity was defined as the presence of VAVFL. The function-structure relationship for the superior and inferior retinal quadrants was evaluated by two established models applicable to other optic neuropathies. RESULTS: The function-structure relationship for each model was consistent with an optic neuropathy. PPRNFL thinning, expressed in micrometres, asymptoted at an equivalent visual field loss of worse than approximately - 10.0 dB, thereby preventing assessment of more substantial thinning. Transformation of the outcomes to retinal ganglion cell soma and axon estimates, respectively, resulted in a linear relationship. CONCLUSIONS: Functional and structural abnormality is strongly related in individuals with vigabatrin toxicity and no evidence of visual pathway comorbidity, thereby implicating retinal ganglion cell dysfunction. OCT affords a limited measurement range compared with perimetry: severity cannot be directly assessed when the PPRNFL quadrant thickness is less than approximately 65 µm, depending on the tomographer. This limitation can be overcome by transformation of thickness to remaining axons, an outcome requiring input from perimetry.

Proposition of a Minimal Effective Dose of Vigabatrin for the Treatment of Infantile Spasms Using Pediatric and Adult Pharmacokinetic Data.

Vigabatrin is an antiepileptic drug indicated as monotherapy in infantile spasms. However, the pharmacokinetic profile of this compound in infants and young children is still poorly understood, as is the minimal effective dose, critical information given the risk of exposure-related retinal toxicity with vigabatrin. A reasonable approach to determining this minimal dose would be to identify the lowest dose providing a low risk of exposure overlap with the 36-mg/kg dose, which is the highest dose associated with an increased risk for treatment failure, based on randomized dose-ranging data. A population pharmacokinetic model was consequently developed from 28 children (aged 0.4-5.7 years) for the active S(+)-enantiomer, using Monolix software. In parallel, a population model was developed from published adult data and scaled to children using theoretical allometry and maturation of the renal function. A one-compartment model with zero-order absorption and first-order elimination described the pediatric data. Mean population estimates (percentage interindividual variability) for the apparent clearance, apparent distribution volume, and absorption duration were 2.36 L/h (24.5%), 17 L (38%), and 0.682 hours, respectively. Apparent clearance and apparent distribution volume were related to body weight by empirical allometric equations. Monte Carlo simulations evidenced that a daily dose of 80 mg/kg should minimize exposure overlap with the 36-mg/kg dose. Similar results were obtained for the adult model scaled to children. Consequently, a minimal effective dose of 80 mg/kg/day could be considered for patients with infantile spasms.

Vigabatrin with hormonal treatment versus hormonal treatment alone (ICISS) for infantile spasms: 18-month outcomes of an open-label, randomised controlled trial.

BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age. METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27. FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], p<0·001) and with higher likelihood of absence of seizures at 18 months (in 39 [17·0%] of 229 infants who achieved spasm cessation vs 67 [51·9%] of 129 who did not; difference 34·9% [24·8 to 45·0], p<0·001). Increasing lead-time to treatment was associated with lower VABS scores (analysis of variance: F[4,354]=6·38, p<0·001) and worse epilepsy outcomes (p=0·023). INTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes. FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.

Síndrome de West criptogénico: perfil clínico, respuesta al tratamiento y factores pronósticos / Cryptogenic West syndrome: Clinical profile, response to treatment and prognostic factors

INTRODUCCIÓN: El síndrome de West (SW) es una encefalopatía epiléptica dependiente de la edad con pronóstico variable según la etiología subyacente, no siempre identificada. OBJETIVOS: Definir el perfil del SW criptogénico en nuestro medio, subgrupo menos estudiado de forma aislada. Estudiar su evolución, respuesta a los distintos tratamientos y establecer factores pronósticos. PACIENTES Y MÉTODOS: Revisión de historias clínicas de 16 pacientes diagnosticados de SW criptogénico durante el período 2000-2015. El tiempo de seguimiento medio fue 6,6 años y mínimo de 2 años. RESULTADOS: 11 de 16 fueron varones, la edad media de inicio fue de 6 meses y 6/16 presentaban antecedente familiar de epilepsia idiopática. El tratamiento de primera línea con vigabatrina tuvo respuesta electroclínica en 5/16 pacientes, respondiendo los casos restantes a hormona adrenocorticotropa (ACTH). El 44% de los pacientes evolucionaron a otras epilepsias, sin diferencia entre los tratados con vigabatrina o ACTH. Se obtuvo un mayor número de efectos adversos con la ACTH, no se evidenció afectación retiniana con la vigabatrina. Durante el seguimiento se llegó a la causa etiológica en 2/16. El sexo femenino, el comienzo tardío y el control precoz de la hipsarritmia resultaron factores de buen pronóstico. CONCLUSIONES: El pronóstico global del SW criptogénico resultó más grave de los esperado. Aunque la incidencia de síndrome de Lennox-Gastaut fue baja, la epilepsia focal resultó la evolución más frecuente apareciendo en los 2 primeros años del diagnóstico. La respuesta inicial a vigabatrina fue menor a la esperada, pero el resultado a largo plazo resultó superponible a la ACTH

INTRODUCTION: West syndrome (WS) is an age-dependent epileptic encephalopathy in which the prognosis varies according to the, not always identified, underlying origin. OBJECTIVES: To define the profile of cryptogenic (a least studied isolated sub-group) WS, in Spain. To study its outcome, response to different treatments, and to establish prognostic factors. PATIENTS AND METHODS: The study included a review of the medical records of 16 patients diagnosed with cryptogenic WS during the period, 2000-2015. The mean follow-up time was 6.6 years, with a minimum of 2 years. RESULTS: The large majority (11/16) were male. The mean age at onset was 6 months, and 6/16 had a family history of idiopathic epilepsy. The first line treatment with vigabatrin had an electrical-clinical response in 5/16 patients, with the remaining cases responding to adrenocorticotropic hormone (ACTH). Almost half (44%) of the patients progressed to other types of epilepsy, with no difference between those treated with vigabatrin or ACTH. A greater number of adverse effects were obtained with ACTH, with no retinal involvement being observed with vigabatrin. The aetiological cause was found in 2/16. Being female, late onset, and early control of the hypsarrhythmia, were factors of a good prognosis. CONCLUSIONS: The overall prognosis of cryptogenic WS was more serious than expected. Although the incidence of Lennox-Gastaut syndrome was low, the progression to focal epilepsy was the most common, with it appearing within the first 2 years of the diagnosis. The initial response to vigabatrin was lower than expected, but the long-term result was comparable to ACTH

Infantile Spasms-Have We Made Progress?

PURPOSE OF THE REVIEW: The care of children with infantile spasms is full of areas of ambiguity, despite practice parameters and randomized trials. This review is to update the current care of children with infantile spasms. RECENT FINDINGS: Several recent studies have generated new data to guide management including a randomized trial supporting combination therapy of hormone treatment and vigabatrin as an initial treatment for infantile spasms. Studies have suggested that we are not consistent in our recognition of hypsarrhythmia, while additional studies suggest that the presence or absence of this pattern may not have any predictive value. Additionally, the use of appropriate medications as well as an early diagnosis has the most impact on short-term outcomes. Children with infantile spasms benefit most from early diagnosis and early treatment with appropriate standard medications such as hormonal therapy (ACTH or prednisolone) or vigabatrin.

The Vigabatrin Induced Retinal Toxicity is Associated with Photopic Exposure and Taurine Deficiency: An In Vivo Study.

BACKGROUND/AIMS: Retinal toxicity is one of the most commonly discussed and concerning adverse effects of vigabatrin (VGB). The present study explored the relationship between the VGB elicited retinal toxicity, photopic exposure, and taurine deficiency, aiming at screening for risk factors to minimize the adverse effects of VGB. METHODS: The effects of VGB on function and morphology of mouse retinas were examined via a series of in vivo tests, including electroretinography (ERG), Spectral domain optical coherence tomography (SD-OCT), and optokinetic testing. Moreover, VGB-treated mice were in addition treated with taurine to verify possible protective effects against retinal toxicity. RESULTS: A close relationship between VGB induced retinal toxicity and light exposure was observed. The VGB-treated mice which were reared in darkness preserved better visual function and retinal architectures as verified by the optokinetic tests, OCT and ERG examinations. The retinal taurine level of the VBG-treated mice which were exposed to light were significantly lower than that of the VBG mice reared in darkness. Furthermore, several in vivo evidence provided by our research confirmed that the VGB induced morphological and functional impairments could be partially alleviated by taurine treatment. The present study showed the retinal toxicity of VGB by in vivo measurements. CONCLUSION: The VGB induced retinal toxicity is closely associated with photopic exposure and taurine deficiency. Patients who are taking VGB might benefit from minimization of light exposure and dietetic taurine supplements.

Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade.

Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease.

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

Stiripentol and vigabatrin current roles in the treatment of epilepsy.

INTRODUCTION: Stiripentol and vigabatrin are the two anticonvulsant drugs currently approved in severe infantile-onset epilepsies, respectively Dravet syndrome and infantile spasms. AREAS COVERED: For both, the indication was discovered by chance thanks to an exploratory study. Both demonstrated indisputable efficacy through randomized-controlled trials. Stiripentol as adjunctive therapy to clobazam and valproate performed better than placebo, and vigabatrin as first-line monotherapy better than the reference steroid therapy in spasms due to tuberous sclerosis. At one-year treatment vigabatrin and steroids were equally efficient in the other etiologies of spasms. However, it took more than 20 years for both drugs to be approved world-wide. EXPERT OPINION: Stiripentol suffered from pharmacokinetic potentiation of clobazam, thus raising the question whether it was efficient per se. Finally, animal models and pharmacogenetic data on CYP2C19 confirmed its specific anticonvulsant effect. Stiripentol (in comedication with clobazam and valproate) is therefore to be recommended for Dravet patients. Vigabatrin was found to have a frequent and irreversible retinal toxicity, which required an alternative visual testing to be detected in young children. Today the benefit/risk ratio of vigabatrin as first-line is considered to be positive in infantile spasms, given the severity of this epilepsy and the lack of a safer alternative therapy.

Epileptic spasms without hypsarrhythmia in infancy and childhood: tonic spasms as a seizure type.

Epileptic spasms were defined by the International League Against Epilepsy Task Force on Classification and Terminology in 2001 as a specific seizure type. Epileptic spasms without hypsarrhythmia have been described in some series of patients, occurring either in infancy or childhood. More prolonged epileptic spasms without hypsarrhythmia were previously defined as a different seizure type, and referred to as "tonic spasm seizures". Here, we present a 5-year-old boy who started having epileptic spasms without hypsarrhythmia at 8 months of age, effectively treated with oxcarbazepine. With the withdrawal of medication, epileptic spasms returned. Video-EEG monitoring revealed high-voltage slow waves superimposed by low-voltage fast activity, followed by an electrodecremental phase and a burst of asymmetric fast activity, time-locked to clinical tonic spasm seizures. Brain MRI showed left temporal atrophy with temporal pole grey/white matter junction blurring and ictal PET-CT showed left basal frontal hypermetabolism. Seizures were refractory to several AEDs and vigabatrin was introduced with seizure cessation. Despite efforts to classify epileptic spasms, these are still considered as part of the group of unknown seizure types. In some cases, a focal origin has been suggested, leading to the term "periodic spasms" and "focal spasms". In this case, epileptic spasms without hypsarrhythmia, associated with tonic spasms, may be a variant of focal spasms and might be considered as an epileptic syndrome. [Published with video sequence].

Does vigabatrin treatment for infantile spasms cause visual field defects? An international multicentre study.

AIM: The aim of this study was to examine whether vigabatrin treatment had caused visual field defects (VFDs) in children of school age who had received the drug in infancy. METHOD: In total, 35 children (14 males, 21 females; median age 11y, SD 3.4y, range 8-23y) were examined by static Humphrey perimetry, Goldmann kinetic perimetry, or Octopus perimetry. The aetiologies of infantile spasms identified were tuberous sclerosis (n=10), other symptomatic causes (n=3), or cryptogenic (n=22). RESULTS: Typical vigabatrin-attributed VFDs were found in 11 out of 32 (34%) children: in one out of 11 children (9%) who received vigabatrin for <1 year (group 1), in three out of 10 children (30%) who received vigabatrin for 12 to 24 months (group 2), and in seven out of 11 children (63%) who received vigabatrin treatment for longer than 2 years (group 3). VFDs were mild in five and severe in six children. Patients with tuberous sclerosis were at higher risk of VFDs (six out of 10 children). The mean cumulative doses of vigabatrin were 140.5, 758.8, and 2712g in group 1, 2, and 3, respectively. INTERPRETATION: VFDs were found in 34% of the cohort of children in this study. The rate of VFD increased from 9% to 63% as duration of treatment increased. The results of this study showed that the risk-benefit ratio should always be considered when using vigabatrin.

Population dose-response analysis of daily seizure count following vigabatrin therapy in adult and pediatric patients with refractory complex partial seizures.

Vigabatrin is an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T) and is used as an adjunctive therapy for adult patients with refractory complex partial seizures (rCPS). The purpose of this investigation was to describe the relationship between vigabatrin dosage and daily seizure rate for adults and children with rCPS and identify relevant covariates that might impact seizure frequency. This population dose-response analysis used seizure-count data from three pediatric and two adult randomized controlled studies of rCPS patients. A negative binomial distribution model adequately described daily seizure data. Mean seizure rate decreased with time after first dose and was described using an asymptotic model. Vigabatrin drug effects were best characterized by a quadratic model using normalized dosage as the exposure metric. Normalized dosage was an estimated parameter that allowed for individualized changes in vigabatrin exposure based on body weight. Baseline seizure rate increased with decreasing age, but age had no impact on vigabatrin drug effects after dosage was normalized for body weight differences. Posterior predictive checks indicated the final model was capable of simulating data consistent with observed daily seizure counts. Total normalized vigabatrin dosages of 1, 3, and 6 g/day were predicted to reduce seizure rates 23.2%, 45.6%, and 48.5%, respectively.

Adrenocorticotropic hormone versus prednisolone in the treatment of infantile spasms post vigabatrin failure.

The Child Neurology Society/American Academy of Neurology practice parameter has recommended adrenocorticotropic hormone or vigabatrin in the short-term treatment of infantile spasms. When vigabatrin is unavailable or ineffective and adrenocorticotropic hormone is not a treatment option because of the prohibitive cost, other forms of corticosteroids have been considered in the treatment of infantile spasms. This retrospective study reviewed the Hospital for Sick Children's experience with the short-term effectiveness of prednisolone versus adrenocorticotropic hormone in patients with infantile spasms who have failed vigabatrin. The results showed that while adrenocorticotropic hormone was more likely to lead to short-term spasm freedom, there was no difference in the likelihood of longer-term spasm resolution without relapse. These findings can guide clinicians in the treatment of infantile spasms post vigabatrin failure.

Population pharmacokinetics analysis of vigabatrin in adults and children with epilepsy and children with infantile spasms.

BACKGROUND AND OBJECTIVES: Vigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration-time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of systemic vigabatrin exposure for patients 1-12 months of age. METHODS: Vigabatrin pharmacokinetic data from six randomized controlled clinical trials and one open-label study were analyzed using nonlinear mixed-effects modeling. Data collected from 349 adults with rCPS and 119 pediatric patients with rCPS or IS were used in the analyses. RESULTS: A two-compartment model with first-order elimination and transit-compartment absorption consisting of five transit compartments adequately described the vigabatrin concentration-time data for these adult and pediatric patient populations. An exponential error model was used to estimate inter-individual variability for the transit-rate constant (k tr) (24.2 %), elimination rate constant (k) (14.7 %) and apparent central volume of distribution (V c/F) (18 %). For the study of children with IS, inter-occasion variability was estimated for k tr (58.1 %) and relative bioavailability (F) (26.9 %). Covariate analysis indicated that age, creatinine clearance (CLCR), and body weight were important predictors of vigabatrin pharmacokinetic parameters. Vigabatrin apparent clearance increased with increasing CLCR, consistent with renal excretion (primary pathway of vigabatrin elimination). Rate of vigabatrin absorption was dependent on age. The rate was slower in younger patients, which resulted in a smaller predicted maximum concentration and longer predicted time to maximum concentrations. Vigabatrin V c/F, apparent inter-compartmental clearance between the central and peripheral compartment, and apparent peripheral volume of distribution were increased with greater patient body weights. Sex did not contribute significantly to vigabatrin pharmacokinetic variability. CONCLUSION: The model adequately described vigabatrin pharmacokinetic and enabled predictions of systemic exposures in pediatric patients 1-12 months of age.