Preventive Antiepileptic Treatment in Tuberous Sclerosis Complex: A Long-Term, Prospective Trial

Jóźwiak, Sergiusz; Słowińska, Monika; Borkowska, Julita; Sadowski, Krzysztof; Łojszczyk, Barbara; Domańska-Pakieła, Dorota; Chmielewski, Dariusz; Kaczorowska-Frontczak, Magdalena; Głowacka, Jagoda; Sijko, Kamil; Kotulska, Katarzyna

doi:10.1016/j.pediatrneurol.2019.07.008

Cited by 57 publications

(44 citation statements)

References 32 publications

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“…There was also a significant difference in the number of patients whose EEG normalized at 24 months on vigabatrin preventive versus standard treatment, eight of 10 (80%) versus two of 22 (9.1%; P = .0001). On longer follow‐up at a median age of 8.8 years, it was possible to withdraw all ASDs in 55% of children in the preventive group, compared to 17% in the control group ( P < .03) …”

Section: Vigabatrinmentioning

confidence: 99%

“…On longer follow-up at a median age of 8.8 years, it was possible to withdraw all ASDs in 55% of children in the preventive group, compared to 17% in the control group (P < .03). 250 Currently, two major prospective, randomized trials are evaluating preventive use of vigabatrin in TSC: the EPISTOP project (ClinicalTrials.gov identifier NCT02098759), 251 a large collaborative study funded by European Union within the Seventh Frame Program; and the PREVeNT trial (Preventing Epilepsy Using Vigabatrin in Infants With Tuberous Sclerosis Complex (ClinicalTrials.gov identifier NCT02849457). 252 Both studies screen prospectively asymptomatic TSC patients with EEG and randomize patients with abnormal interictal EEGs to treatment with vigabatrin before versus after onset of seizures.…”

Section: Vigabatrinmentioning

confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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Section: Vigabatrinmentioning

confidence: 99%

Section: Vigabatrinmentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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“…6,19 In a small prospective single center nonrandomized clinical trial, antiepileptic treatment with Vigabatrin, given early when IED were first detected on EEG, improved long-term epilepsy and developmental outcomes compared to when Vigabatrin treatment was started after the onset of clinical seizures. 20,21 However, to what degree seizures play a causative role for later ASD/ DD, and if early treatment has the potential to prevent the subsequent development of ASD/DD remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Moavero

Kotulska

Lagae

et al. 2020

Ann Clin Transl Neurol

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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.

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“…A small non-randomized pilot clinical trial of early intervention with vigabatrin at the time of multifocal interictal epileptiform discharges (IED) detection, led to a significant reduction in drug-resistant epilepsy, more seizurefree patients, and fewer patients with intellectual disability at 24 months in comparison to an historical control group in which vigabatrin was started only after seizure onset (18). More recent follow-up of these TSC children showed persistent improvement at school age (19).…”

Section: Introductionmentioning

confidence: 99%

Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics

Ridder¹,

Lavanga²,

Verhelle³

et al. 2020

Front. Neurol.

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Preventive Antiepileptic Treatment in Tuberous Sclerosis Complex: A Long-Term, Prospective Trial

Cited by 57 publications

References 32 publications

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

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

Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics

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