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We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC. A comprehensive multi-omic analysis of the EPISTOP trial for Tuberous Sclerosis Complex (TSC). was performed. Here, authors show many differences in serum proteins and metabolites, and blood RNA species, including associations with seizure development. [ABSTRACT FROM AUTHOR]

Objective: Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to market authorization (MA). For treatment of – especially young – children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to "off‐label" use of ASMs. Even though "off‐label" ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if "on‐label" ASM, in mono‐ or polytherapy, fails to achieve adequate seizure control. Methods: The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first‐ and second‐line treatment preferences but also to illustrate the use of "off‐label" drugs in childhood epilepsies. Results: Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed "off‐label" in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap. Significance: We report the relatively common use of "off‐label" prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence‐based guidelines. [ABSTRACT FROM AUTHOR]

Objective: The objectives of this study were to assess the accuracy of parental seizure detection in infants with antenatally diagnosed tuberous sclerosis complex (TSC), and to document the total seizure burden (clinical and subclinical) in those patients who met criteria for prolonged electroencephalography (EEG) recording. Methods: Consecutive infants at a single institution with antenatally diagnosed TSC who met criteria for prolonged video‐EEG (vEEG) were recruited to this study. The vEEG data were reviewed and when a seizure was identified on EEG, the video and audio recording was assessed for evidence of clinical seizure and, if present, whether there was evidence of parent seizure identification. Results: Nine infants were enrolled, for whom 674 focal seizures were identified in eight of nine patients across 24 prolonged vEEG recordings, with vEEG total duration of 634 h 49 min (average seizure frequency of 1 focal seizure/h). Only 220 of 674 (32.6%) were clinical seizures, 395 of 674 (58.6%) were subclinical seizures, and 59 of 674 seizures could not be classified. Only 63 of 220 clinical seizures (28.6%) were identified by parents, with 157 of 220 (71.4%) not identified. Thirty clusters of epileptic spasms were detected in one patient. At least one clinical epileptic spasm occurred in 2 of 30 clusters (6.7%), 24 of 30 clusters of epileptic spasms (80%) were electrographic only, and classification was uncertain for 4 of 30 clusters (13.3%). No clinical epileptic spasms were detected by parents. Clinical seizure frequency was significantly underestimated by parents for all patients. Significance: This study demonstrates that in infants with TSC who met criteria for prolonged vEEG, (1) parents significantly under recognize total clinical seizure count, (2) parents fail to identify epileptic spasms, and (3) seizure frequency is high. This highlights that epilepsy treatment decisions should not be based solely on parental clinical seizure identification. Prolonged vEEG monitoring may have an important role in the routine epilepsy care of infants with TSC, as demonstrating undetected high clinical seizure frequency may allow improved epilepsy management decisions. [ABSTRACT FROM AUTHOR]

Summary: Objective: To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED‐EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC). Methods: Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy – Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED‐EEG were studied in relation to clinical outcome. Epilepsy‐related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]). Results: Eighty‐three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14–54). Seventy‐nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23–111). Patients with a pathogenic TSC2 variant were significantly younger (P‐value.009) at first ED‐EEG and more frequently had multifocal IED (P‐value.042) than patients with a pathogenic TSC1 variant. A younger age at first ED‐EEG was significantly associated with lower cognitive (P‐value.010), language (P‐value.001), and motor (P‐value.013) developmental quotients at 24 months. In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED‐EEG was predictive of earlier seizure onset (P‐value.030). Earlier recording of epileptiform discharges (P‐value.019), especially when multifocal (P‐value.026) was associated with higher risk of drug‐resistant epilepsy. In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED‐EEG, preventive treatment delayed the onset of seizures significantly (P‐value <.001). Significance: Early EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin. [ABSTRACT FROM AUTHOR]

Objective: Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants. Methods: In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open‐label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure. Results: In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty‐seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223–535) vs 124 days (95% CI = 33–149); OLT: 426 days (95% CI = 258–628) vs 106 days (95% CI = 11–149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug‐resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted. Interpretation: Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304–314 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is highly prevalent in subjects with Tuberous Sclerosis Complex (TSC), but we are not still able to reliably predict which infants will develop ASD. This study aimed to identify the early clinical markers of ASD and/or developmental delay (DD) in infants with an early diagnosis of TSC. We prospectively evaluated 82 infants with TSC (6–24 months of age), using a detailed neuropsychological assessment (Bayley Scales of Infant Development—BSID, and Autism Diagnostic Observation Schedule—ADOS), in the context of the EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy—Tuberous SclerOsis ComPlex) project (NCT02098759). Normal cognitive developmental quotient at 12 months excluded subsequent ASD (negative predictive value 100%). The total score of ADOS at 12 months clearly differentiated children with a future diagnosis of ASD from children without (p = 0.012). Atypical socio-communication behaviors (p < 0.001) were more frequently observed than stereotyped/repetitive behaviors in children with ASD at 24 months. The combined use of BSID and ADOS can reliably identify infants with TSC with a higher risk for ASD at age 6–12 months, allowing for clinicians to target the earliest symptoms of abnormal neurodevelopment with tailored intervention strategies. [ABSTRACT FROM AUTHOR]