Early Treatment with Vigabatrin Does Not Decrease Focal Seizures or Improve Cognition in Tuberous Sclerosis Complex: The PREVeNT Trial.

OBJECTIVE: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age. METHODS: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months. Secondary outcomes were prevalence of drug-resistant epilepsy, additional developmental outcomes, and safety of vigabatrin. RESULTS: Of 84 infants enrolled, 12 were screen failures, 4 went straight to open label vigabatrin, and 12 were not randomized (normal EEG throughout). Fifty-six were randomized to early vigabatrin (n = 29) or placebo (n = 27). Nineteen of 27 in the placebo arm transitioned to open label vigabatrin, with a median delay of 44 days after randomization. Bayley-III cognitive composite scores at 24 months were similar for participants randomized to vigabatrin or placebo. Additionally, no significant differences were found between groups in overall epilepsy incidence and drug-resistant epilepsy at 24 months, time to first seizure after randomization, and secondary developmental outcomes. Incidence of infantile spasms was lower and time to spasms after randomization was later in the vigabatrin group. Adverse events were similar across groups. INTERPRETATION: Preventative treatment with vigabatrin based on EEG epileptiform activity prior to seizure onset does not improve neurocognitive outcome at 24 months in TSC children, nor does it delay onset or lower the incidence of focal seizures and drug-resistant epilepsy at 24 months. Preventative vigabatrin was associated with later time to onset and lower incidence of infantile spasms. ANN NEUROL 2023.

Common epilepsy variants from the general population are not associated with epilepsy among individuals with tuberous sclerosis complex.

Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC-associated epilepsy. Such knowledge is important to help uncover the underlying pathogenesis of epilepsy in TSC which is not fully understood, and critical as uncontrolled epilepsy is a major problem in this population. To evaluate common genetic modifiers of epilepsy, our study pooled phenotypic and genotypic data from 369 individuals with TSC to evaluate known and novel epilepsy common variants. We did not find evidence of enhanced genetic penetrance for known epilepsy variants identified across the largest genome-wide association studies of epilepsy in the general population, but identified support for novel common epilepsy variants in the context of TSC. Specifically, we have identified a novel signal in SLC7A1 that may be functionally involved in pathways relevant to TSC and epilepsy. Our study highlights the need for further evaluation of genetic modifiers in TSC to aid in further understanding of epilepsy in TSC and improve outcomes.

Longitudinal impact of cannabidiol on EEG measures in subjects with treatment-resistant epilepsy.

OBJECTIVE: To assess the longitudinal impact of highly purified cannabidiol (CBD) on the electroencephalogram (EEG) of children and adults. METHODS: Participants received an EEG prior to starting CBD, after approximately 12 weeks of CBD (FU1) and after approximately one year of CBD therapy (FU2). Longitudinal changes in five EEG measures (background frequency, focal slowing, reactivity, frequency of interictal, and ictal discharges) were examined following CBD exposure. Data were compared between pediatric and adult groups at two follow-up time points and within groups over time. Population-averaged models with generalized estimation equations or linear mixed effects models were used to analyze data where appropriate. Correlation analysis was used to assess any association between changes in seizure frequency and changes in EEG interictal discharge (IED) frequency. An alpha level of 5% was used to assess statistical significance. RESULTS: At FU1, the adult group showed significant decrease in IED/minute (IDR 0.07, 95% CI [0.04, 0.14], P < 0.001); a nonsignificant decrease was observed among children (IDR 0.87, 95% CI [0.47, 0.64], P = 0.67). The difference in changes over time between participant groups was significant after adjusting for last CBD dose (IDR 11.8, 95% CI [4.86, 28.65], P < 0.0001). At FU2 both groups showed significant reduction from baseline after controlling for last CBD dose. This decrease was more pronounced in children (IDR 15.38, 95% CI [4.93, 47.99], P < 0.001). There was no significant correlation between changes in seizure frequency and EEG IED frequency at each timepoint (P = 0.542, 0.917 and 0.989 from baseline to FU1, FU1 to FU2 and baseline to FU2, respectively). SIGNIFICANCE: This longitudinal EEG study shows that highly-purified plant-derived CBD has positive effects on interictal epileptiform discharge frequency but no effects on other EEG measures. The effect of CBD does not appear to be dose or treatment-duration dependent.

The Connectivity Fingerprint of the Fusiform Gyrus Captures the Risk of Developing Autism in Infants with Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by benign tumors throughout the body; it is generally diagnosed early in life and has a high prevalence of autism spectrum disorder (ASD), making it uniquely valuable in studying the early development of autism, before neuropsychiatric symptoms become apparent. One well-documented deficit in ASD is an impairment in face processing. In this work, we assessed whether anatomical connectivity patterns of the fusiform gyrus, a central structure in face processing, capture the risk of developing autism early in life. We longitudinally imaged TSC patients at 1, 2, and 3 years of age with diffusion compartment imaging. We evaluated whether the anatomical connectivity fingerprint of the fusiform gyrus was associated with the risk of developing autism measured by the Autism Observation Scale for Infants (AOSI). Our findings suggest that the fusiform gyrus connectivity captures the risk of developing autism as early as 1 year of age and provides evidence that abnormal fusiform gyrus connectivity increases with age. Moreover, the identified connections that best capture the risk of developing autism involved the fusiform gyrus and limbic and paralimbic regions that were consistent with the ASD phenotype, involving an increased number of left-lateralized structures with increasing age.

Defining the phenotype of FHF1 developmental and epileptic encephalopathy.

Fibroblast growth-factor homologous factor (FHF1) gene variants have recently been associated with developmental and epileptic encephalopathy (DEE). FHF1 encodes a cytosolic protein that modulates neuronal sodium channel gating. We aim to refine the electroclinical phenotypic spectrum of patients with pathogenic FHF1 variants. We retrospectively collected clinical, genetic, neurophysiologic, and neuroimaging data of 17 patients with FHF1-DEE. Sixteen patients had recurrent heterozygous FHF1 missense variants: 14 had the recurrent p.Arg114His variant and two had a novel likely pathogenic variant p.Gly112Ser. The p.Arg114His variant is associated with an earlier onset and more severe phenotype. One patient carried a chromosomal microduplication involving FHF1. Twelve patients carried a de novo variant, five (29.5%) inherited from parents with gonadic or somatic mosaicism. Seizure onset was between 1 day and 41 months; in 76.5% it was within 30 days. Tonic seizures were the most frequent seizure type. Twelve patients (70.6%) had drug-resistant epilepsy, 14 (82.3%) intellectual disability, and 11 (64.7%) behavioral disturbances. Brain magnetic resonance imaging (MRI) showed mild cerebral and/or cerebellar atrophy in nine patients (52.9%). Overall, our findings expand and refine the clinical, EEG, and imaging phenotype of patients with FHF1-DEE, which is characterized by early onset epilepsy with tonic seizures, associated with moderate to severe ID and psychiatric features.

Increased electroencephalography connectivity precedes epileptic spasm onset in infants with tuberous sclerosis complex.

OBJECTIVE: To identify whether abnormal electroencephalography (EEG) connectivity is present before the onset of epileptic spasms (ES) in infants with tuberous sclerosis complex (TSC). METHODS: Scalp EEG recordings were collected prospectively in infants diagnosed with TSC in the first year of life. This study compared the earliest recorded EEG from infants prior to ES onset (n = 16) and from infants who did not develop ES (n = 28). Five minutes of stage II or quiet sleep was clipped and filtered into canonical EEG frequency bands. Mutual information values between each pair of EEG channels were compared directly and used as a weighted graph to calculate graph measures of global efficiency, characteristic path length, average clustering coefficient, and modularity. RESULTS: At the group level, infants who later developed ES had increased EEG connectivity in sleep. They had higher mutual information values between most EEG channels in all frequency bands adjusted for age. Infants who later developed ES had higher global efficiency and average clustering coefficients, shorter characteristic path lengths, and lower modularity across most frequency bands adjusted for age. This suggests that infants who went on to develop ES had increased local and long-range EEG connectivity with less segregation of graph regions into distinct modules. SIGNIFICANCE: This study suggests that increased neural connectivity precedes clinical ES onset in a cohort of infants with TSC. Overconnectivity may reflect progressive pathologic network synchronization culminating in generalized ES. Further research is needed before scalp EEG connectivity measures can be used as a potential biomarker of ES risk and treatment response in pre-symptomatic infants with TSC.

Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

OBJECTIVE: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016. METHODS: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit. RESULTS: Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%). SIGNIFICANCE: Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.

Epilepsy Risk Prediction Model for Patients With Tuberous Sclerosis Complex.

BACKGROUND: Individuals with tuberous sclerosis complex are at increased risk of epilepsy. Early seizure control improves developmental outcomes, making identifying at-risk patients critically important. Despite several identified risk factors, it remains difficult to predict. The purpose of the study was to evaluate the combined risk prediction of previously identified risk factors for epilepsy in individuals with tuberous sclerosis complex. METHODS: The study group (n = 333) consisted of individuals with tuberous sclerosis complex who were enrolled in the Tuberous Sclerosis Complex Autism Center of Excellence Research Network and UT TSC Biobank. The outcome was defined as having an epilepsy diagnosis. Potential risk factors included sex, TSC genotype, and tuber presence. Logistic regression was used to calculate the odds ratio and P value for the association between each variable and epilepsy. A clinical risk prediction model incorporating all risk factors was built. Area under the curve was calculated to characterize the full model's ability to discriminate individuals with tuberous sclerosis complex with and without epilepsy. RESULTS: The strongest risk for epilepsy was presence of tubers (95% confidence interval: 2.39 to 10.89). Individuals with pathogenic TSC2 variants were three times more likely (95% confidence interval: 1.55 to 6.36) to develop seizures compared with those with tuberous sclerosis complex from other causes. The combination of risk factors resulted in an area under the curve 0.73. CONCLUSIONS: Simple characteristics of patients with tuberous sclerosis complex can be combined to successfully predict epilepsy risk. A risk assessment model that incorporates sex, TSC genotype, protective TSC2 missense variant, and tuber presence correctly predicts epilepsy in 73% of patients with tuberous sclerosis complex.

Resting-State fMRI Networks in Children with Tuberous Sclerosis Complex.

BACKGROUND AND PURPOSE: There are no published studies examining resting state networks (RSNs) and their relationship with neurodevelopmental metrics in tuberous sclerosis complex (TSC). We aimed to identify major resting-state functional magnetic resonance imaging (rs-fMRI) networks in infants with TSC and correlate network analyses with neurodevelopmental assessments, autism diagnosis, and seizure history. METHODS: Rs-fMRI data from 34 infants with TSC, sedated with propofol during the scan, were analyzed to identify auditory, motor, and visual RSNs. We examined the correlations between auditory, motor, and visual RSNs at approximately 11.5 months, neurodevelopmental outcome at approximately 18.5 months, and diagnosis of autism spectrum disorders at approximately 36 months of age. RESULTS: RSNs were obtained in 76.5% (26/34) of infants. We observed significant negative correlations between auditory RSN and auditory comprehension test scores (p = .038; r = -.435), as well as significant positive correlations between motor RSN and gross motor skills test scores (p = .023; r = .564). Significant positive correlations between motor RSNs and gross motor skills (p = .012; r = .754) were observed in TSC infants without autism, but not in TSC infants with autism, which could suggest altered motor processing. There were no significant differences in RSNs according to seizure history. CONCLUSIONS: Negative correlation between auditory RSN, as well as positive correlation between motor RSN and developmental outcome measures might reflect different brain mechanisms and, when identified, may be helpful in predicting later function. A larger study of TSC patients with a healthy control group is needed before auditory and motor RSNs could be considered as neurodevelopmental outcome biomarkers.

Tuberous Sclerosis Complex Genotypes and Developmental Phenotype.

BACKGROUND: Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to increase the risk, compared with TSC1. However, the effect of TSC2 pathogenic variants on early and specific domains of development hasn't been studied. Using an extensively phenotyped group, we aimed to characterize differences in early intellectual development between genotypes. METHODS: The study group (n = 92) included participants with TSC enrolled in a multicenter study involving genetic testing and detailed prospective phenotyping including the Mullen Scales of Early Learning, a validated measure of cognition, language, and motor development in babies and preschool children. Mean T-scores at 24 months for each Mullen Scales of Early Learning domain were calculated for children with, versus without, a TSC2 pathogenic variant. Multivariable linear regression models were used to compare the groups, adjusting for seizures. RESULTS: T-scores on every Mullen Scales of Early Learning domain were significantly worse in the TSC2 group. Below average composite scores were present in three-fourths of the TSC2 group, compared with one-fourth of those without TSC2. Having a TSC2 pathogenic variant was associated with lower composite Mullen Scales of Early Learning scores, even when corrected for seizures. CONCLUSIONS: In a well-characterized patient population with standardized assessment of multiple aspects of development, we found that having a TSC2 pathogenic variant was associated with significantly lower Mullen Scales of Early Learning scores at age 24 months, independent of seizures. These data suggest that a baby with a TSC2 pathogenic variant is at high risk for significant developmental delays by 24 months.