Abstract
Introduction:
Tuberous Sclerosis Complex (TSC) is associated with high prevalence of epilepsy, intellectual and developmental disability (IDD), and autism spectrum disorder (ASD). PREVeNT, a Phase IIb, multicenter, double-blind placebo-controlled trial, evaluated the efficacy of vigabatrin in preventing IDD and ASD in infants with TSC. Phenotypic, developmental, and ASD-specific outcomes at 36 months are presented.
Methods:
Eighty-four infants with TSC were enrolled in PREVeNT across 13 TSC clinics in the United States. Participants underwent neurodevelopmental assessments at ages 6 months through 36 months. Clinical best estimate diagnosis of ASD or non-ASD along with a rating of clinical certainty was determined at 36 months.
Results:
Sixty-five participants completed assessments through 36 months of age. Mean cognitive scores on the Bayley-III were in the low average range at 12 months. Cognitive scores declined slightly in all groups over time. Adaptive scores were in the low average range for the seizure groups. For all neurocognitive measures, those in the watchful waiting group exhibited higher scores compared to the other cohorts. Language scores became more commensurate with cognitive scores by 36 months. The Clinical Certainty Rating was available for 58 patients, with 31% rated as having ASD; this did not differ by treatment assignment.
Conclusions:
No significant differences in developmental or autism-specific outcomes were seen between treatment groups, and no participants without epilepsy were diagnosed with ASD. This may be due to early detection of seizures, closer developmental monitoring and follow-up in the trial, and impacts of the pandemic on study participation.
Keywords: Tuberous Sclerosis Complex, vigabatrin, development, autism
INTRODUCTION
Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic condition with high prevalence of epilepsy, developmental delays (DD), and autism spectrum disorder (ASD). Development of therapeutic interventions targeting TSC epileptogenesis may improve neurodevelopmental outcomes and possibly prevent or reduce the impact of DD and ASD in this population.
Much of what is known about the natural history of DD and ASD in children with TSC has emerged from multi-site, prospective observational studies. Longitudinal observation of infants with TSC over the first two years of life suggests significant developmental delays occur as early as 6-10 months of age [1], [2]. Medical factors associated with increased risk for DD include TSC2, higher seizure frequency, and earlier onset of seizures (i.e., particularly within the first 12 months of life [1], [2], [3], [4]). TSC is one of the genetic conditions most highly associated with ASD, with rates of ASD ranging from 26-45% in children with TSC. Approximately one-third of children with TSC have both epilepsy and ASD [5].
The TSC Autism Center of Excellence Research Network (TACERN) was designed to characterize ASD in TSC, including a goal of developing precision treatments. Results showed that early onset of seizures was associated with lower developmental scores and higher levels of autism-related behaviors, highlighting an important window of time for therapeutics [6]. In fact, for each one month increase in age at seizure onset, the odds of a child not having DD increased by 34% at age 18 months and 61% at age 24 months. For patients who started having seizures early, early developmental trajectories were not improved with reduction in seizures, further highlighting the importance of a preventative approach. Additional detailed analysis of seizure diaries found that participants who seized early, often, and had infantile spasms in addition to focal seizures scored lower on developmental assessments at 36 months [7]. Additionally, of participants who seized early and had both focal seizures and spasms, outcomes were more favorable if seizures occurred infrequently and were impacted by treatment.
Within TACERN, a subset of participants was enrolled in an EEG biomarker study to determine the use of clinical EEG as a biomarker of impending epilepsy, providing critical knowledge regarding the predictive value of EEG in determining seizure onset in infants with TSC [8]. This prompted the PREVeNT trial, a Phase IIb, multicenter, double blind, placebo-controlled trial evaluating the efficacy of vigabatrin in preventing DD and ASD in infants with TSC. Participants with epileptiform discharges on their first EEG were randomized to early vigabatrin treatment or placebo. Participants in the placebo group who started having seizures (19 of 27 infants) were started on vigabatrin with a median start of vigabatrin 44 days after randomization. Recently published results [9] showed no significant differences in vigabatrin versus placebo (or delayed start) in the cognitive assessment score at 24 months, which was the primary outcome measure. However, participants in both groups exhibited low average development with mean cognitive scores in the upper 80s at 12 months and declining to the lower 80s at 24 months of age, suggesting that exposure to vigabatrin may be more impactful than the timing of administration. Regarding seizure outcomes, there were no differences in focal seizures between groups. However, patients in the vigabatrin group had lower incidence and later onset of infantile spasms. Participants were followed through 36 months to address secondary outcomes of the trial.
Expanding on the primary outcomes reported in Bebin et al. [9], the current report presents more detailed phenotypic, developmental, and autism-specific outcome results through 36 months in participants who never developed epilepsy, those who developed epilepsy but were treated with vigabatrin early, and those who were treated with vigabatrin at seizure onset. Additional goals include understanding the full impact of early treatment in the vigabatrin-exposed groups at 36 months and determining any differences in developmental outcomes as well as the role of seizures in affecting neurodevelopmental trajectories.
METHODS
Subject Recruitment
Eighty-four infants with TSC were enrolled in the PREVeNT trial [9] across 13 TSC clinics in the United States, with each site receiving IRB approval from its institution. Informed consent was obtained from at least one caregiver prior to enrollment. Inclusion criteria for infants included age of 6 months or younger with a TSC diagnosis and no history of seizures or evidence of subclinical seizures on EEG. Exclusion criteria included birth prior to 30 weeks gestation, having received anti-seizure medication or an MTOR inhibitor, or plans to enroll in an experimental behavioral study. Seventy-two infants (85.7%) remained in the study through the 24-month timepoint, and 64 infants (76.2%) remained in the study through the 36-month timepoint.
Study Design
PREVeNT was a Phase IIb multicenter, randomized, double-blind, placebo-controlled clinical trial. Please refer to Bebin et al. [9] for full description of study design and patient randomization. Participants were evaluated longitudinally by the developmental team at ages 6, 9, 12, 18, 24, and 36 months in addition to the medical and other assessments for the overall trial. Information regarding seizure type, date/age of onset, and frequency of seizures was collected during the study. Developmental assessments were obtained or supervised by psychologists who were blinded to participant treatment assignment, seizure control, and concomitant medications. Participant families and the medical team received a written summary of developmental assessment results, and referrals for early intervention and other developmental services were provided when concerns were mentioned by the caregivers, study team, and/or indicated by assessment findings. Calibration was achieved by the developmental teams at the study launch meeting, and measures requiring research reliability were monitored by the lead developmental team at the primary study site (UAB); evaluators provided previous certification or submitted videos to achieve within-study reliability. Several clinical or developmental psychologists were available throughout the study for evaluator concerns or questions.
Study Evaluations
Assessments were conducted in-person initially, as enrollment began in 2018. As with many research protocols [10], modification to the developmental assessment protocol was required during the COVID-19 pandemic to overcome restrictions to patient travel and/or the ability to conduct face-to-face evaluations at many sites during the study period. Table 1 illustrates the study visit schedule for neurodevelopmental assessments before the onset of the COVID-19 pandemic in comparison to those completed after.
Table 1.
Developmental Assessment Schedule Plan and Modifications
| 6 months | 12 months | 24 months | 36 months | |
|---|---|---|---|---|
| Bayley-III | X (SEAB only) | X | X | X |
| Vineland-II | X | X | X | X |
| ADOS-2 | X | X | ||
| COVID-19 Precautions Protocol (Replacing ADOS-2) | ||||
| BOSA | X | X | ||
| DSM-5 Checklist | X | X | ||
| ADI-R | -- | X | ||
| Clinical Certainty Rating | X | X | ||
Cognitive and Adaptive Assessments
Developmental assessments included the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) [11] and Vineland-II (Survey Interview Form) [12] administered at 12, 24, and 36 months of age. At the 6-month visit, only the Bayley-III Social, Emotional, and Adaptive Behavior Questionnaire (SEAB) and Vineland-II Survey Interview Form were completed by caregivers. The Bayley-III is an individually administered assessment of development that elicits behavior using age-appropriate manipulatives and prompts; some items allow caregiver report in place of observed elicited behavior. The Bayley-III yields age-normed standard scores for Cognitive, Language, and Motor domains; domain standard scores have a mean of 100 and standard deviation is 15, and domain scaled scores for receptive language, expressive language, fine motor, and gross motor skills have a mean of 10 and a standard deviation of 3. The Vineland-II Survey Interview is a semi-structured clinical interview obtaining information from a caregiver about behaviors and skills a child typically exhibits. The Vineland-II yields age-normed standard scores for the domains of communication, daily living skills, socialization, and motor skills, and an overall adaptive behavior composite; these scores all have a mean of 100 and standard deviation of 15. Across these measures, standard scores between 85 and 115 are considered to be within the average range and scaled scores between 7 and 13 are considered average. Standard scores were used for the current analyses.
Assessment of Autism Symptoms
The original study protocol included assessment of autism symptoms utilizing the Autism Diagnostic Observation Schedule- Second Edition (ADOS-2) [13], [14] at the 24- and 36-month timepoints. The ADOS-2 is an individually administered play-based assessment that structures social interactions with a child to observe the presence or absence of autism symptoms. This measure typically lasts about 45 to 60 minutes, and at younger ages, a caregiver is present in the room during the administration. Following the assessment, the evaluator assigns ratings to items describing behaviors and skills in the domains of Language and Communication, Reciprocal Social Interaction, Play, Stereotyped Behaviors and Restricted Interests, and Other Abnormal Behaviors. These scores contribute to algorithms intended to guide diagnosis. Modifications during and after the pandemic included replacement of the ADOS-2 with the Brief Observation of Symptoms of Autism (BOSA) [15] at the 24- and 36-month visits and the Autism Diagnostic Interview-Revised (ADI-R) [16] at the 36-month visit. The BOSA is similar to the ADOS-2 in structuring observation of social interaction, play, and behaviors but takes less than 20 minutes to administer and can be administered by a caregiver, with scoring completed by an evaluator observing the interaction. This modification allowed the child and caregiver to interact without a mask while an evaluator observed from a safe social distance (e.g., behind an observation mirror), whereas the ADOS-2 had not been validated with use of masks by evaluators or children at the time of the PREVeNT data collection. Evaluators who administered the ADOS-2 had achieved independent research reliability on this measure, which was extended as the standard for BOSA reliability. Although the BOSA can be administered remotely via telehealth, for this study the BOSA was completed at in-person visits when permitted by the clinical setting’s COVID-19 precautions. There were some sites post-pandemic that were permitted to complete testing with a mask; in these cases, the ADOS-2 was completed by a different evaluator than the BOSA post-pandemic when possible. However, if the ADOS-2 was not permitted un-masked, the BOSA was considered the primary autism diagnostic measure. For all participants completing 36-month visits after the pandemic, the BOSA was the primary measure for autism assessment. Psychometrics for the BOSA were published following the completion of the current study, so cutoff scores were not available for the evaluators to guide diagnostic conclusions; instead, the BOSA provided structured behavior observations similar to those typically obtained with the ADOS-2. Notably, the BOSA has demonstrated good convergent validity with the ADOS-2 for the Toddler Module (r = .74), as well as sensitivity between 91 and 96% and specificity between 83 and 100% for BOSA cutoffs [17].
The ADI-R is a comprehensive semi-structured interview with a caregiver regarding the child’s early development and the presence or absence of autism-related behaviors and symptoms. Algorithm scores are intended to guide consideration of an autism diagnosis. Evaluators who administered the ADI-R had achieved independent research reliability on this measure; due to clinical limits and attrition of available psychologists at some sites, the ADI-R was completed by a research reliable evaluator within the PREVeNT network when necessary. Given the length of time required for the ADI-R (i.e., approximately 1.5 hours for this age group) and restrictions on the amount of time clinicians could be in a room with a family due to the pandemic, this measure was often completed via phone or zoom. The shift from ADOS-2 to BOSA plus ADI-R provided an opportunity to continue to assess autism symptoms at each visit while COVID-19 restrictions were in place. A checklist based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) was also completed at each 24- and 36- month visit as part of the COVID-19 modifications.
Finally, the research team, including the developmental evaluator and the medical team, completed a Clinical Certainty Rating (CCR) utilizing information from developmental assessments, clinical history, and direct observation of the child. The completed CCR indicated whether a diagnosis of autism spectrum disorder (ASD) appeared appropriate (yes vs no). In addition, a clinical certainty score was provided ranging from a score of 1 (not at all certain) to 5 (very certain) regarding the ASD diagnosis.
STATISTICAL ANALYSIS
Justification for the sample size has been described previously (Bebin et al, 2024). A general linear model with repeated measures was used to compare the Bayley-III cognitive standard scores and Vineland-II adaptive behavior composite standard scores between early vigabatrin and placebo groups at 12, 24, and 36 months of age. Time was treated as a categorial variable, and an unstructured covariance was assumed among the cognitive scores between time points. In addition to treatment group, the models also included as covariates: participant sex and whether they were randomized before or after 7 months of age, both of which were used as stratifying factors for randomization. Pairwise comparisons were tested between groups at each time point via a contrast statement using the Kenward-Roger degrees of freedom for an approximated F statistic. Models were fit using SAS 9.4 software via Proc Mixed and a repeated statement, with parameter estimates obtained via restricted maximum likelihood. General linear multivariate models and the Hotelling-Lawley trace test were used to jointly test whether Bayley-III language and motor composite standard scores differed between early vigabatrin and placebo groups at each of the 12-, 24-, or 36-month time points while controlling for patient sex and whether the patient was randomized before or after 7 months of age. This multivariate approach was likewise used to compare Vineland-II communication, daily living skills, socialization, and motor skills standard scores between groups at these time points. Analysis was performed on an intent to treat basis, but no adjustments were made for missing data beyond the use of likelihood-based estimation methods assuming data to be missing at random. All statistical hypotheses were 2-sided with significance evaluated at an alpha level of 0.05 with no adjustments to multiple comparisons. No further statistical comparisons were made; rather, summary statistics of results are provided and should not be used to make definitive statistical statements.
RESULTS
Eighty-four participants were initially enrolled in the study, with 72 participants completing visits through 24 months of age. Seven participants did not complete their final 36-month visits, leaving 65 participants who completed visits through 36 months of age, which is the focus of the subsequent analyses. We assessed whether participants with missing 36-month outcome data differed from those with available 36-month data in terms of treatment assignment (Vigabatrin, Placebo, Watchful Waiting), sex, age of randomization, and seizure types. Participants with both seizure types had no missing data, while those with only one seizure type had more missing data.
Table 2 reports on participants completing at least one developmental assessment measure at the 36-month visit. Vigabatrin and placebo groups were equal in terms of sex. However, differences were noted in variant genotype with more participants with TSC2 variants in the vigabatrin group and more TSC1 and Variants of uncertain significance in the placebo group. Of those who were randomized, the majority of participants (77%) exhibited seizure onset prior to 7 months of age. Of the nine participants with both types of seizures in the placebo group, all of them had onset of spasms prior to onset of focal seizures. Focal seizures presented before spasm in 3 participants in the vigabatrin group.
Table 2:
Participant Demographics (N=65)
| Vigabatrin n=28 |
Placebo n=22 |
Straight to Open Label n=4 |
Watchful Waiting n=11 |
|
|---|---|---|---|---|
| Sex, n (%) | ||||
| Male | 12 (43%) | 10 (45%) | 2 (50%) | 8 (73%) |
| Female | 16 (57%) | 12 (55%) | 2 (50%) | 3 (27%) |
|
| ||||
| Genotyping, n (%) | ||||
| TSC1 | 1 (4%) | 3 (14%) | 0 (0%) | 4 (36%) |
| TSC2 | 27 (96%) | 16 (73%) | 3 (75%) | 5 (45%) |
| VUS or NMI | 0 (0%) | 3 (14%) | 1 (25%) | 2 (18%) |
|
| ||||
| Enrollment Age (months), mean (SD) | ||||
| 2.3 (1.4) | 1.9 (1.4) | 1.4 (0.6) | 4.2 (2.1) | |
|
| ||||
| Randomization Age Cohort, n (%) | ||||
| Randomized before age 7 months | 23 (82%) | 14 (64%) | — | — |
| Randomized after age 7 months | 5 (18%) | 8 (36%) | — | — |
|
| ||||
| Randomization Age (months), mean (SD) | ||||
| 5.0 (2.8) | 5.6 (3.4) | — | — | |
|
| ||||
| Seizure Type | ||||
| Spasm Only | 0 | 0 | 1 | — |
| Focal Only | 13 | 6 | 1 | — |
| Both | 6 | 9 | 2 | — |
|
| ||||
| Drug Resistant Epilepsy at 36 months | ||||
| Yes | 13 | 14 | 3 | |
| No | 15 | 7 | 1 | |
|
| ||||
| Age at Seizure Onset (months), mean (SD) | ||||
| 11.2 (5.8) | 7.8 (6.3) | 6.3 (4.8) | — | |
Neurocognitive Outcomes
Among the seven participants who were lost to follow-up between 24 and 36 months, neurocognitive outcomes were available at 24 months of age for only two participants. One participant was seizure-free at 24 months, with average cognitive and adaptive scores at the 12- and 24-month visits. The other participant had controlled seizures with low average cognitive and adaptive scores at both timepoints. Both participants were given non-ASD ratings on the CCR at 24 months. Figures 1 and 2 present composite scores for the Bayley-III domain scores as well as the Vineland-3 overall and domain scores.
Figure 1.
Bayley-III Outcomes at 36 months
Figure 2.
Vineland-3 Outcomes at 36 months
Cognitive Function:
At 12 months, Bayley-III mean cognitive scores were broadly within age-based expectations in the low average to average range [9]. Language and motor scores were somewhat lower, in the low average to below average range, approximately 1-1.5 standard deviations below the mean. Cognitive scores declined from 12 to 24 months but then remained stable between 24 and 36 months. Language and motor scores were generally stable over time with only slight declines in scores between the 12- and 36-month time points. No difference in the vigabatrin versus delayed group was seen at 36 months (see Table 3).
Table 3.
Neurocognitive Outcomes at Each Developmental Timepoint
| Repeated measure GLM estimated difference in Bayley-III cognitive standard score population means between early and delayed randomized vigabatrin groups | Wald Test p-value | |
|---|---|---|
| 12 months of age (n=51) | 3.04 (Vigabatrin - placebo) | 0.4413 |
| 24 months of age (n=52) | −1.12 (Vigabatrin - placebo) | 0.7775 |
| 36 months of age (n=46) | −4.33 (Vigabatrin - placebo) | 0.2695 |
| Randomized at age <7 months or >7 | −10.72 (<7 - >7) | 0.0083 |
| Male vs Female | −13.17 (Male - Female) | 0.0002 |
|
| ||
| Repeated measure GLM estimated difference in Vineland-II adaptive behavior composite standard score population means between early and delayed randomized vigabatrin groups | Wald Test p-value | |
| 12 months of age (n=53) | 0.91 (Vigabatrin - placebo) | 0.7644 |
| 24 months of age (n=53) | −4.44 (Vigabatrin - placebo) | 0.1697 |
| 36 months of age (n=49) | −6.77 (Vigabatrin - placebo) | 0.0819 |
| Male vs Female | −6.29 (Male - Female) | 0.0252 |
| Randomized at age <7 months or >7 | −10.27 (<7 - >7) | 0.0023 |
|
| ||
| Multivariate test of difference in mean Bayley-III Language and Motor composite scores between early and delayed randomized vigabatrin groups | HLT p-value | |
| 12 months (n=49) | 0.7744 | |
| 24 months (n=51) | 0.5037 | |
| 36 months (n=43) | 0.9637 | |
|
| ||
| Multivariate test of difference in mean Vineland-II subdomain standard scores (communication, daily living skills, socialization, and motor skills) between early and delayed randomized vigabatrin groups | HLT p-value | |
| 12 months (n=53) | 0.5949 | |
| 24 months (n=53) | 0.4888 | |
| 36 months (n=49) | 0.0495 | |
Table excludes patients in the watchful waiting and straight to open label groups.
Adaptive Function:
Adaptive scores were in the low average range for the seizure groups at 12 and 24 months and dropped to the below average range for early or straight to open label vigabatrin groups by 36 months (see Table 3). For all developmental measures, those in the watchful waiting group (i.e., never developed seizures) exhibited higher scores compared to the other cohorts.
Overall, few group differences were observed in developmental outcomes at 36 months. Males received lower scores on overall cognitive and adaptive skills as measured by the Bayley-III and Vineland-II. Adaptive behaviors were measured as lower among those participants who were randomized prior to 7 months of age.
Autism Symptoms:
Only three of the participants completed the 36-month visit utilizing the originally planned autism assessment battery pre-pandemic. Fifty-three participants received the full post-COVID battery outlined in Table 1 above. The Clinical Certainty Rating (CCR) was available for most of the participants, (n=58, 90.6%). Of the missing CCR, three were not completed because the measure was not in place at the participant’s 36-month visit (i.e., the pre-pandemic visits). A DSM-5 checklist was only available for one of these participants who did not have a CCR or the full ASD battery. Thus, for most cases with ASD outcomes, evaluators and the developmental teams had access to information from ASD-specific assessment measures to guide their completion of the CCR and/or the DSM-5 checklist.
On the CCR, 31% were rated as having ASD on the dichotomous variable (i.e., diagnosis of ASD vs no diagnosis of ASD). Participants identified with ASD in the placebo versus vigabatrin arm were not significantly different. In addition, most participants received a certainty score of 5, indicating the clinical research team was very certain in the outcome diagnosis selected. Overall, evaluators had higher certainty for cases believed not to have ASD (i.e., it was easier to rule out autism than determine it was present at 36 months).
DISCUSSION
Here we present the neurodevelopmental outcomes of the PREVeNT clinical trial at 36 months of age. Early treatment with vigabatrin did not alter neurodevelopmental outcomes at 36 months. Participants with epilepsy exhibited lower developmental scores on the Bayley-III and Vineland-II compared to those who did not develop seizures. Bayley-III cognitive scores declined over time in the participants with epilepsy, which is consistent with other studies [1], [6], [18], [19]. Language scores in all groups were lower at 12 months [9]. However, participants with epilepsy continued to perform in the below average range whereas participants without epilepsy improved over time. Repeated measures assessment did not detect any differences in Bayley-III or Vineland-II composite scores, except for sex and age at randomization. The reasons for the sex differences are unclear. Notably, the difference between placebo and treatment groups was a median of 44 days, and the short duration between time of treatment for both the treatment group and placebo group may be an additional factor in the lack of differences in outcomes.
Developmental quotient decreased over time. This decrease is likely due to several factors including a widening of the gap between children with TSC and their peers due to a slower rate of acquisition of skills, increased sensitivity of assessment measures at later ages, and the presence of seizures. Further studies following long-term neurodevelopmental outcomes are critical in understanding the best way to measure development in rare neurodevelopmental conditions, the dynamic nature of developmental trajectories, and impact of early interventions (pharmacologic and non-pharmacologic).
At 36 months, 31% of participants were rated as exhibiting a diagnosis of ASD, which is consistent with rates of comorbid ASD and epilepsy in TSC found in prior research [5]. Rates of ASD did not differ among participants with epilepsy. No participants without epilepsy were diagnosed with ASD. Epilepsy is a known risk factor for developmental delay and ASD in TSC [20], [21]. In the TACERN study, participants with a higher seizure burden exhibited significantly lower developmental quotients at 36 months [7] and seizure onset prior to 12 months was associated with higher rates of developmental delay and autistic behaviors at 24 months [6]. Consistent with the natural history of TSC, most participants in PREVeNT exhibited seizure onset prior to 12 months. Most commonly reported seizure types were infantile spasms and focal seizures with several participants in all treatment groups exhibiting both seizure types.
EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy—Tuberous SclerOsis ComPlex) investigated early clinical markers of ASD in 82 young children up to age 24 months with TSC [22]. Similar to PREVeNT, children underwent cognitive and behavioral assessments with the Bayley-III and the ADOS-2. In EPISTOP, ASD risk was identified in 30% of participants based on the ADOS-2 score and DSM-5 clinical criteria at 24 months of age; 17% of these children also exhibited exceptionally low cognitive scores on the Bayley-III. Of the participants without ASD (N=44), 13 had exceptionally low cognitive scores. Like PREVeNT, EPISTOP evaluated treatment response to vigabatrin, and there was no difference in ASD risk or developmental scores in participants receiving early versus conventional treatment. In the EPISTOP trial the median Cognitive Bayley-III score exceeded 70 at 24 months of age, while Cognitive Bayley-III score exceeded 80 in the PREVeNT study.
The effect of the COVID-19 pandemic on this longitudinal follow-up study must also be considered when interpreting developmental findings. Shifts in access to intervention may have impacted outcomes, given that services such as speech therapy, occupational therapy, and early intervention were stopped, limited, and/or shifted to virtual delivery during the course of the study. Data regarding intensity and frequency of interventions during the study were not collected, so the impact of these changes is unknown. However, it is possible these shifts undermined developmental gains in the participants. Further, given this was a multisite study, some communities may have shut down longer or more completely, so this effect may not have had the same impact upon all participants.
Overall, this initial analysis of endpoint outcomes for PREVeNT supports previous suggestions that patients’ participation in the trial itself may contribute to developmental outcomes in a manner that is not impacted by pharmacological treatment of seizures [23].Taken together, intervention studies with infants with TSC are demonstrating small but notable gains in developmental outcomes that may not be clearly associated with the treatment but instead result from earlier diagnosis, monitoring epilepsy, initiating treatment, and referral to early intervention services. The approach of closely monitoring infants with TSC has impacted clinical decision-making and care in research and non-research settings, so the comparison of outcomes cannot be made directly. In other words, the outcomes of TSC are indirectly impacted by the study designs themselves, and each later cohort benefits from the clinical and research experiences of previous cohorts.
Limitations
A clear limitation of the current study is the number of participants that were lost to follow-up between the 24- and 36-month visits. This is likely related to multiple factors, including that some of these participants were doing well medically and developmentally and that many of the 36-month visits were scheduled in a time where COVID-19 restrictions and concerns were heightened across sites. In general, participants who did not complete the final assessments were less impacted by TSC at 24 months, characterized as having no seizures or controlled seizures, and exhibited low average to average cognitive and adaptive development. It is possible that the families who presented for 36-month follow up navigated and risked the COVID-19 concerns due to ongoing medical and developmental concerns for their child. There was also variability in the level of COVID-19 restrictions across the sites included in the study, where scheduling and completion of measures was more limited in some sites versus some sites that had less stringent clinical guidelines during the last 6-9 months of the study. Finally, recruitment and retention may have also been impacted, as families may not have been able to enter or continue their participation given the greater burdens placed upon them during COVID-19 (e.g., homeschooling their children).
As noted by Aman and Pearson [10], the COVID-19 pandemic introduced additional variability to research studies that were in the data collection phase during this period—and studies that included data collected before, during, and after shutdowns were likely the most affected. Given the stressors on families during this time, there may have also been increased variability with regard to medication adherence and monitoring physical and behavioral effects of the study drug (e.g., not being able to “read” nonverbal cues of the children and their parents). Participants may have also completed their interviews (e.g., Vineland-II) virtually from home during the pandemic, as opposed to completing them in the clinic prior to COVID-19. Fortunately, previous studies have suggested that the effect of procedural variability from these sources may not be significant, given that data completed in the home or the office/clinic are essentially identical [24], [25], [26].
Further, although clinical teams utilized ASD-specific assessment measures that can guide clinical diagnosis, the evaluations were conducted in the research context and were not corroborated by external clinical evaluators. Specifically, evaluators did not endeavor to complete a comprehensive diagnostic evaluation for clinical purposes. However, the obtained measures, including the Clinical Certainty Rating and DSM-5 checklist, were well-informed in most cases and were determined by licensed clinical psychologists. The variability of assessment tools and limited time spent with the participant likely contributed to variability in outcomes as well. Specifically, clinician judgement and approaches to diagnostics may have varied across sites. Further analysis of ASD evaluation scores in this cohort is warranted and ongoing for this cohort and, more broadly, in other longitudinal studies of infants with TSC.
The 36-month end point of this study does not allow for understanding ongoing changes in neurodevelopmental outcomes as participants age, indicating the need for longer-term follow-up in this population. Harmonization of data for participants from PREVeNT and other infant TSC studies who are subsequently enrolled in longitudinal studies as older children has potential to connect data from younger ages to track longer-term developmental and ASD diagnostic outcomes. These longer-term follow-up strategies would continue to elucidate the neurodevelopmental trajectory of infants with TSC, seizures, and ASD. Future evaluations should consider additional contextual variables, such as SES, presence of TSC in parents and family members, TSC type, and other factors that may influence outcomes in this population.
The current study did not explore the impact of concomitant medications as a variable impacting outcomes, which is one of many important variables related to cognitive outcomes that should be considered in this population in both research and clinical settings. Such other factors are highlighted in recent findings by Farach and colleagues [27] within the PREVeNT sample, suggesting that TSC genotype impacts age of seizure onset and severity and providing context for the complexity of this population. Participants in the study with medically refractory seizures were on multiple medications, although it is hypothesized that the primary driver of cognitive outcomes was more related to seizure onset and burden. The impact of medications and the outcomes for a broader range of seizure types is the emphasis for ongoing analyses within this sample.
CONCLUSION
Results of early versus conventional treatment with vigabatrin did not alter neurodevelopmental outcomes at 36 months in infants with TSC. This is likely due to multiple factors including trial design, differences in underlying genotype, close monitoring of participants, and impact of the COVID-19 pandemic. These factors may have significantly impacted developmental outcomes independent of initiation of vigabatrin.
Supplementary Material
Highlights.
Cognitive scores declined over time in participants with epilepsy.
At 36 months, 31% of participants were diagnosed with ASD.
Rates of ASD did not differ among participants with epilepsy.
No participants without epilepsy were diagnosed with ASD.
Early versus standard vigabatrin treatment did not alter developmental outcomes.
Acknowledgments:
Research reported in this publication was supported by the NIH National Institute of Neurological Diseases and Stroke (NINDS) under award number 1U01NS092595. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Special gratitude and recognition go to the TSC families and especially the infants with TSC who participated. Without the support of the TSC community and the TSC Alliance and their dedication to the PREVeNT Trial, this effort would not have been possible. We would like to thank Lundbeck for generously providing the Sabril for the PREVeNT Trial, the TSC Alliance for supplemental funding for data analysis, and Bcureful and Pediatric Epilepsy Research Foundation for participant travel support.
Disclosures:
JKC is on the Scientific Advisory Board for Marinus Pharmaceuticals.
DAP has received travel reimbursement and research support from Curemark LLC,and has served as a consultant to Curemark LLC.
PED receives partial salary support from the NIH for participation in studies related to TSC, and previously received funding from Aucta Pharmaceuticals for a study of topical sirolimus for facial angiofibromas in TSC and Marinus Pharmaceuticals for a study of ganaxolone for TSC-related epilepsy.
MS had grant support from Neurvati Neurosciences and has served on Scientific Advisory Boards for Neurogene and Noema.
DAN has received a speaking honorarium from Upsher-Smith.
GRC engages in the following: Data and Safety Monitoring Boards- Applied Therapeutics, AI therapeutics, AMO Pharma, Argenx, Astra-Zeneca, Avexis Pharmaceuticals, Bristol Meyers Squibb, CSL Behring, Cynata Therapeutics, DiamedicaTherapeutics, Horizon Pharmaceuticals, Immunic, Inhibrix, Karuna Therapeutics, Kezar Life Sciences, Medtronic, Merck, Meiji Seika Pharma, Mitsubishi Tanabe Pharma Holdings, Prothena Biosciences, Novartis, Pipeline Therapeutics (Contineum), Regeneron, Sanofi-Aventis, Teva Pharmaceuticals, United BioSource LLC, University of Texas Southwestern.Consulting or Advisory Boards- Alexion, Antisense Therapeutics/Percheron, Avotres, Biogen, Clene Nanomedicine, Clinical Trial Solutions LLC, Endra Life Sciences, Cognito Therapeutics, Genzyme, Genentech, Hoya Corporation, Immunic, Immunosis Pty Ltd, Klein-Buendel Incorporated, Kyverna Therapeutics, Inc. , Linical, Merck/Serono, Noema, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Revelstone Consulting, Roche, SAB Biotherapeutics, Sapience Therapeutics, Scott&Scott LLP, Tenmile.
DAK has received consulting fees and/or honoraria from serving on Advisory Boards to Jazz Pharmaceuticals, Longboard Pharmaceuticals, and BioCodex. DAK also recently served on the Board of Directors of the TSC Alliance.
Potential Conflicts of Interest
MS had grant support from Neurvati Neurosciences and has served on Scientific Advisory Boards for Neurogene and Noema.
Footnotes
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Data Availability Statement
All data generated during the performance of the project will be fully disseminated to the research community through presentations at national/international meetings as well as publication of results and interpretation in peer-reviewed articles. Data collected via this trial (in deidentified format) will be available to interested researchers for secondary analyses after trial completion. In compliance with the NIH guidelines, a complete, cleaned, and deidentified dataset and any supporting documentation will be submitted to the NINDS Office of Clinical Research within 1 year of the primary publication or within 18 months of the last study visit of the last subject, whichever occurs first.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data generated during the performance of the project will be fully disseminated to the research community through presentations at national/international meetings as well as publication of results and interpretation in peer-reviewed articles. Data collected via this trial (in deidentified format) will be available to interested researchers for secondary analyses after trial completion. In compliance with the NIH guidelines, a complete, cleaned, and deidentified dataset and any supporting documentation will be submitted to the NINDS Office of Clinical Research within 1 year of the primary publication or within 18 months of the last study visit of the last subject, whichever occurs first.