Abstracts

Rationale: Rett syndrome (RTT) is often associated with epilepsy. However, estimates of prevalence vary due to study design. Seizure frequency is thought to decrease with age, yet no prospective study of seizure remission exists. Seizure severity has been associated with Methyl CpG 2 (MECP2) mutation and disease severity. Using a large prospective, longitudinal cohort of subjects with typical RTT, we examined prevalence, age, mutation, severity, and remission of epilepsy in RTT.Methods: The Rare Diseases Clinical Research Network for RTT is a prospective natural history study. Evaluations included clinical diagnosis and severity, MECP2 mutation, and physician assessment of seizures. We determined prevalence of epilepsy and drug-resistant epilepsy (DRE) in our cohort, and compared: ages of onset and remission using t-test, effect of mutation using ANOVA, and seizure type, polypharmacy, VNS, and KD using chi-square test. Results: 1121 subjects were recruited; 862 met criteria for typical RTT and were followed for a mean of 3.4y (up to 7y). Epilepsy prevalence was 30% at first visit (260/862) and 39% at last visit (327/833). Risk of seizures was 55% based on history of seizures prior to first visit (471/862) and 53% based on seizures during the study (454/862). Of those with active seizures at first visit, 24% (63) experienced remission, 19% (12) off medication. Of 88 with weekly seizures, 20% (18) decreased to monthly or less, and 23% (20) experienced remission on medication. Of 69 with daily seizures, 17% (12) decreased to weekly, 17% to monthly or less, 12% (8) experienced remission on medication and 10% (7) off medication. Polypharmacy, use of VNS and KD were all associated with persistent seizures (p<0.001). However, 18% of those on 2 or more medications achieved remission, and 6% discontinued medication. VNS was used in 26; 2 were seizure free at last visit. The KD was used in 28; 8 were seizure free at last visit. Overall, 33% (155/471) had DRE, 15% of whom had daily seizures. Subjects who experienced remission (15.4y +/-9y) were younger on average than those who did not (18.0y +/-10y, p<0.05), however age of onset (mean 4.2y, range 0.2-16) was not associated with remission. DRE was not associated with mutation category or seizure type, but was associated with scoliosis (p<0.001), hyperventilation and difficulty chewing/swallowing (p<0.05).Conclusions: Seizure prevalence in this RTT cohort, representing 5% of the entire US RTT population, was lower than previous estimates. Prevalence of DRE was similar to the general epilepsy population (20-40%). Frequent seizures are rare in Rett syndrome, with a high likelihood of improvement. Polypharmacy often results in remission; however, additional management strategies (i.e. VNS/KD) are rarely helpful in RTT. Certain comorbidities of RTT are associated with DRE, and while seizure remission often occurs in adolescence, age range is broad. These findings demonstrate that although seizures occur in about half of all patients with RTT, the majority can be managed using traditional medical strategies, with high likelihood of remission and persistent epilepsy in 1/3.