Introduction

• Prevalence: Epilepsy affects 50–70% of individuals with RTT, though earlier studies suggested rates as high as 90%. Variability in study designs and diagnostic criteria contribute to these differences.
• Epileptic and Nonepileptic Events: RTT patients often experience nonepileptic paroxysmal events, which can complicate diagnosis.
• MECP2 Mutations: Epilepsy is more common in individuals without MECP2 mutations, often due to the early epileptic variant linked to CDKL5 mutations.

Natural History

• Onset: Seizures typically appear around 3–4 years of age (Stage 3). Earlier onset is associated with more severe disease and poor prognosis.
• Age Trends: Epilepsy peaks in severity during adolescence but may improve by the second decade of life, though findings vary across cohorts.
• Seizure Types: Generalized tonic-clonic, simple partial, and complex partial seizures are most common. Fever-induced seizures and ESES are notable concerns.
• EEG Features: Centrotemporal spikes, slow-wave discharges, and rhythmic slowing of the background are characteristic.

Genotype-Phenotype Relationships

• Mutations: Specific MECP2 mutations (e.g., p.Thr158Met) are linked to more severe epilepsy. Other mutations (e.g., p.Arg255X) are associated with milder forms.
• BDNF Polymorphisms: Variants influencing BDNF expression are associated with seizure onset and severity.

Treatment

• Medications:
  • First-line: Valproic acid (effective for multiple seizure types and interictal EEG abnormalities) and lamotrigine.
  • Alternatives: Carbamazepine (caution for generalized spike discharges), topiramate (especially for hyperventilation), levetiracetam, and benzodiazepines.
  • Avoid: Phenobarbitone (causes drowsiness, less effective).
• Advanced Therapies: Ketogenic diet and vagal nerve stimulation may help in drug-resistant cases.
• Management Approach: Avoid overtreatment of infrequent or mild seizures. Epileptiform activity without clinical seizures does not require treatment.

Special Considerations

• Variants:
  • Early Epileptic Variant: Typically linked to CDKL5 mutations, presenting with early drug-resistant seizures.
  • Preserved Speech Variant (PSV): May show milder epilepsy, but severity varies within the subtype.
  • MECP2 Duplications: More common in males, associated with severe epilepsy and developmental regression.

Conclusion

• Diagnosis and Management: Early diagnosis and tailored management of epilepsy are critical for improving the quality of life for RTT patients and their families.
• Prognosis: While epilepsy can be severe, it often becomes more manageable with age and appropriate treatment.