Tough to treat: What we know about managing PCDH19-related epilepsy - Systematic review

Abstract

Background

PCDH19-related epilepsy is a rare, X-linked developmental and epileptic encephalopathy that primarily affects heterozygous females. It is caused by pathogenic variants in the PCDH19 gene, encoding protocadherin-19, a calcium-dependent adhesion protein involved in neurodevelopment. The disorder’s hallmark is cellular interference, leading to brain mosaicism and clinical features including early-onset clustered focal seizures, cognitive impairment, and frequent comorbidity with autism.

Objective

This review synthesizes current evidence on treatment approaches for PCDH19-related epilepsy, covering conventional anti-seizure medications, adjunctive therapies, and non-pharmacological interventions, while highlighting emerging strategies and research gaps.

Methods

A systematic literature search was conducted in PubMed and Scopus (January 2008 – April 2025).

Results

27 studies were included, involving patients with genetically or clinically confirmed PCDH19-related epilepsy and reported treatment outcomes. The condition is often pharmacoresistant, with highly variable responses. Levetiracetam, especially when initiated early, showed the most consistent seizure reduction, followed by clobazam and potassium bromide. Topiramate and stiripentol showed potential in isolated reports. Carbamazepine was often ineffective or worsened seizures. Adjunctive agents – including corticosteroids, ganaxolone – had variable efficacy; ganaxolone showed promise in recent trials. Non-pharmacological interventions, like vagus nerve stimulation, ketogenic diet, and temporal lobectomy, reduced seizures in some cases but lacked standardized evidence.

Conclusions

Treatment remains challenging due to clinical heterogeneity and limited high-quality data. Early, individualized, multimodal approaches appear most beneficial. There is a need for genotype-informed, multicenter trials and standardized outcome measures to guide evidence-based care.