Defining the electroclinical phenotype and outcome of PCDH19‐related epilepsy: A multicenter study

Abstract

Summary Objective PCDH19‐related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever‐induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19‐related epilepsy and better define the epileptic phenotype, genotype‐phenotype correlations, and related outcome‐predicting factors. Methods We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19‐related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. Results At last follow‐up (median = 12 years, range = 1.9‐42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure‐free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty‐six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). Significance We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long‐term follow‐up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

A standardized patient-centered characterization of the phenotypic spectrum of PCDH19 girls clustering epilepsy

“…We also showed that individuals with seizure onset before 12 months of age had more severe ID than those with seizure onset after 12 months 9 . A recent retrospective study validated this finding and also showed an association between earlier seizure onset and the presence of ASD 4 . Reviewed studies were typically based on small samples, lacked systematized approaches, and focused on only one clinical outcome.…”

“…The hallmark of GCE is clusters of focal seizures, often coinciding with fever 1 . While the seizure semiology associated with GCE has been characterized [1][2][3][4] , the neuropsychiatric profile has not been well established.…”

Complex Febrile Seizures: An Update

“…Further, PCDH19-positive mutations, also known as epilepsy with mental retardation in females, are invariably linked to a high sensitivity to fever. 16,17…”

Febrile Seizure Plus and PCDH19-Related Epilepsy Syndromes

“…The seizure frequency decreases after the age of 2 and 10 years. 29 Some patients become seizure free at the age of 12 years. This finding is independent of age at seizure onset.…”

“…This finding is independent of age at seizure onset. 29,30 Clinically, the seizures may start with a myoclonic jerk followed by a period of reactivity with a fearful look or startled jerks, followed by mild tonic, asymmetric tremulous-ness movements, and mild clonic activity. This semiological sequence is usually seen associated with PCDH19-related epilepsy.…”