Elsevier

Epilepsy & Behavior

Volume 51, October 2015, Pages 321-327
Epilepsy & Behavior

Phenotypic and imaging features of FLNA-negative patients with bilateral periventricular nodular heterotopia and epilepsy

https://doi.org/10.1016/j.yebeh.2015.07.041Get rights and content

Highlights

  • In the 71 patients with bilateral PVNH, the incidence of febrile seizures was 21.2%.

  • High heterotopia burden, female gender, and trigonal location are correlated.

  • Hemispheric heterotopia burden and laterality of ictal onset may not be correlated.

Abstract

Purpose

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development due to impaired neuronal migration resulting in the formation of nodular masses of neurons and glial cells in close proximity to the ventricular walls. We report the clinical characteristics of the largest case series of FLNA-negative patients with seizures and bilateral periventricular heterotopia.

Methods

Participants were recruited through the Epilepsy Phenome/Genome Project (EPGP), a multicenter collaborative effort to collect detailed phenotypic data and DNA on a large number of individuals with epilepsy, including a cohort with symptomatic epilepsy related to PVNH. Included subjects had epilepsy, and MRI confirmed bilateral PVNH. Magnetic resonance imaging studies were visually and quantitatively reviewed to investigate the topographic extent of PVNH, symmetry, and laterality.

Key findings

We analyzed data on 71 patients with bilateral PVNH. The incidence of febrile seizures was 16.6%. There was at least one other family member with epilepsy in 36.9% of this population. Developmental delay was present in 21.8%. Focal onset seizures were the most common type of seizure presentation (79.3%). High heterotopia burden was strongly associated with female gender and trigonal nodular localization. There was no evidence for differences in brain volume between PVNH subjects and controls. No relationship was observed between heterotopic volume and gender, developmental delay, location of PVNH, ventricular or cerebellar abnormalities, laterality of seizure onset, age at seizure onset, and duration of epilepsy.

Significance

A direct correlation was observed between high heterotopia burden, female gender, and trigonal location in this large cohort of FLNA-negative bilateral PVNH patients with epilepsy. Quantitative MRI measurements indicated that this correlation is based on the diffuse nature of the heterotopic nodules rather than on the total volume of abnormal heterotopic tissue.

Introduction

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development due to impaired neuronal migration, resulting in the formation of nodular masses of neurons and glial cells in close proximity to the ventricular walls and through the white matter [1]. Several large case series of patients have described nodular heterotopia that include the periventricular, subcortical, and leptomeningeal varieties [2]. Most of these studies have included a variety of patients with different imaging abnormalities (unilateral or bilateral) and associated neurologic phenotypes. The most common presenting findings of patients with PVNH are central nervous system (CNS) malformations, other congenital malformations, seizures, and developmental delay [3]. Central nervous system malformations typically include ventriculomegaly, cortical and cerebellar abnormalities, and abnormalities of the corpus callosum [3]. Cardiac malformations are the most common non-CNS abnormality associated with FLNA-related PVNH [3]. The majority of the seizures in this population are focal onset and frequently difficult to treat [3], [4], [5]. Periventricular nodular heterotopia has been described in association with Filamin 1 (FLNA) mutations, particularly in females and in families [8]. However, the vast majority of sporadic cases have no known mutations.

We report the imaging and clinical characteristics of a large case series of FLNA mutation-negative patients with bilateral periventricular heterotopia and epilepsy ascertained by the Epilepsy Phenome/Genome Project (EPGP). The aim of this study was to determine how MRI-based imaging measures, utilizing qualitative and quantitative MRI assessments, relate to clinical features of individuals with PVNH. Specifically, we investigated the relationship between clinical characteristics of FLNA mutation-negative patients with bilateral periventricular heterotopia and qualitative assessment of (i) lesion location and (ii) number of nodules, and (iii) quantitative assessment of heterotopic gray matter (GM) volume.

Section snippets

Ascertainment

The present series includes 77 patients enrolled from 19 sites located within and outside of the United States recruited through the Epilepsy Phenome/Genome Project (EPGP), a multicenter collaborative effort to collect detailed phenotypic data and DNA on a large number of individuals with epilepsy, including a cohort with symptomatic epilepsy related to PVNH, with the ultimate goal of establishing genotype–phenotype correlations in epilepsy [6]. Each site's local institutional review board

Descriptive results

Six patients were excluded after exome analysis revealed a FLNA mutation that had not been identified prior to enrollment in the EPGP cohort. Thus, 71 FLNA-negative cases were included with bilateral PVNH. Of these, 56 cases had MRI data that were suitable for visual assessment and 43 cases (28 female, mean age: 22.81 ± 10.7 years) had MRI scans that were adequate for processing using the quantitative methods described above. For each category described below, n denotes the total number of

Discussion

This is the largest reported cohort of FLNA-negative bilateral PVNH patients with epilepsy. Filamin 1 mutations are frequently found in females as an X-linked trait [15]. The mutation is also associated with a high rate of prenatal lethality in males [12]. Although not statistically significant, there was a trend towards a female predominance in our cohort of FLNA-negative patients. Interestingly, when controlling for gender, this analysis of FLNA-negative patients showed a marginally

Acknowledgments

This study was supported by NINDS U01 NS 053998, as well as planning grants from the Finding a Cure for Epilepsy and Seizures (FACES) Foundation, the Andrew's Foundation and the Richard Thalheimer Philanthropic Fund. A.P. was supported by the NINDS (K23 NS069784).

We would like to acknowledge the recruitment contributions of the EPGP Community Referral Network (CRN). The CRN consists of health-care professionals not paid by the EPGP grant who refer eligible families to EPGP. A list of individual

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      Previous studies also reported that 51–74% of anterior predominant PVNH were negative for FLNA variants [2,17,22]. As for other associated features, we found that FLNA positive cases are likely to have more systemic manifestations (∼78%) while none of the FLNA negative patients had associated internal organ abnormality or cardiovascular abnormality [23–25]. The most common extracerebral features are cardiac abnormalities followed by gut dysfunction and joint hypermobility.

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