The presence of PVNH is commonly associated with seizures and cognitive delay.11,14 Therefore, the finding of heterotopia on prenatal imaging was thought to be a contraindication initially to fetal repair of MMC. We report that the presence of PVNH in patients with a prenatal diagnosis of MMC is not associated with increased neurodevelopmental at approximately 1 year of age and is also not significantly associated with postnatal epilepsy/seizures. To our knowledge, this is the first reported account of neurocognitive and epilepsy outcomes in patients with a prenatal diagnosis of both open spinal dysraphism and PVNH.
MMC is associated with Chiari II malformation as well as other neocortical anomalies such as PVNH.13,23,24 Heterotopia has previously been reported in 11% of fetal myelomeningocele cases,25 and cerebellar heterotopia has been associated with hydrocephalus and other gyration disorders (90% and 33%, respectively).26 The sensitivity and specificity of PVNH detection on prenatal MRI has been previously reported as 73% and 92%, respectively.27 In this study cohort, the sensitivity of prenatal MRI predicting heterotopia confirmed on postnatal MRI was 43%, specificity was 89%, positive predictive value was 63%, and negative predictive value was 78%. For those patients who initially did not exhibit heterotopia but then ultimately had confirmed PVNH on postnatal MRI, we hypothesize that the imaging quality may be the primary limiting factor rather than a true absence of PVNH on prenatal imaging.
Prenatal atrial diameter, postnatal FOR, and heterotopia were not significant risk factors for seizures/epilepsy in our cohort. The incidence of ventriculomegaly in the second trimester in patients with open spina bifida, which is defined as lateral ventricular diameter of \(\ge\) 10 mm, has been reported to range from 45–89%.28,29 Mild-to-moderate and severe ventriculomegaly occurs as frequently as 85 and 15%, respectively.30 Ventricular enlargement has previously been shown to be a common radiographic finding in children with seizures/epilepsy.31 PVNH has also been linked with ventricular dilation and clinical hydrocephalus,6,9,15 but our findings do not show that there is an association between ventricular size and presence of seizures/epilepsy.
Across all subtypes of gray matter heterotopia, epilepsy has been reported to be diagnosed at a mean age of 8.2 years (range: 3 months to 16 years).15 An autosomal recessive form of PVNH caused by an ARFGEF2 gene mutation exhibits seizures in infancy,32 while X-linked PVNH has been reported to be diagnosed around 15 years.33 Mean seizure onset for sporadic forms of PVNH has been reported to be 7.9 years.34 Therefore, the absence of an association with epilepsy in our case series does not necessarily mean that seizures will not develop later. This speaks to the importance of long-term follow-up in this specific population.
The median age at the time of formal neurodevelopmental testing was 14.1 months in our study for no heterotopia, 12.2 months for unilateral heterotopia, and 11.8 months for bilateral heterotopia. The average test scores were not significantly different for cognitive, language, or motor domains on standardized neurodevelopmental testing for the no heterotopia cohort compared to the unilateral/bilateral heterotopia groups. We have previously detailed a “characteristic” profile of specific neurobehavioral challenges seen in MMC children and adolescents, in which assembled processing is often negatively impacted by underlying neuropathophysiology, but associative processing is more impacted by environment.35 Given that our study does not demonstrate significant differences for the components of the neurodevelopmental testing, specifically in the context of heterotopia, further long-term studies are needed to discern the neurobehavioral profile in these patients from PVNH.
The present study has some limitations, primarily due to its retrospective nature. Patients seen at the Center for Fetal Diagnosis and Treatment are referred nationally and internationally, and as such, follow-up for seizures/epilepsy and neurodevelopmental care often occurs at local care institutions and were not available. Separately, genetic testing was not performed to better characterize underlying pathological contributions. In this study, the neurodevelopmental testing was administered at approximately 1 year of age, and therefore, long-term follow-up is needed to better understand both neurocognitive outcomes and the true incidence of epilepsy at older ages. Given the advancement of neuroimaging to evaluate MMC pregnancies, it is imperative that the multidisciplinary teams involved in fetal consultation understand the prognosis of PVNH to better counsel families.