Abnormal structural and functional brain connectivity in gray matter heterotopia.

PURPOSE: Periventricular nodular heterotopia (PNH) is a malformation of cortical development associated with epilepsy and dyslexia. Evidence suggests that heterotopic gray matter can be functional in brain malformations and that connectivity abnormalities may be important in these disorders. We hypothesized that nodular heterotopia develop abnormal connections and systematically investigated the structural and functional connectivity of heterotopia in patients with PNH. METHODS: Eleven patients were studied using diffusion tensor tractography and resting-state functional connectivity MRI with bold oxygenation level-dependent (BOLD) imaging. Fiber tracks with a terminus within heterotopic nodules were visualized to determine structural connectivity, and brain regions demonstrating resting-state functional correlations to heterotopic nodules were analyzed. Relationships between these connectivity results and measures of clinical epilepsy and cognitive disability were examined. KEY FINDINGS: A majority of heterotopia (69%) showed structural connectivity to discrete regions of overlying cortex, and almost all (96%) showed functional connectivity to these regions (mean peak correlation coefficient 0.61). Heterotopia also demonstrated connectivity to regions of contralateral cortex, other heterotopic nodules, ipsilateral but nonoverlying cortex, and deep gray matter structures or the cerebellum. Patients with the longest durations of epilepsy had a higher degree of abnormal functional connectivity (p = 0.036). SIGNIFICANCE: Most heterotopic nodules in PNH are structurally and functionally connected to overlying cortex, and the strength of abnormal connectivity is higher among patients with the longest duration of epilepsy. Along with prior evidence that cortico-cortical tract defects underlie dyslexia in this disorder, the current findings suggest that altered connectivity is likely a critical substrate for neurologic dysfunction in brain malformations.

Early cognitive and behavioral problems in children with nodular heterotopia.

Adults with periventricular nodular heterotopia (PNH) have epilepsy and dyslexia, but most have normal intelligence. It is not known whether PNH-related reading difficulty can be detected earlier in childhood or whether associated behavioral problems are present. We studied 10 children with PNH, 3 of whom did not have seizures, and 10 matched controls with neuropsychological testing and parental rating instruments at two time points separated by about 1 year. Children with PNH performed significantly worse than controls on a task related to reading fluency. In addition, those with PNH showed significantly worse adaptive skills, and a measure of conduct problems significantly worsened over time. Mood and behavioral problems were reported more commonly, though not significantly so, in children with PNH. These findings demonstrate that reading dysfluency can be evident in children with nodular heterotopia, even in the absence of epilepsy, but also highlight difficulties with behavior in this population.

Cerebral volumetric analysis over time in children with malformations of cortical development: a quantitative investigation.

Malformations of cortical development are common neurological disorders characterized by disruptions in the normal development of cerebral gray and white matter during fetal life. We performed a quantitative, partly longitudinal investigation of cerebral volumes in a cohort of children with cortical malformations to investigate how their anatomical abnormalities change over time. Cortical malformation subjects showed volumetric curves that were comparable with those reported for healthy individuals, and reached peak cerebral volume, gray matter volume, and white matter volume at ages similar to those reported for healthy children. Volumes of heterotopic gray matter, however, demonstrated increases that were out of proportion to changes in cortical volume or caudate nucleus volume, suggesting that misplaced gray matter can have a unique pattern of maturation. Our findings demonstrate that overall brain growth in children with cortical malformations appears to mirror that of the healthy population, although malformed regions can show distinct growth patterns.

The relationship of interictal epileptiform discharges to clinical epilepsy severity: a study of routine electroencephalograms and review of the literature.

Electroencephalograms are widely used to detect interictal epileptiform discharges (IEDs) in patients with a known history of seizures. However, previous studies have not found a consistent association between the presence or frequency of IEDs and clinical epilepsy severity, possibly because of differences in subject characteristics and recording techniques. We sought to investigate this relationship in a population and setting reflective of the most common clinical usage. We analyzed electroencephalograms and clinical records of all consenting patients with a history of at least two presumed focal-onset seizures who presented for routine electroencephalograms recording over 1-year time in an academic neurophysiology laboratory (n = 129). Despite adequate statistical power, we did not find an association between the presence or absence of IEDs or IED frequency and the most recently determined seizure frequency (median, 4 per year). A higher IED incidence was seen in subjects with longer epilepsy duration (P = 0.04). Neither IED incidence nor frequency (median, 10.0 per hour) correlated with age or antiepileptic drug use. Our results differ from those of some previous studies, most of which focused on more narrow subject populations, suggesting that the patient's clinical circumstances must be taken into account before assuming the utility of IEDs on routine electroencephalography in predicting epilepsy severity.

Gray matter volumes and cognitive ability in the epileptogenic brain malformation of periventricular nodular heterotopia.

Periventricular nodular heterotopia (PNH) is a brain malformation clinically characterized by the triad of epilepsy, normal intelligence, and dyslexia. We investigated the structure-function relationship between cerebral volumes and cognitive ability in this disorder by studying 12 subjects with PNH and 6 controls using volumetric analysis of high-resolution anatomical MRI and neuropsychological testing. Total cerebral volumes and specific brain compartment volumes (gray matter, white matter, and cerebrospinal fluid) in subjects with PNH were comparable to those in controls. There was a negative correlation between heterotopic gray matter volume and cortical gray matter volume. Cerebral and cortical volumes in PNH did not correlate with Full Scale IQ, unlike in normal individuals. Our findings support the idea that heterotopic nodules contain misplaced neurons that would normally have migrated to the cortex, and suggest that structural correlates of normal cognitive ability may be different in the setting of neuronal migration failure.