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.     

Cerebro-cerebellar functional connectivity profile of an epilepsy patient with periventricular nodular heterotopia

Periventricular nodular heterotopia (PNH) is a rare malformation of cortical development often associated with drug resistant focal onset epilepsy. The link between nodules and neocortex have been demonstrated with depth electrodes investigations showing that seizures may arise from both structures. In the last years fMRI resting-state (fMRI-RS) have received a surge in interest due to its capability to track non-invasively physiological and pathological relevant differences in brain network organization. We performed a cerebro-cerebellar voxel-wise and region-of-interest resting state fMRI (RS-fMRI) functional connectivity analysis in a seizure-free epilepsy patient with a PNH in the right temporal horn. Our finding confirms a spontaneous synchronization between PNH and its surrounding cortex, specifically in the inferior temporal, fusiform and occipital gyrus. We also found a significant connectivity with bilateral cerebellum, more intense and widespread on the PNH cerebellar contralateral lobule. RS-fMRI confirmed its potential as a promising tool for non-invasive mapping of cortical and subcortical brain functional organization.     

Functional MRI interactions between dysplastic nodules and overlying cortex in periventricular nodular heterotopia

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development associated with epilepsy. It is unclear whether the epileptogenic focus is the nodule, overlying cortex, or both. We performed electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) in a patient with bilateral PVNH, capturing 45 "left temporal" epileptiform discharges. The relative time at which fMRI-involved regions became active was assessed. Additionally, nodule-cortex interactions were explored using fMRI functional connectivity. There was EEG-fMRI activity in specific periventricular nodules and overlying cortex in the left temporoparietal region. In both nodules and cortex, the peak BOLD response to epileptiform events occurred earlier than expected from standard fMRI hemodynamic modeling. Functional connectivity showed nodule-cortex interactions to be strong in this region, even when the influence of fMRI activity fluctuations due to spiking was removed. Nonepileptogenic, contralateral nodules did not show connectivity with overlying cortex. EEG-fMRI and functional connectivity can help identify which of the multiple abnormal regions are epileptogenic in PVNH.     

Electroencephalographic recordings of focal seizures in patients affected by periventricular nodular heterotopia: role of the heterotopic nodules in the genesis of epileptic discharges

Patients affected by periventricular nodular heterotopia are frequently characterized by focal drug-resistant epilepsy. To investigate the role of periventricular nodules in the genesis of seizures, we analyzed the electroencephalographic (EEG) features of focal seizures recorded by means of video-EEG in 10 patients affected by different types of periventricular nodular heterotopia and followed for prolonged periods of time at the epilepsy center of our institute. The ictal EEG recordings with surface electrodes revealed common features in all patients: all seizures originated from the brain regions where the periventricular nodular heterotopia were located; EEG patterns recorded on the leads exploring the periventricular nodular heterotopia were very similar both at the onset and immediately after the seizure's end in all patients. Our data suggest that seizures are generated by abnormal anatomic circuitries, including the heterotopic nodules and adjacent cortical areas. The major role of heterotopic neurons in the genesis and propagation of epileptic discharges must be taken into account when planning surgery for epilepsy in patients with periventricular nodular heterotopia.     

室管膜下型灰质异位脑纤维结构连接的MR弥散张量成像研究

目的观察室管膜下型灰质异位（PNH）所发出白质纤维束的空间分布形式以及与正常脑组织的空间位置关系。方法8例以癫痫症状就诊的PNH患者经3．0T磁共振仪T1及T：加权成像诊断,并采集弥散张量成像数据。采用白质纤维束追踪技术,以异位灰质团块作为种子点,对异位灰质相连的白质纤维束进行描绘,并观察总结其空间分布模式及与其他大脑结构之间的关系。结果异位灰质白质纤维束有以下分布特点：①异位灰质均能发出自身的白质纤维,其中有4例表现为仅与位于同侧大脑半球的长联络纤维连接;3例除联络纤维外,还可见到其白质纤维参与对侧的胼胝体连接;6例可见到连接至皮层的弓状纤维;②结构连接空间模式与灰质异位所处位置有关,位于侧脑室前角旁的异位灰质发出的联络纤维主要分布于前方,位于侧脑室后角旁的异位灰质发出的联络纤维主要分布于后方,靠近胼胝体的异位灰质其自质纤维较易连接到对侧,靠近皮层的异位灰质较易发出弓状纤维与皮层相连。结论异位灰质不是孤立的结构,其可发出或长或短的白质纤维,并较广泛地与正常脑结构保持连接;其纤维连接分布的空间模式与异位灰质所处的位置有关。     

Periventricular nodular heterotopia functionally couples with the overlying hippocampus

Patients with periventricular nodular heterotopia (PVNH) often have severe epilepsy. However, it is unclear how the heterotopia contributes to epileptogenesis. Recently, electrophysiologic studies using intraoperative depth electrodes have indicated that interaction between the heterotopia and overlying cortex is crucial for seizure onset. We performed an in vitro physiologic study using slices of resected brain from a 22-year-old man with PVNH, who manifested medically refractory mesial temporal lobe epilepsy. Preoperative evaluation indicated that the right mesial temporal structure and PVNH were the epileptogenic focus. The resected tissue was immediately immersed in cold artificial cerebrospinal fluid, and then slices of the brain tissue including the heterotopic nodules and overlying hippocampus were prepared. We electrically stimulated the incubated slices, and the elicited neural activities were analyzed as changes in the flavoprotein fluorescence signals. When we stimulated either the heterotopic nodule or the overlying hippocampus, clear functional coupling of neural activities between these structures was observed. The coupling response evoked by stimulation of the subiculum and developing within the heterotopic nodule was enhanced by application of bicuculline. Therefore, activities of the hippocampus and the nodule are closely correlated.     

Periventricular nodular heterotopia: classification, epileptic history, and genesis of epileptic discharges

PURPOSE: Periventricular nodular heterotopia (PNH) is among the most common malformations of cortical development, and affected patients are frequently characterized by focal drug-resistant epilepsy. Here we analyzed clinical, MRI, and electrophysiologic findings in 54 PNH patients to reevaluate the classification of PNH, relate the anatomic features to epileptic outcome, and ascertain the contribution of PNH nodules to the onset of epileptic discharges. METHODS: The patients were followed up for a prolonged period at the Epilepsy Center of our Institute. In all cases, we related MRI findings to clinical and epileptic outcome and analyzed interictal and ictal EEG abnormalities. In one patient, EEG and stereo-EEG (SEEG) recordings of seizures were compared. RESULTS: We included cases with periventricular nodules, also extending to white matter and cortex, provided that anatomic continuity was present between nodules and malformed cortex. Based on imaging and clinical data, patients were subdivided into five PNH groups: (a) bilateral and symmetrical; (b) bilateral single-noduled; (c) bilateral and asymmetrical; (d) unilateral; and (e) unilateral with extension to neocortex. The latter three groups were characterized by worse epileptic outcome. No differences in outcome were found between unilateral PNH patients regardless the presence of cortical involvement. Interictal as well as ictal EEG abnormalities were always related to PNH location. CONCLUSIONS: The distinctive clinical features and epileptic outcomes in each group of patients confirm the reliability of the proposed classification. Ictal EEG and SEEG recordings suggest that seizures are generated by abnormal anatomic circuitries including the heterotopic nodules and adjacent cortical areas.     

Localized activity alternations in periventricular nodular heterotopia-related epilepsy

Objective

Periventricular nodular heterotopia (PNH) is a common type of heterotopia usually characterized by epilepsy. Previous studies have identified alterations in structural and functional connectivity related to this disorder, but its local functional neural basis has received less attention. The purpose of this study was to combine univariate analysis and a Gaussian process classifier (GPC) to assess local activity and further explore neuropathological mechanisms in PNH-related epilepsy.

Methods

We used a 3.0-T scanner to acquire resting-state data and measure local regional homogeneity (ReHo) alterations in 38 patients with PNH-related epilepsy and 38 healthy controls (HCs). We first assessed ReHo alterations by comparing the PNH group to the HC group using traditional univariate analysis. Next, we applied a GPC to explore whether ReHo could be used to differentiate PNH patients from healthy patients at an individual level.

Results

Compared to HCs, PNH-related epilepsy patients exhibited lower ReHo in the left insula extending to the putamen as well as in the subgenual anterior cingulate cortex (sgACC) extending to the orbitofrontal cortex (OFC) [p < 0.05, family-wise error corrected]. Both of these regions were also correlated with epilepsy duration. Furthermore, the ReHo GPC classification yielded a 76.32% accuracy (sensitivity = 71.05% and specificity = 81.58%) with p < 0.001 after permutation testing.

Interpretation

Using the resting-state approach, we identified localized activity alterations in the left insula extending to the putamen and the sgACC extending to the OFC, providing pathophysiological evidence of PNH. These local connectivity patterns may provide a means to differentiate PNH patients from HCs.     

带状灰质异位的磁共振弥散张量白质束成像研究

目的采用磁共振弥散张量白质束成像技术,观察带状灰质异位脑白质异常分布情况,探讨异位灰质的神经病理机制以及弥散张量白质束成像技术的应用价值。方法采用磁共振弥散张量白质束成像技术,对1例癫痫症状的带状灰质异位患者进行白质束描绘,观察其不同灰、白质的分布情况,并和1例正常人进行对比研究。结果弥散张量白质束成像技术很好地描绘了白质束结构。整体观察发现带状灰质异位患者脑白质整体结构紊乱,与正常人相比其联络弓状纤维稀疏、大部缺失,胼胝体纤维稀疏不整;局部分析发现内层灰质为主要的白质纤维发出处,而外层灰质仅发出细碎短小的纤维。结论对于带状灰质异位,异位的内层灰质不仅具有神经生理功能,并且可能起着主要作用,外层"正常"的灰质由于脑结构紊乱而丧失主要功能地位;灰质结构的紊乱导致白质纤维结构的缺失;弥散张量白质束成像技术可以很好地应用于带状灰质异位的神经机制研究。     

Brain glucose utilization in band heterotopia: Synaptic activity of “double cortex”

Regional brain glucose utilization was investigated with positron emission tomography and fluorodeoxy-glucose in 2 patients with a seizure disorder associated with diffuse band heterotopia, a condition known as “double cortex.” Although 1 patient was examined shortly after the onset of the first seizures, the other had a long history of intractable epilepsy before examination. Magnetic resonance imaging revealed a symmetric and generalized band of ectopic gray matter and an overlying normal-looking cortex, without focal abnormality. Metabolic studies yielded comparable results in both patients, with similar and even higher glucose uptake in the layer of gray matter heterotopia compared to the normal cortex. These data suggest the persistence of some synaptic activity in the heterotopic neurons, which seems unaffected by age or by the time-course of epilepsy.     

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.     

Initiation of epileptiform activity in a rat model of periventricular nodular heterotopia

Purpose: Periventricular nodular heterotopia (PNH) is, in humans, often associated with difficult‐to‐control epilepsy. However, there is considerable controversy about the role of the PNH in seizure generation and spread. To study this issue, we have used a rat model in which injection of methylazoxymethanol (MAM) into pregnant rat dams produces offspring with nodular heterotopia‐like brain abnormalities. Methods: Electrophysiologic methods were used to examine the activity of the MAM‐induced PNH relative to activity in the neighboring hippocampus and overlying neocortex. Recordings were obtained simultaneously from these three structures in slice preparations from MAM‐exposed rats and in intact animals. Bath application or systemic injection of bicuculline was used to induce epileptiform activity. Key Findings: In the in vitro slice, epileptiform discharge was generally initiated in hippocampus. In some cases, independent PNH discharge occurred, but the PNH never “led” discharges in hippocampus or neocortex. Intracellular recordings from PNH neurons confirmed that these cells received synaptic drive from both hippocampus and neocortex, and sent axonal projections to these structures—consistent with anatomic observations of biocytin‐injected PNH cells. In intact animal preparations, bicuculline injection resulted in epileptiform discharge in all experiments, with a period of ictal‐like electrographic activity typically initiated within 2–3 min after drug injection. In almost all animals, the onset of ictus was seen synchronously across PNH, hippocampal, and neocortical electrodes; in a few cases, the PNH electrode (histologically confirmed) did not participate, but in no case was activity initiated in the PNH electrode. Interictal discharge was also synchronized across all three electrodes; again, the PNH never “led” the other two electrodes, and typically followed (onset several milliseconds after hippocampal/neocortical discharge onset). Significance: These results do not support the hypothesis that the PNH lesion is the primary epileptogenic site, since it does not initiate or lead epileptiform activity that subsequently propagates to other brain regions.     

Microstructural white matter abnormalities in nodular heterotopia with overlying polymicrogyria.

Nodular heterotopia (NH) with overlying polymicrogyria can result in medically uncontrolled seizures. Most patients also exhibit deficits of function related to the location of the abnormal cortex. However, functional imaging studies show that the abnormal cortex can retain some function, making surgical planning difficult. It is not known if the connectivity of the abnormal cortex is normal. In this article, we performed an evaluation of molecular diffusion within the white matter in a patient with refractory epilepsy due to NH with overlying polymicrogyria. We observed that the white matter underlying the polymicrogyric area shows signs of microstructural abnormalities. This result suggests that the deficit of function from polymicrogyria result from both the structurally abnormal cortex and from its impaired connectivity.     

Synaptic responses of neurons in heterotopic gray matter in an animal model of cortical dysgenesis

Neuronal heterotopia is a malformation of cortical development that is closely associated with epilepsy in humans. Despite emerging interest in the structure and function of the heterotopic cortex, little is known about the membrane properties and synaptic connections of these displaced neurons. We used whole-cell patch-clamp and extracellular field potential recordings from heterotopic neurons in slices from young adult rats with experimentally induced cortical dysgenesis to determine if local synaptic connections were present in nodular heterotopia. Complex synaptic responses were observed after electrical stimulation of adjacent white matter. The results suggest that neurons in nodular heterotopic gray matter can form local excitatory and inhibitory synaptic connections and may participate in epileptiform events. Copyright Copyright 1999 S. Karger AG, Basel     

Prenatal methylazoxymethanol treatment in rats produces brain abnormalities with morphological similarities to human developmental brain dysgeneses

A double methylazoxymethanol (MAM) intraperitoneal injection was prenatally administered to pregnant rats at gestational day 15 to induce developmental brain dysgeneses. Thirty adult rats from 8 different progenies were investigated with a combined electrophysiological and neuroanatomical analysis. The offspring of treated dams was characterized by extensive cortical layering abnormalities, subpial bands of heterotopic neurons in layer I, and subcortical nodules of heterotopic neurons extending from the periventricular region to the hippocampus and neocortex. The phenotype of cell subpopulations within the heterotopic structures was analyzed by means of antibodies raised against glial and neuronal markers, calcium binding proteins, GABA, and AMPA glutamate receptors. Neurons within the subcortical heterotopic nodules were characterized by abnormal firing properties, with sustained repetitive bursts of action potentials. The subcortical nodules were surrounded by cell clusters with ultrastructural features of young migrating neurons. The immunocytochemical data suggested, moreover, that the subcortical heterotopia were formed by neurons originally committed to the neocortex and characterized by morphological features similar to those found in human periventricular nodular heterotopia. The present study demonstrates that double MAM treatment at gestational day 15 induces in rats developmental brain abnormalities whose anatomical and physiological features bear resemblance to those observed in human brain dysgeneses associated with intractable epilepsy. Therefore, MAM treated rats could be considered as useful tools in investigating the pathogenic mechanisms involved in human developmental brain dysgeneses.     

Clinical features and long term outcome of epilepsy in periventricular nodular heterotopia. Simple compared with plus forms

OBJECTIVES: Little is known about the long term outcome of patients with periventricular nodular heterotopia (PNH) and epilepsy, particularly the course of seizures. This study investigated the electroclinical and prognostic features of 16 patients with PNH. METHODS: Of 120 patients with epilepsy and malformations of cortical development, 16 had PNH. Of these, eight patients had periventricular nodules only (simple PNH) and eight also presented with other cortical or cerebral malformations (subcortical heterotopia; polymicrogyria; focal dysplasia; schizencephaly; cortical infolding; agenesis of the corpus callosum; mega cisterna magna and cerebellar atrophy) (PNH plus). All patients underwent clinical, neurophysiological, and MRI investigation. The mean follow up was 17.3 years (2-40 years). RESULTS: Two electroclinical patterns emerged: (1) The first pattern, associated with simple PNH, was characterised by normal intelligence and seizures, usually partial, which began during the second decade of life. The seizures never became frequent and tended to disappear or become very rare. The EEG showed focal abnormalities. (2) The second pattern, associated with PNH plus, was characterised by mental retardation and seizures that began during the first decade of life. The seizures were very frequent in most cases and sudden drops were observed in six patients. Seizures were medically refractory in four patients. The EEG showed focal and bisynchronous abnormalities. CONCLUSIONS: Two groups of PNH patients with different electroclinical and neuroradiological features can be identified after a long term follow up. The presence of other types of cortical or cerebral malformations, in addition to periventricular nodules, determines a poor prognosis.     

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

PurposePeriventricular 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.MethodsParticipants 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 findingsWe 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.SignificanceA 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.     

Subcortical nodular heterotopia: a functional MRI and somatosensory evoked potentials study

Abstract. Subcortical nodular heterotopia (SNH) associated with refractory epilepsy may be surgically treated, and a positive outcome can be expected following the complete excision of the malformed tissue. Recent functional neuroimaging studies have suggested the possible functional relevance of cerebral malformations, and may make it possible to improve presurgical planning, thus allowing extended resections and minimising post–operative deficits. We here report the case of a 19–year–old man with epilepsy and a giant SNH associated with diffused abnormal gyrations of the right temporal–parietal regions. Cortical functional organisation was investigated by means of functional magnetic resonance imaging (MRI) during sensory and motor tasks, and somatosensory evoked potentials. The results revealed enlarged and displaced motor and sensory cortical areas with heterotopic tissue functional activation. The relevance of these findings is discussed in the light of the possible surgical treatment of drug–refractory epilepsy associated with cerebral malformations: surgical treatment based on conventional MRI studies alone, without taking the functional nature of dysplastic tissues into account, may lead to considerable side effects.     

Exploring white matter tracts in band heterotopia using diffusion tractography

Band heterotopia is a malformation of cortical development characterized by bands of gray matter in the white matter parallel to the surface of the neocortex. Histopathological studies have suggested that small white matter tracts pass through the heterotopia, and functional magnetic resonance imaging studies have shown activation in the malformation. We used diffusion tractography to explore the anatomical connectivity of band heterotopia and, in particular, whether in vivo white matter tracts traverse the heterotopic gray matter. Five patients with band heterotopia and five control subjects were scanned with whole brain diffusion tensor imaging. Anisotropy maps were calculated. Using fast marching tractography, we produced maps of connectivity and tract traces from two seed points, in the splenium of the corpus callosum and the right parietal lobe. Eigenvectors were found to pass through the band heterotopia in an aligned fashion. Patterns for maps of connectivity were similar in patients and control subjects. Areas of high connectivity were found in the band heterotopia and in cortical areas on the far side of the malformation from the seed point. The tracts hence appeared to traverse or end within the band heterotopia. The results are in agreement with previous histopathological studies and indicate the structural basis of the functional connectivity and absence of focal deficits in these patients.     

Sensorimotor organization in double cortex syndrome

Subcortical band heterotopia is a diffuse malformation of cortical development related to pharmacologically intractable epilepsy. On magnetic resonance imaging (MRI), patients with "double cortex" syndrome (DCS) present with a band of heterotopic gray matter separated from the overlying cortex by a layer of white matter. The function and connectivity of the subcortical heterotopic band in humans is only partially understood. We studied six DCS patients with bilateral subcortical band heterotopias and six healthy controls using functional MRI (fMRI). In controls, simple motor task elicited contralateral activation of the primary motor cortex (M1) and ipsilateral activation of the cerebellum and left supplementary motor area (SMA). All DCS patients showed task-related contralateral activation of both M1 and the underlying heterotopic band. Ipsilateral motor activation was seen in 4/6 DCS patients. Furthermore, there were additional activations of nonprimary normotopic cortical areas. The sensory stimulus resulted in activation of the contralateral primary sensory cortex (SI) and the thalamus in all healthy subjects. The left sensory task also induced a contralateral activation of the insular cortex. Sensory activation of the contralateral SI was seen in all DCS patients and secondary somatosensory areas in 5/6. The heterotopic band beneath SI became activated in 3/6 DCS patients. Activations were also seen in subcortical structures for both paradigms. In DCS, motor and sensory tasks induce an activation of the subcortical heterotopic band. The recruitment of bilateral primary areas and higher-order association normotopic cortices indicates the need for a widespread network to perform simple tasks.