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BACKGROUND AND PURPOSE: MR imaging studies and neuropathologic findings in individuals with 22q11.2 deletion syndrome show anomalous early brain development. We aimed to retrospectively evaluate cerebral abnormalities, focusing on gray matter heterotopia, and to correlate these with subjects’ neuropsychiatric impairments. MATERIALS AND METHODS: Three raters assessed gray matter heterotopia and other morphologic brain abnormalities on 3D T1WI and T2*WI in 75 individuals with 22q11.2 deletion syndrome (27 females, 15.5 [SD, 7.4] years of age) and 53 controls (24 females, 12.6 [SD, 4.7] years of age). We examined the association among the groups’ most frequent morphologic findings, general cognitive performance, and comorbid neuropsychiatric conditions. RESULTS: Heterotopia in the white matter were the most frequent finding in individuals with 22q11.2 deletion syndrome (n = 29; controls, n = 0; between-group difference, P < .001), followed by cavum septi pellucidi and/or vergae (n = 20; controls, n = 0; P < .001), periventricular cysts (n = 10; controls, n = 0; P = .007), periventricular nodular heterotopia (n = 10; controls, n = 0; P = .007), and polymicrogyria (n = 3; controls, n = 0; P = .3). However, individuals with these morphologic brain abnormalities did not differ significantly from those without them in terms of general cognitive functioning and psychiatric comorbidities. CONCLUSIONS: Taken together, our findings, periventricular nodular heterotopia or heterotopia in the white matter (possibly related to interrupted Arc cells migration), persistent cavum septi pellucidi and/or vergae, and formation of periventricular cysts, give clues to the brain development disorder induced by the 22q11.2 deletion syndrome. There was no evidence that these morphologic findings were associated with differences in psychiatric or cognitive presentation of the 22q11.2 deletion syndrome.

To figure out the spectra features of malformations of cortical development (MCDs) and the differences between MCDs subcategories. Twenty patients and 18 controls were studied. The patients included two subcategories: disorders of migration (DOM) and postmigration (DOPM). Spectra of patients were acquired from both the lesion and the normal-appearing contralateral side (NACS), and they were compared to those of the controls obtained from the frontal lobe. Compared to the controls, a decreased NAA (P = 0.002) was identified in MCDs. After dividing the MCDs into the DOM and DOPM, we found that NAA reduction was only notable in the DOM (P = 0.007). Moreover, Ins and Cr of the DOPM were higher than those of the controls (P = 0.017 and 0.013) and the DOM (P = 0.027 and 0.001). Compared to the NACS, a decreased NAA (P = 0.042) and an increased Ins (P = 0.039) were identified in the lesion of MCDs. After dividing the MCDs into the DOM and DOPM, we found no significant differences in the DOM, but Ins, Cr, and Glx of the lesion were higher than those of the NACS (P = 0.007, 0.005 and 0.047) in the DOPM. In addition, we found that Cr and Glx correlated positively to the seizure frequency (P = 0.003 and 0.016). Decreased NAA was the prominent abnormality confirmed in MCDs. Spectra of different MCDs subcategories were different: the DOM was characterized by decreased NAA, while the DOPM was characterized by increased Ins.

Background Hypothalamic hamartomas (HH) are rare, and it is even rare when combined with gray matter heterotopia (GMH) and polymicrogyria (PMG). Case Description A 5 years-old boy with HH, GMH and PMG were retrospectively evaluated. The clinical data which include the symptoms, examinations, diagnosis and treatment were collected. The patient had a chief complaint of gelastic seizures (GSs) and intellectual deficiency. Brain MRI showed HH, paraventricular nodular heterotopia and PMG. Video-electroencephalographys (V-EEGs) were normal. The patient underwent resection of the HH via transcallosal transseptal interforniceal approach. Seizures disappeared immediately after complete resection of HH, and the intellectual development was getting better. Conclusions In this extremely rare case, resection of the HH eliminates the symptoms. However, we still need to be cautious about the possible epilepsy that may be caused by GMH and PMG.

BACKGROUND AND PURPOSE: Fetal imaging is crucial in the evaluation of open neural tube defects. The identification of intraventricular hemorrhage prenatally has unclear clinical implications. We aimed to explore fetal imaging findings in open neural tube defects and evaluate associations between intraventricular hemorrhage with prenatal and postnatal hindbrain herniation, postnatal intraventricular hemorrhage, and ventricular shunt placement. MATERIALS AND METHODS: After institutional review board approval, open neural tube defect cases evaluated by prenatal sonography between January 1, 2013 and April 24, 2018 were enrolled (n = 504). The presence of intraventricular hemorrhage and gray matter heterotopia by both prenatal sonography and MR imaging studies was used for classification. Cases of intraventricular hemorrhage had intraventricular hemorrhage without gray matter heterotopia (n = 33) and controls had neither intraventricular hemorrhage nor gray matter heterotopia (n = 229). A total of 135 subjects with findings of gray matter heterotopia were excluded. Outcomes were compared with regression analyses. RESULTS: Prenatal and postnatal hindbrain herniation and postnatal intraventricular hemorrhage were more frequent in cases of prenatal intraventricular hemorrhage compared with controls (97% versus 79%, 50% versus 25%, and 63% versus 12%, respectively). Increased third ventricular diameter, specifically >1 mm, predicted hindbrain herniation (OR = 3.7 [95% CI, 1.5–11]) independent of lateral ventricular size and prenatal intraventricular hemorrhage. Fetal closure (n = 86) was independently protective against postnatal hindbrain herniation (OR = 0.04 [95% CI, 0.01–0.15]) and postnatal intraventricular hemorrhage (OR = 0.2 [95% CI, 0.02–0.98]). Prenatal intraventricular hemorrhage was not associated with ventricular shunt placement. CONCLUSIONS: Intraventricular hemorrhage is relatively common in the prenatal evaluation of open neural tube defects. Hindbrain herniation is more common in cases of intraventricular hemorrhage, but in association with increased third ventricular size. Fetal closure reverses hindbrain herniation and decreases the rate of intraventricular hemorrhage postnatally, regardless of the presence of prenatal intraventricular hemorrhage.

ÖzetAmaç: Çalışmanın amacı, pediatrik hastalarda saptanan gri cevher heterotopilerini manyetik rezonans görüntüleme bulgularına göre sınıflandırmak ve eşlik eden serebral malformasyonları tanımlamaktır.Gereç ve Yöntemler: Ocak 2012-Haziran 2020 tarihleri arasında beyin manyetik rezonans görüntülemelerinde heterotopi tespit ettiğimiz tüm çocuk hastaların görüntüleri retrospektif olarak değerlendirildi. Heterotopinin tipi, yeri ve eşlik eden serebral anomaliler incelendi.Bulgular: Çalışmaya gri cevher heterotopisi bulunan ortalama yaşı 7.80±4.53 yıl (2-16 yıl) olan 22’si erkek, 20’si kız toplam 42 hasta dahil edildi. Hastaların 33’ünde (%78.6) subependimal, 7’sinde (%16.7) subkortikal ve 2’sinde (%4.7) bant heterotopi saptandı. Yirmi dört hastanın epilepsisi vardı.Sonuç: Çalışmamıza göre pediatrik hastalarda en sık subependimal heterotopi görüldü. Subependimal heterotopiler en sık lateral ventriküllerin trigon kısmında yerleşmişti. Subkortikal heterotopilerin tümü frontalde ve unifokal yerleşimli idi. Bant heterotopiler bilateral serebral hemisferde subkortikal bölgede simetrik yerleşimli idi. Başlıca eşlik eden serebral anomaliler Chiari 2 malformasyonu ve korpus kallosum agenezisi idi. Pediatrik hastalarda hasta yönetimi açısından heterotopinin tipinin ve ilişkili serebral anomalilerin tanımlanması önemlidir., Objective: The aim of the study is to classify gray matter heterotopias detected in pediatric patients according to magnetic resonance imaging findings and to define the accompanying cerebral malformations.Material and Methods: Images of all pediatric patients who were detected to have heterotopia in brain magnetic resonance imaging between January 2012 and June 2020 were retrospectively evaluated. The type, location of heterotopia, and accompanying cerebral anomalies were analyzed.Results: A total of 42 patients, 22 male, and 20 female, with a mean age of 7.80±4.53 years (2-16 years) with gray matter heterotopia were included in the study. Of the patients 33 (78.6%) had subependymal, 7 (16.7%) had subcortical, and 2 (4.7%) had band heterotopia. Twenty-four patients had epilepsy.Conclusion: According to our study, subependymal heterotopia was most common in pediatric patients. The subependymal heterotopias were most commonly located in the trigon region of the lateral ventricles. All of the subcortical heterotopies were located in the frontal and unifocal. Band heterotopias were located symmetrically in the subcortical region of the bilateral cerebral hemispheres. The main accompanying anomalies were Chiari II malformation, and corpus callosum agenesis. Defining the type of heterotopia and associated anomalies in pediatric patients is important for patient management.

Objective A vast network involving the nodules and overlying cortices is believed to be responsible for the epileptogenicity in gray matter heterotopia with multiple nodules, which often associated with difficult‐to‐treat epilepsy. We sought to determine if functional magnetic resonance imaging (fMRI) could detect internodular functional connectivity (FC), and if this connectivity reflects an actual synchronized neuronal activity and partakes in epileptogenicity. Methods We studied 16 epilepsy patients with multiple heterotopic nodules; eight underwent subsequent intracerebral EEG. We examined the internodular FC using fMRI and its correspondence with internodular synchrony of intracerebral interictal activity. We then compared the spreading speed of ictal activity between connected and unconnected nodules; and the FC among possible combinations of nodule pairs in terms of their involvement at seizure onset. Results Seventy nodules were studied: 83% have significant connection to at least one other nodule. Among the 49 pairs studied with intracerebral EEG, (1) synchronized interictal activity is more prevalent in fMRI‐connected pairs (P

International audience; Objective: Malformations of cortical development are common causes of intellectual disability and epilepsy, yet there is a crucial lack of relevant preclinical models associating seizures and cortical malformations. Here, we describe a novel rat model with bilateral subcortical band heterotopia (SBH) and examine whether this model develops spontaneous epileptic seizures. Methods: To generate bilateral SBH in rats, we combined RNAi-mediated knockdown of Dcx and in utero electroporation with a tripolar electrode configuration enabling simultaneous transfection of the two brain hemispheres. To determine whether bilateral SBH leads to epileptiform activity, rats of various ages were implanted for telemetric electrocorticographic recordings and histopathologi-cal examination was carried out at the end of the recording sessions. Results: By 2 months, rats with bilateral SBH showed nonconvulsive spontaneous seizures consisting of spike-and-wave discharges (SWDs) with dominant frequencies in the alpha and theta bands and secondarily in higher-frequency bands. SWDs occurred during both the dark and the light period, but were more frequent during quiet awake state than during sleep. Also, SWDs were more frequent and lasted longer at older ages. No sex differences were found. Although frequencies and durations of SWDs were found to be uncorrelated with the size of SBH, SWDs were initiated in some occasions from brain hemispheres comprising a larger SBH. Lastly, SWDs exhibited absence-like pharmacological properties , being temporarily alleviated by ethosuximide administration. Significance: This novel model of bilateral SBH with spontaneous epilepsy may potentially provide valuable new insights into causality between cortical malfor-mations and seizures, and help translational research aiming at designing novel treatment strategies for epilepsy. K E Y W O R D S animal model, epilepsy, gray matter heterotopia, malformation of cortical development-This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Summary Hippocampal sclerosis (HS) is the most common neuropathologic findings in patients with intractable temporal lobe epilepsy (TLE). The international league against epilepsy has proposed a new classification of HS based on pyramidal cell loss on different subfields to facilitate the study of HS pathology in patients after anterior temporal lobectomy (ATL), and the influence of these HS patterns on the prognosis of patients with TLE is contradictory. This study aims to investigate the relationship between different HS subtypes and postoperative seizure outcomes for intractable patients with TLE. From January 2008 to December 2018, we retrospectively reviewed 198 TLE patients with ATL surgery, and all patients had a complete preoperative evaluation, a specimen of hippocampal tissue after surgery, cognitive test after surgery, and more than 2 years of postoperative follow-up. The main findings were as follows: 1) temporal neocortical gray matter heterotopia were more common in the no-HS group; 2) HS type 1 was associated with a longer duration of epilepsy; 3) history of meningitis was the independent predictor of HS type 1; 4) no-HS patients experienced worse postoperative seizure outcomes than those with HS type1 and type 2, whereas no difference in seizure outcomes was obtained between HS type 1 and type 2; 5) no-HS patients were at increased risk for verbal memory decline after left hippocampal resection. The HS subtypes were associated with the prognosis of patients with TLE, and other variables were the predictors of different HS types. `Further study was to identify the HS subtypes by noninvasive evaluation to approve better postoperative outcomes.

Objective To investigate the clinical characteristics and neuroimaging features of childhood presenting with gray matter heterotopia observed in a single tertiary Pediatric Department in Catania and compare the data with those reported in the literature. Methods A retrospectively review of the history, clinical findings, electrophysiological features and magnetic resonance images of 22 children presenting with gray matter heterotopia observed from January 2010 to January 2020. Results Among the 22 children included in the study, 17 presented with periventricular heterotopia (PVNH), two with Subcortical Band Heterotopia (SBH), and three with other subcortical heterotopia (SUBH). In the affected children, the ages at first diagnosis ranged from 3 months to 16 years with a mean age of 8.2 years (± 5.4); twelve (54.5%) suffered by developmental delay and intellectual deficit; eleven children (50%) complained of epileptic seizures, mostly focal to bilateral tonic–clonic seizure. In addition, in the periventricular heterotopia group (PVNH), cerebral and systemic malformations were reported in twelve (70%) and in ten (58%) children, respectively, out of seventeen. In the SBH plus SUBH group, epileptic seizures were recorded in 3 (60%) out of 5 children, cerebral malformations in one child and systemic malformations in two children. Conclusions Heterotopic gray matter malformations include a group of disorders that manifest with a variety of neurological implications, such as cognitive impairment and epilepsy, and often related with epilepsy, other cerebral malformations and systemic anomalies.

Teaching point: Since some minor congenital brain defects manifest long after birth, even in adults they should be kept in the differential of new epileptic seizures or focal neurologic deficits.

International audience; EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.

Ring chromosome 6, r(6), is an extremely rare cytogenetic abnormality with clinical heterogeneity which arises typically de novo. The phenotypes of r(6) can be highly variable, ranging from almost normal to severe malformations and neurological defects. Up to now, only 33 cases have been reported in the literature. In this 10-year follow-up study, we report a case presenting distinctive facial features, severe developmental delay, and gray matter heterotopia with r(6) and terminal deletions of 6p25.3 (115426-384174, 268 kb) and 6q26-27 (168697778-170732033, 2.03 Mb) encompassing 2 and 15 candidate genes, respectively, which were detected using G-banding karyotyping, FISH, and chromosomal microarray analysis. We also analyzed the available information on the clinical features of the reported r(6) cases in order to provide more valuable information on genotype-phenotype correlations. To the best of our knowledge, this is the first report of gray matter heterotopia manifested in a patient with r(6) in China, and the deletions of 6p and 6q in our case are the smallest with the precise size of euchromatic material loss currently known.

For general radiologists, congenital brain malformations pose substantial challenges in terms of recognition, description, and classification. This review describes a practical approach to imaging and classifying the most common supratentorial brain malformations. It begins with a discussion of embryology and optimal imaging technique and then summarizes distinguishing imaging features for several major categories of cerebral malformation, including holoprosencephaly, gray matter heterotopia, lissencephaly/pachygyria, focal cortical dysplasia, polymicrogyria, and cobblestone malformation. The importance of identifying abnormalities in the corpus callosum and basal ganglia is also discussed, both for detection and characterization of cerebral malformations.

International audience; Malformations of cortical development (MCDs), a complex family of rare disorders, result from alterations of one or combined developmental steps, including progenitors proliferation, neuronal migration and differentiation. They are an important cause of childhood epilepsy and frequently associate cognitive deficits and behavioral alterations. Though the physiopathological mechanisms of epilepsy in MCD patients remain poorly elucidated, research during the past decade highlighted the contribution of some factors that will be reviewed in this paper and that include: (i) the genes that caused the malformation, that can be responsible for a significant reduction of inhibitory cells (e.g., ARX gene) or be inducing cell-autonomous epileptogenic changes in affected neurons (e.g., mutations on the mTOR pathway); (ii) the alteration of cortical networks development induced by the malformation that will also involve adjacent or distal cortical areas apparently sane so that the epileptogenic focus might be more extended that the malformation or even localized at distance from it; (iii) the normal developmental processes that would influence and determine the onset of epilepsy in MCD patients, particularly precocious in most of the cases.

To investigate the clinical and imaging features of gray matter heterotopia (GMH) and improve the clinicians’ understanding of the disease. A retrospective study was performed on 15 patients with GMH diagnosed at The Affiliated Hospital of Xuzhou Medical University from November 2014 to November 2016. Their clinical and imaging features are also summarized. The proportion of male and female patients was 2:1. The age of onset was 2~45 years and the average age was 19.1 years. There were 13 patients with epilepsy who also had cognitive decline (5 cases) and neurological deficit (3 cases). There were 2 patients with headache or dizziness. The imaging findings of GMH are unilateral or multiple spots in the periventricular or subependymal, subcortical, and centrum semiovale and are often accompanied by other cerebral malformations. We found that 10 patients had the subcortical type of GMH and 5 patients had the subependymal type or periventricular nodular heterotopia type. There were 8 cases of ventricular compression, 5 cases of ventriculomegaly, 5 cases of cerebral fissure malformation, 3 cases of pachygyria, 1 case of callosal agenesis, and 1 case of undeveloped septum pellucidum. All the patients were given symptomatic and supportive therapies and 3 patients were treated with antiepileptic drugs. Seizures were, however, poorly controlled. GMH should also be suspected in patients with juvenile onset of seizures, cognitive decline, and neurological deficits. Magnetic resonance scans may show lesions in the white matter of the brain with signals similar to the normal gray matter.

Background Vestibular schwannomas and meningiomas account for the great majority of lesions arising in the cerebellopontine angle. In this report, we present a case of glioneuronal heterotopia, also known as glioneuronal hamartoma, arising from cranial nerve VIII, which is an extremely uncommon lesion. Important radiologic and surgical aspects are reviewed, which may help in early recognition and intraoperative decision making when these lesions are encountered. Case Description A healthy 29-year-old female presented with intermittent right facial numbness. Magnetic resonance imaging showed an incidental, minimally enhancing cerebellopontine angle lesion on the right cranial nerve VII–VIII complex. The patient declined serial observation and opted for operative intervention for resection. Intraoperatively, the lesion resembled neural tissue and was continuous with the VIII cranial nerve. Pathologic analysis demonstrated mature glioneuronal tissue consistent with hamartomatous brain tissue. The patient maintained normal hearing and facial nerve function after surgery. Radiologic, surgical, and pathologic characteristics are described. Conclusions Ectopic glioneuronal tissue of cranial nerve VIII is a rare non-neoplastic lesion and should be considered in the differential diagnosis of unusual-appearing intracanalicular and cerebellopontine angle lesions. The congenital and benign nature of this entity makes observation a valid option for these cases, although they are so infrequent that they are often presumptively managed as vestibular schwannomas. Attempts to radically resect these lesions may result in higher rates of hearing loss or facial palsy due to their continuity with cranial nerves.

OBJECT Surgical exposure of the peritrigonal or periatrial region has been challenging due to the depth of the region and overlying important functional cortices and white matter tracts. The authors demonstrate the operative feasibility of a contralateral posterior interhemispheric transfalcine transprecuneus approach (PITTA) to this region and present a series of patients treated via this operative route. METHODS Fourteen consecutive patients underwent the PITTA and were included in this study. Pre- and postoperative clinical and radiological data points were retrospectively collected. Complications and extent of resection were reviewed. RESULTS The mean age of patients at the time of surgery was 39 years (range 11–64 years). Six of the 14 patients were female. The mean duration of follow-up was 4.6 months (range 0.5–19.6 months). Pathology included 6 arteriovenous malformations, 4 gliomas, 2 meningiomas, 1 metastatic lesion, and 1 gray matter heterotopia. Based on the results shown on postoperative MRI, 1 lesion (7%) was intentionally subtotally resected, but ≥ 95% resection was achieved in all others (93%) and gross-total resection was accomplished in 7 (54%) of 13. One patient (7%) experienced a temporary approach-related complication. At last follow-up, 1 patient (7%) had died due to complications of his underlying malignancy unrelated to his cranial surgery, 2 (14%) demonstrated a Glasgow Outcome Scale (GOS) score of 4, and 11 (79%) manifested a GOS score of 5. CONCLUSIONS Based on this patient series, the contralateral PITTA potentially offers numerous advantages, including a wider, safer operative corridor, minimal need for ipsilateral brain manipulation, and better intraoperative navigation and working angles.

Objective Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the underlying physiological predisposition to seizures is unclear. We sought to characterize the cortical excitability profile of a developmental form of epilepsy known to have structural and functional connectivity abnormalities. Methods We employed transcranial magnetic stimulation (TMS) with simultaneous electroencephalographic (EEG) recording in 8 patients with epilepsy from periventricular nodular heterotopia and matched healthy controls. We used connectivity imaging findings to guide TMS targeting and compared the evoked responses to single-pulse stimulation from different cortical regions. Results Heterotopia patients with active epilepsy demonstrated a relatively augmented late cortical response that was greater than that of matched controls. This abnormality was specific to cortical regions with connectivity to subcortical heterotopic gray matter. Topographic mapping of the late response differences showed distributed cortical networks that were not limited to the stimulation site, and source analysis in 1 subject revealed that the generator of abnormal TMS-evoked activity overlapped with the spike and seizure onset zone. Interpretation Our findings indicate that patients with epilepsy from gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and that this abnormality is specifically linked to the presence of aberrant connectivity. These results support the idea that TMS-EEG could be a useful biomarker in epilepsy in gray matter heterotopia, expand our understanding of circuit mechanisms of epileptogenesis, and have potential implications for therapeutic neuromodulation in similar epileptic conditions associated with deep lesions. Ann Neurol 2015;77:487–503

The objective of this article is to review the pathophysiological bases of gray matter heterotopia and to appreciate their involvement in brain cortical development and functional consequences, namely epilepsy. The development of the cerebral cortex results from complex sequential processes including cell proliferation, cell migration, cortical organization, and formation of neuronal networks. Disruption of these steps yields different types of cortical malformations including gray matter heterotopia, characterized by the ectopic position of neurons along the ventricular walls or in the deep white matter. Cortical malformations are major causes of epilepsy, being responsible for up to 40% of drug-resistant epilepsy, and the cognitive level of affected patients varies from normal to severely impaired. This review reports data from human patients and animal models highlighting the genetic causes for these disorders affecting not only neuronal migration but also the proliferation of cortical progenitors. Therefore, gray matter heterotopias should not be considered as solely due to an abnormal neuronal migration and classifying them as such may be too restrictive. The review will also summarize literature data indicating that besides ectopic neurons, neighbor cortical areas also play a consistent role in epileptogenesis, supporting the notion that plastic changes secondary to the initial malformation are instrumental in the pathophysiology of epilepsy in affected patients.

Summary Objective Astrocytic inclusions (AIs) have been identified on histologic specimens of patients with early onset seizures, and the proteomic contents have been described. The aim of this study was to compare the clinical, electroencephalography (EEG), magnetoencephalography (MEG), magnetic resonance imaging (MRI), and surgical outcomes of AIs relative to focal cortical dysplasia (FCD). Methods We assessed the clinical manifestations, semiology, ictal and interictal features on video-EEG, MEG, MRI features, and surgical outcomes of children with histologically proven AIs compared to FCD. Results Six children had AIs and 27 had FCD. Children with AIs had an earlier age at seizure onset, periodic spasms (all children), and interictal epileptiform discharges consisting of a mixture of generalized or diffuse hemispheric slow waves, sharp waves, spikes and polyspikes. Children with FCD were less likely to have spasms (4/27 [15%]), and the morphology of the diffuse hemispheric or generalized discharges were different from those of AI, consisting of spike-and-waves, polyspike-and-waves, sharp-and-slow waves, and paroxysmal fast activity. Patients with AIs were less likely to have tightly clustered MEG spike sources (3/6 [50%] vs. 23/27 [85%]), and more likely to demonstrate abnormal sulcation and gyration pattern (4/6 [67%] vs. 2/27 [7%]) and gray matter heterotopia (2/6 [33%] vs. 0/27 [0%]) than patients with FCD. Four children with AIs had resection and two had biopsy but did not undergo resection. Children with AIs had lower rates of seizure freedom after surgery compared to FCD (1/4 [25%] vs. 15/27 [56%], respectively). Significance Although there were some similarities between AIs and FCD, patients with AIs were more likely to present with early onset periodic spasms, have unusual interictal epileptiform discharges, abnormal sulcation, gyration pattern, and gray matter heterotopia, and were less likely to be seizure free following surgical resection relative to FCD. Further study with a larger sample size is needed to validate our findings.

Summary Background Gray matter heterotopia (GMH) is a malformation of the central nervous system characterized by interruption of normal neuroblasts migration between the 7th and 16th week of fetal development. The aim of the study was the analysis of clinical symptoms, prevalence rate and the most common concurrent central nervous system (CNS) developmental disorders as well as assessment of characteristic morphological changes of gray matter heterotopia in children hospitalized in our institution between the year 2001 and 2012. Material/Methods We performed a retrospective analysis of patients’ data who were hospitalized in our institution between the year 2001 and 2012. We assessed clinical data and imaging exams in children diagnosed with gray matter heterotopia confirmed in MRI (magnetic resonance imaging). Results GMH occurred in 26 children hospitalized in our institution between the year 2001 and 2012. Among children with gray matter heterotopia most common clinical symptoms were: epilepsy, intellectual disability and hemiparesis. The commonest location of heterotopic gray matter were fronto-parietal areas of brain parenchyma, mostly subependymal region. Gray matter heterotopia occurred with other developmental disorders of the central nervous system rather than solely and in most cases it was bilateral. Schizencephaly and abnormalities of the corpus callosum were the most often developmental disorders accompanying GMH. Conclusions 1. Subependymal gray matter heterotopia was more common than subcortical GMH. Subependymal GMH showed tendency to localize in the region of the bodies of the lateral ventricles. The least common was laminar GMH. 2. Gray matter heterotopia occurred more often with other developmental disorders of the central nervous system rather than solely. The most frequent concurrent disorders of the central nervous system were: schizencephaly, developmental abnormalities of the corpus callosum, arachnoid cyst, abnormalities of the septum pellucidum and the fornix. 3. GMH foci were more often bilateral than unilateral. 4. In the diagnostics of cell migration abnormalities, gray matter heterotopia included, MR imaging remains the method of choice.

Objective Heterotopia is a rare condition typically identified in the context of seizures. This case study presents a cognitive profile in a child with a history of heterotopia and hearing problems but without any known seizure history. Method An 8-year-old referred for evaluation by her neurologist due to concerns about persistent academic and social difficulties. Medical history was remarkable for small size, hearing problems, multiple pressure equalization tube placements, food allergies, and a left lateral ventricle gray matter heterotopia found on brain MRI. EEG was normal. Genetic testing found no dysmorphia. Developmental history was remarkable for delayed speech and early intervention, as well as social delays. She began receiving special education for learning disability and speech/language impairment in first grade. Results WISC-V IQ was Low Average and significantly lower than GAI. WMI was Below Average and PSI was Low. Language performance was variable. Visual scanning was Below Average. Verbal memory ranged from Below Average to Impaired, with worse performance on WRAML-2 Story Memory subtests. Attention and hyperactivity deficits were found on a continuous performance task. Executive function was Average to Above Average on phonemic fluency, category switching and Stroop tasks. BASC-3 parent ratings indicated greatest concerns in areas of atypicality, withdrawal, and adaptive skills. ABAS-3 indicated Low conceptual skills and Average to Low Average skills on other composites. Conclusions Aside from language deficits likely related to hearing problems, these findings indicated deficits in visual scanning, attention/hyperactivity, visually-based processing speed, and memory in the context of heterotopia without seizures. Social delays may be multifactorial.

Alterations in neuronal circuitry are recognized as an important substrate of many neurological disorders, including epilepsy. Patients with the developmental brain malformation of periventricular nodular heterotopia (PNH) often have both seizures and dyslexia, and there is evidence to suggest that aberrant neuronal connectivity underlies both of these clinical features. We used task-based functional MRI (fMRI) to determine whether heterotopic nodules of gray matter in this condition are integrated into functional cortical circuits. Blood oxygenation level-dependent (BOLD) fMRI was acquired in eight participants with PNH during the performance of reading-related tasks. Evidence of neural activation within heterotopic gray matter was identified, and regions of cortical coactivation were then mapped systematically. Findings were correlated with resting-state functional connectivity results and with performance on the fMRI reading-related tasks. Six participants (75%) demonstrated activation within at least one region of gray matter heterotopia. Cortical areas directly overlying the heterotopia were usually coactivated (60%), as were areas known to have functional connectivity to the heterotopia in the task-free resting state (73%). Six of seven (86%) primary task contrasts resulted in heterotopia activation in at least one participant. Activation was most commonly seen during rapid naming of visual stimuli, a characteristic impairment in this patient population. Our findings represent a systematic demonstration that heterotopic gray matter can be metabolically coactivated in a neuronal migration disorder associated with epilepsy and dyslexia. Gray matter nodules were most commonly coactivated with the anatomically overlying cortex and other regions with resting-state connectivity to heterotopia. These results have broader implications for understanding the network pathogenesis of both seizures and reading disabilities.

Despite pharmacological and surgical interventions, some children with periventricular nodular heterotopia (PNH) remain refractory to treatment, which suggests more diffuse pathology potentially involving perilesional white matter. The purpose of this study was to evaluate MR diffusion tensor imaging (MRDTI) metrics within perilesional white matter in children with PNH. Six children with PNH (four boys; average age 3.2 years, range 2 months to 6 years) were studied with MRDTI at 3 T. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were quantified within perilesional white matter at distances of 5 mm, 10 mm, 15 mm, and 20 mm from focal areas of PNH and compared to location-matched ROIs in six healthy control patients (two boys, average age 3.3 years, range 2–6 years). Statistical significance was set at an overall level of α = 0.05, corrected for multiple comparisons. Perilesional white matter showed significantly decreased fractional anisotropy and elevated mean and radial diffusivity at all evaluated distances. No significant differences in axial diffusivity were detected at any distance. PNH is associated with microstructural white matter abnormalities as indicated by abnormal perilesional MRDTI metrics detectable at least 20 mm from visible nodular lesions.

Various etiologic diagnoses are put forward for certain forms of infant epilepsy. We report four cases illustrating a rare cause: gray matter heterotopia. There were three girls and one boy, aged 3 months to 4 years at onset of seizures and 8 to 30 years at diagnosis of gray matter heterotopia. All patients sought healthcare because of repeated seizures. One patient also presented severe mental retardation. No consanguinity was noted. Magnetic resonance imaging showed the interposition of an ectopic ribbon of gray matter within the white matter in all cases. Ectopic gray matter formed bilateral subependymal nodules in one patient and bilateral nodules in the subcortical region suggestive of concentric laminar organization in another. The two other patients presented both of these forms. Other anomalies were associated: partial agenesis of the corpus callosum associated with colpocephaly causing cortical atrophy in one patient and hippocampal sclerosis in another.

Constitutional mismatch repair deficiency (CMMR-D) syndrome is a rare inherited childhood cancer predisposition caused by biallelic germline mutations in one of the four mismatch repair (MMR)-genes, MLH1, MSH2, MSH6 or PMS2. Owing to a wide tumor spectrum, the lack of specific clinical features and the overlap with other cancer predisposing syndromes, diagnosis of CMMR-D is often delayed in pediatric cancer patients. Here, we report of three new CMMR-D patients all of whom developed more than one malignancy. The common finding in these three patients is agenesis of the corpus callosum (ACC). Gray matter heterotopia is present in two patients. One of the 57 previously reported CMMR-D patients with brain tumors (therefore all likely had cerebral imaging) also had ACC. With the present report the prevalence of cerebral malformations is at least 4/60 (6.6%). This number is well above the population birth prevalence of 0.09-0.36 live births with these cerebral malformations, suggesting that ACC and heterotopia are features of CMMR-D. Therefore, the presence of cerebral malformations in pediatric cancer patients should alert to the possible diagnosis of CMMR-D. ACC and gray matter heterotopia are the first congenital malformations described to occur at higher frequency in CMMR-D patients than in the general population. Further systematic evaluations of CMMR-D patients are needed to identify possible other malformations associated with this syndrome. European Journal of Human Genetics (2013) 21, 55-61; doi: 10.1038/ejhg.2012.117; published online 13 June 2012

Periventricular heterotopia (PH) is a disorder of neuronal migration during fetal development that is characterized by morphologically normal neurons being located in an anatomically abnormal position in the mature brain. PH is usually diagnosed in patients presenting with a seizure disorder, when neuroimaging demonstrates the ectopically placed nodules of neurons. PH is a genetically and phenotypically heterogeneous disorder. The most commonly identified genetic cause is the X-linked dominant inheritance of mutations in the Filamin A (FLNA) gene. Multiple lines of evidence support the contribution of genetic factors in dyslexia. As dyslexia does not show a single-gene pattern of inheritance, it is classified as a complex genetic disorder. We have recently identified a specific reading fluency deficit in a variable group of patients with PH, in the context of normal intelligence. Here, we present a study of a mother-daughter pair who share bilateral widespread gray matter heterotopia caused by a novel mutation in FLNA and the same pattern of X-chromosome inactivation but who exhibit divergent reading and cognitive profiles. This novel observation highlights the uncertainty of using heterotopia anatomy in clinical practice to predict behavioral outcome.

Summary 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.

We report on a child with Chudley-McCullough syndrome and re-evaluate the spectrum of imaging findings (in 15 previously reported patients) which appear to be variable and, to some extent, ambiguous in the literature. Magnetic resonance imaging of the brain revealed asymmetric colpocephaly with agenesis of the splenium corporis callosi, ribbon-like subcortical gray matter heterotopia along the cingulate gyri, malrotation of both hippocampi, and dysplasia of the cerebellum. Macrocrania together with sensorineural hearing loss, colpocephaly, and posterior or complete agenesis of the corpus callosum can be considered the hallmarks of the autosomal recessive Chudley-McCullough syndrome. These may be variably associated with interhemispheric arachnoid cyst, cortical dysplasia, gray matter heterotopia, and cerebellar dysplasia. While early support with hearing aids may lead to improved language and cognitive outcome, shunting of ventricular dilatation is not indicated in the Chudley-McCullough syndrome.