Clinical Features, Neuropathology, and Surgical Outcome in Patients With Refractory Epilepsy and Brain Somatic Variants in the SLC35A2 Gene.

BACKGROUND AND OBJECTIVES: The SLC35A2 gene, located at chromosome Xp11.23, encodes for a uridine diphosphate-galactose transporter. We describe clinical, genetic, neuroimaging, EEG, and histopathologic findings and assess possible predictors of postoperative seizure and cognitive outcome in 47 patients with refractory epilepsy and brain somatic SLC35A2 gene variants. METHODS: This is a retrospective multicenter study where we performed a descriptive analysis and classical hypothesis testing. We included the variables of interest significantly associated with the outcomes in the generalized linear models. RESULTS: Two main phenotypes were associated with brain somatic SLC35A2 variants: (1) early epileptic encephalopathy (EE, 39 patients) with epileptic spasms as the predominant seizure type and moderate to severe intellectual disability and (2) drug-resistant focal epilepsy (DR-FE, 8 patients) associated with normal/borderline cognitive function and specific neuropsychological deficits. Brain MRI was abnormal in all patients with EE and in 50% of those with DR-FE. Histopathology review identified mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy in 44/47 patients and was inconclusive in 3. The 47 patients harbored 42 distinct mosaic SLC35A2 variants, including 14 (33.3%) missense, 13 (30.9%) frameshift, 10 (23.8%) nonsense, 4 (9.5%) in-frame deletions/duplications, and 1 (2.4%) splicing variant. Variant allele frequencies (VAFs) ranged from 1.4% to 52.6% (mean VAF: 17.3 ± 13.5). At last follow-up (35.5 ± 21.5 months), 30 patients (63.8%) were in Engel Class I, of which 26 (55.3%) were in Class IA. Cognitive performances remained unchanged in most patients after surgery. Regression analyses showed that the probability of achieving both Engel Class IA and Class I outcomes, adjusted by age at seizure onset, was lower when the duration of epilepsy increased and higher when postoperative EEG was normal or improved. Lower brain VAF was associated with improved postoperative cognitive outcome in the analysis of associations, but this finding was not confirmed in regression analyses. DISCUSSION: Brain somatic SLC35A2 gene variants are associated with 2 main clinical phenotypes, EE and DR-FE, and a histopathologic diagnosis of MOGHE. Additional studies will be needed to delineate any possible correlation between specific genetic variants, mutational load in the epileptogenic tissue, and surgical outcomes.

Expert Opinion on the Management of Growth Hormone Deficiency in Brain Tumor Survivors: Results From an Italian Survey.

Background: Growth hormone deficiency (GHD) is the first and most common endocrine complication in pediatric brain tumor survivors (BTS). GHD can occur due to the presence of the tumor itself, surgery, or cranial radiotherapy (CRT). Aims: This study aimed to evaluate management and adherence to current guidelines of the Italian centers engaged in the diagnosis and follow-up of GHD patients with BTS. Methods: A multidisciplinary scientific board of pediatric endocrinologists, oncologists and radiologists with neuroimaging expertise discussed and reviewed the main issues relating to the management of GHD in pediatric BTS and developed a survey. The survey included questions relating to organizational aspects, risk factors, diagnosis, definition of stable disease, and treatment. The online survey was sent to an expanded panel of specialists dedicated to the care of pediatric BTS, distributed among the three specialty areas and throughout the country (23 Italian cities and 37 Centers). Results: The online questionnaire was completed by 86.5% (32 out of 37) of the Centers involved. Most had experience in treating these patients, reporting that they follow more than 50 BTS patients per year. Responses were analyzed descriptively and aggregated by physician specialty. Overall, the results of the survey showed some important controversies in real life adherence to the current guidelines, with discrepancies between endocrinologists and oncologists in the definition of risk factors, diagnostic work-up, decision-making processes and safety. Furthermore, there was no agreement on the neuroimaging definition of stable oncological disease and how to manage growth hormone therapy in patients with residual tumor and GHD. Conclusions: The results of the first Italian national survey on the management of GHD in BTS highlighted the difference in management on some important issues. The time to start and stop rhGH treatment represent areas of major uncertainty. The definition of stable disease remains critical and represents a gap in knowledge that must be addressed within the international guidelines in order to increase height and to improve metabolic and quality of life outcomes in cancer survivors with GHD.

Multicenter Validation of a Deep Learning Detection Algorithm for Focal Cortical Dysplasia.

BACKGROUND AND OBJECTIVE: To test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD). METHODS: We used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2-55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity. RESULTS: Overall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls. DISCUSSION: This first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.

Resting State Functional Connectivity Signatures of MRgFUS Vim Thalamotomy in Parkinson's Disease: A Preliminary Study.

Magnetic Resonance-guided high-intensity Focused Ultrasound (MRgFUS) of the thalamic ventral intermediate nucleus (Vim) for tremor has increasingly gained interest as a new non-invasive alternative to standard neurosurgery. Resting state functional connectivity (rs-FC) correlates of MRgFUS have not been extensively investigated yet. A region of interest (ROI)-to-ROI rs-FC MRI "connectomic" analysis focusing on brain regions relevant for tremor was conducted on 15 tremor-dominant patients with Parkinson's disease who underwent MRgFUS. We tested whether rs-FC between tremor-related areas was modulated by MRgFUS at 1 and 3 months post-operatively, and whether such changes correlated with individual clinical outcomes assessed by the MDS-UPDRS-III sub items for tremor. Significant increase in FC was detected within bilateral primary motor (M1) cortices, as well as between bilateral M1 and crossed primary somatosensory cortices, and also between pallidum and the dentate nucleus of the untreated hemisphere. Correlation between disease duration and FC increase at 3 months was found between the putamen of both cerebral hemispheres and the Lobe VI of both cerebellar hemispheres, as well as between the Lobe VI of untreated cerebellar hemisphere with bilateral supplementary motor area (SMA). Drop-points value of MDS-UPDRS at 3 months correlated with post-treatment decrease in FC, between the anterior cingulate cortex and bilateral SMA, as well as between the Lobe VI of treated cerebellar hemisphere and the interpositus nucleus of untreated cerebellum. Tremor improvement at 3 months, expressed as percentage of intra-subject MDS-UPDRS changes, correlated with FC decrease between bilateral occipital fusiform gyrus and crossed Lobe VI and Vermis VI. Good responders (≥50% of baseline tremor improvement) showed reduced FC between bilateral SMA, between the interpositus nucleus of untreated cerebellum and the Lobe VI of treated cerebellum, as well as between the untreated SMA and the contralateral putamen. Good responders were characterized at baseline by crossed hypoconnectivity between bilateral putamen and M1, as well as between the putamen of the treated hemisphere and the contralateral SMA. We conclude that MRgFUS can effectively modulate brain FC within the tremor network. Such changes are associated with clinical outcome. The shifting mode of integration among the constituents of this network is, therefore, susceptible to external redirection despite the chronic nature of PD.

Advanced intraoperative ultrasound (ioUS) techniques in focal cortical dysplasia (FCD) surgery: A preliminary experience on a case series.

INTRODUCTION: Focal Cortical Dysplasia (FCD) represents a broad spectrum of histopathological entities that cause drug-resistant epilepsy. Surgery has been shown to be the treatment of choice, but incomplete resection represents the leading cause of seizure persistence. Preliminary experiences with intraoperative ultrasound (ioUS) have proven its potential in defining and characterizing the lesion. In this study we analyzed the feasibility of advanced ultrasound techniques such as sono-elastography (SE) and contrast enhancement ultrasound (CEUS) in a small cohort of patients with FCD. MATERIAL AND METHODS: We retrospectively reviewed all clinical records and images of patients with drug resistant epilepsy who underwent at least one advanced sonographic technique (SE and/or CEUS) during ioUS guided surgery between November 2014 and October 2017. We excluded from our analysis all patients with lesions other than FCD or those who had FCD associated with other pathological entities. RESULTS: Four patients with type IIb FCD in the right frontal lobe were evaluated. All of them underwent SE, which highlighted heterogeneous stiffness in the dysplastic foci, also multiple areas of higher consistency were detected in all patients. Three patients evaluated with CEUS had visible enhancement in the FCD. Neither SE nor CEUS were better than ioUS in the identification of lesion boundaries. In the three patients who underwent both SE and CEUS we found no correspondence between stiffer areas and enhancement in the dysplastic areas. CONCLUSION: Ourpreliminary report confirms the feasibility of SE and CEUS in FCD surgery and describes the imaging findings in this category of patients. Studies on larger cohorts of patients are warranted to better clarify the role of these advanced intraoperative ultrasound techniques in patients with FCD.

Intraoperative ultrasonography (ioUS) characteristics of focal cortical dysplasia (FCD) type II b.

PURPOSE: Focal cortical dysplasia (FCD) is one of the major causes of drug-resistant epilepsy. Surgery has proved to be the treatment of choice, however up to a third of patients experience only partial resection. Ill-defined borders and lesions embedded in eloquent areas are two of the main drawbacks of FCD surgery. Preliminary experiences with intraoperative ultrasound (ioUS) have proved its feasibility and potential. We analyzed FCD' ioUS findings in our patients with FCD and compared them with magnetic resonance (MRI) ones. METHODS: We retrospectively reviewed all records of patients with focal medically refractory epilepsy who underwent ioUS guided surgery between November 2014 and October 2017. Lesions other than FCD or FCD associated with other pathological entities were not considered. Patients' preoperative MRI and ioUS features were analyzed according to up-to-date literature and than compared. RESULTS: A homogeneous population of five patients with type IIb FCD was evaluated. Focal cortical thickening and cortical ribbon hyper-intensity, blurring of the grey-white matter junction and hyper-intensity of the subcortical white matter on T2-weighted/FLAIR images were present in all patients. Cortical features had a complete concordance between ioUS and MRI. In particular ioUS thickening and hyper-echogenicity of cortical ribbon were identified in all cases (100%). Contrary, hyper-echoic subcortical white matter was detected in 60% of the patients. IoUS images resulted in clearer lesion borders than MRI images. CONCLUSION: Our study confirms the potentials of ioUS as a valuable diagnostic tool to guide FCD surgeries.

Tracking the Re-organization of Motor Functions After Disconnective Surgery: A Longitudinal fMRI and DTI Study.

Objective: Mechanisms of motor plasticity are critical to maintain motor functions after cerebral damage. This study explores the mechanisms of motor reorganization occurring before and after surgery in four patients with drug-refractory epilepsy candidate to disconnective surgery. Methods: We studied four patients with early damage, who underwent tailored hemispheric surgery in adulthood, removing the cortical motor areas and disconnecting the corticospinal tract (CST) from the affected hemisphere. Motor functions were assessed clinically, with functional MRI (fMRI) tasks of arm and leg movement and Diffusion Tensor Imaging (DTI) before and after surgery with assessments of up to 3 years. Quantifications of fMRI motor activations and DTI fractional anisotropy (FA) color maps were performed to assess the lateralization of motor network. We hypothesized that lateralization of motor circuits assessed preoperatively with fMRI and DTI was useful to evaluate the motor outcome in these patients. Results: In two cases preoperative DTI-tractography did not reconstruct the CST, and FA-maps were strongly asymmetric. In the other two cases, the affected CST appeared reduced compared to the contralateral one, with modest asymmetry in the FA-maps. fMRI showed different degrees of lateralization of the motor network and the SMA of the intact hemisphere was mostly engaged in all cases. After surgery, patients with a strongly lateralized motor network showed a stable performance. By contrast, a patient with a more bilateral pattern showed worsening of the upper limb function. For all cases, fMRI activations shifted to the intact hemisphere. Structural alterations of motor circuits, observed with FA values, continued beyond 1 year after surgery. Conclusion: In our case series fMRI and DTI could track the longitudinal reorganization of motor functions. In these four patients the more the paretic limbs recruited the intact hemisphere in primary motor and associative areas, the greater the chances were of maintaining elementary motor functions after adult surgery. In particular, DTI-tractography and quantification of FA-maps were useful to assess the lateralization of motor network. In these cases reorganization of motor connectivity continued for long time periods after surgery.

Contrast-enhanced MR Imaging versus Contrast-enhanced US: A Comparison in Glioblastoma Surgery by Using Intraoperative Fusion Imaging.

Purpose To compare contrast material enhancement of glioblastoma multiforme (GBM) with intraoperative contrast-enhanced ultrasonography (US) versus that with preoperative gadolinium-enhanced T1-weighted magnetic resonance (MR) imaging by using real-time fusion imaging. Materials and Methods Ten patients with GBM were retrospectively identified by using routinely collected, anonymized data. Navigated contrast-enhanced US was performed after intravenous administration of contrast material before tumor resection. All patients underwent tumor excision with navigated intraoperative US guidance with use of fusion imaging between real-time intraoperative US and preoperative MR imaging. With use of fusion imaging, glioblastoma contrast enhancement at contrast-enhanced US (regarding location, morphologic features, margins, dimensions, and pattern) was compared with that at gadolinium-enhanced T1-weighted MR imaging. Results Fusion imaging for virtual navigation enabled matching of real-time contrast-enhanced US scans to corresponding coplanar preoperative gadolinium-enhanced T1-weighted MR images in all cases, with a positional discrepancy of less than 2 mm. Contrast enhancement of gadolinium-enhanced T1-weighted MR imaging and contrast-enhanced US was superimposable in all cases with regard to location, margins, dimensions, and morphologic features. The qualitative analysis of contrast enhancement pattern demonstrated a similar distribution in contrast-enhanced US and gadolinium-enhanced T1-weighted MR imaging in nine patients: Seven lesions showed peripheral inhomogeneous ring enhancement, and two lesions showed a prevalent nodular pattern. In one patient, the contrast enhancement pattern differed between the two modalities: Contrast-enhanced US showed enhancement of the entire bulk of the tumor, whereas gadolinium-enhanced T1-weighted MR imaging demonstrated peripheral contrast enhancement. Conclusion Glioblastoma contrast enhancement with contrast-enhanced US is superimposable on that provided with preoperative gadolinium-enhanced T1-weighted MR imaging regarding location, margins, morphologic features, and dimensions, with a similar enhancement pattern in most cases. Thus, contrast-enhanced US is of potential use in the surgical management of GBM. © RSNA, 2017 Online supplemental material is available for this article.

Type II focal cortical dysplasia: Ex vivo 7T magnetic resonance imaging abnormalities and histopathological comparisons.

OBJECTIVE: In the present report, the correlations between ex vivo high-resolution imaging and specific histological and ultrastructural patterns in type II focal cortical dysplasia (FCD) have been studied to explain the differences in the magnetic resonance imaging (MRI) detection of dysplasia and to contribute to the presurgical imaging evaluation of this pathology. METHODS: Surgical specimens from 13 patients with FCD IIa/b were submitted to 7T MRI scanning, and then analyzed histologically and ultrastructurally to compare the results with the MRI findings. Region of interest (ROI)-based measures on T2-weighted images (T2wi) were quantitatively evaluated in the lesion and in adjacent perilesional gray and white matter. RESULTS: Matched histological sections and 7T T2wi showed that the core of the lesion was characterized by patchy aggregates of abnormal cells and fiber disorganization related to inhomogeneity of intracortical signal intensity. The quantitative approach on T2wi can help to distinguish the lesions and perilesional areas even in a clinical MRI-negative case. The ultrastructural study showed that the strong signal hyperintensity in the white matter of FCD IIb was related to a dysmyelination process associated with severe fiber loss and abnormal cells. Less severe histopathological features were found in FCD IIa, thus reflecting their less evident MRI alterations. INTERPRETATION: We suggest that white matter abnormalities in type IIb FCD are due to defects of the myelination processes and maturation, impaired by the presence of balloon cells. To reveal the presence and the border of type II cortical dysplasia on MRI, a quantitative ROI-based analysis (coefficient of variation) is also proposed.

Focal seizures versus epileptic spasms in children with focal cortical dysplasia and epilepsy onset in the first year.

PURPOSE: Focal cortical dysplasia (FCD) has been recognized as one of the most frequent causes of drug resistant epilepsy, especially in children. In infancy, onset of FCD-related epilepsy is substantially characterized by epileptic spasms (ES) or focal seizures. Which elements pertaining to the FCD are responsible for the onset of one type of seizure over the other is still unclear. Purpose of our study was to compare the characteristics of FCDs in terms of lateralization and site in patients with epileptic spasms versus patients with focal seizures. METHODS: We retrospectively reviewed data from 41 patients with FCD related epilepsy with onset during the first 14 months of life. Seizure semeiology and drug resistance were analyzed, as were age at onset and FCD site and lateralization. RESULTS: Twenty-one children had focal seizures, 11 had ES and nine had focal seizures followed by ES. Mean age at onset was respectively 8.2, 5.1 and 1.8 months. Drug resistance was present in respectively 38.5%, 34.6% and 26.9% of children. Among patients with only ES, 90.9% had an exclusively frontal FCD localization, versus 42.9% of patients with focal seizures and 11.1% of patients with focal seizures followed by ES. FCD lateralization was right sided respectively in 47.6%, 81.8% and 66.7% of patients. CONCLUSIONS: Frontal lobe localization of FCDs was closely associated with ES (p=0.001). Moreover we also found that patients with focal seizures followed by ES had a significantly earlier age at onset compared to patients with focal seizures only (p<0.001). The association between ES and right-sided FCD lateralization, even if numerically suggestive, did not reach statistical significance (p=0.16). There was no significant association between seizure type and drug resistance (p=0.08).

Recurrent generalized seizures, visual loss, and palinopsia as phenotypic features of neuronal ceroid lipofuscinosis due to progranulin gene mutation.

We detail the phenotype of a novel form of neuronal ceroid lipofuscinosis due to a homozygous progranulin gene mutation (c.813_816del; CLN11 MIM #614706). The symptoms appeared in two young adult siblings, and included progressive retinopathy, recurrent generalized seizures, moderate ataxia, and subtle cognitive dysfunction. Long-lasting episodes of palinopsia were a recurring symptom and associated with polyphasic visual-evoked potential waveform that suggested hyperexcitability of the occipital cortex. Electroencephalography showed rare spike-wave paroxysms, and magnetic resonance imaging revealed selective cerebellar atrophy. Skin biopsy revealed fingerprint storage and the absence of progranulin protein. Electron microscopy of peripheral blood leukocytes showed fingerprint profiles in 1/100 lymphocytes. These findings define a novel phenotype and provide clues for better understanding of progranulin function. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Blurring in patients with temporal lobe epilepsy: clinical, high-field imaging and ultrastructural study.

Magnetic resonance imaging-positive temporal lobe atrophy with temporo-polar grey/white matter abnormalities (usually called 'blurring') has been frequently reported in patients with temporal lobe epilepsy associated with hippocampal sclerosis. The poor distinction of grey and white matter has been attributed to various causes, including developmental cortical abnormalities, gliosis, myelin alterations, a non-specific increase in temporal lobe water content and metabolic/perfusion alterations. However, there is still no consensus regarding the genesis of these abnormalities and no histopathological proof for a structural nature of magnetic resonance imaging changes. The aim of this study was to investigate the pathological substrate of temporo-polar blurring using different methodological approaches and evaluate the possible clinical significance of the abnormalities. The study involved 32 consecutive patients with medically intractable temporal lobe epilepsy and hippocampal sclerosis who underwent surgery after a comprehensive electroclinical and imaging evaluation. They were divided into two groups on the basis of the presence/absence of temporo-polar blurring. Surgical specimens were examined neuropathologically, and selected samples from both groups underwent high-field 7 T magnetic resonance imaging and ultrastructural studies. At the clinical level, the two groups were significantly different in terms of age at epilepsy onset (earlier in the patients with blurring) and epilepsy duration (longer in the patients with blurring). Blurring was also associated with lower neuropsychological test scores, with a significant relationship to abstract reasoning. On 7 T magnetic resonance image examination, the borders between the grey and white matter were clear in all of the samples, but only those with blurring showed a dishomogeneous signal in the white matter, with patchy areas of hyperintensity mainly in the depth of the white matter. Sections from the patients with blurring that were processed for myelin staining revealed dishomogeneous staining of the white matter, which was confirmed by analyses of the corresponding semi-thin sections. Ultrastructural examinations revealed the presence of axonal degeneration and a significant reduction in the number of axons in the patients with blurring; there were no vascular alterations in either group. These data obtained using different methodological approaches provide robust evidence that temporo-polar blurring is caused by the degeneration of fibre bundles and suggest slowly evolving chronic degeneration with the redistribution of the remaining fibres. The article also discusses the correlations between the morphological findings and clinical data.

Accuracy of pre-surgical fMRI confirmed by subsequent crossed aphasia.

Atypical patterns of language activation in functional MRI (fMRI) are not unusual, particularly in patients with severe epilepsy. Still, the functional significance of these activations is under debate. We describe a case of a right-handed patient affected by drug-refractory right temporal lobe epilepsy in whom pre-surgical fMRI showed bilateral language activations, greater in the right hemisphere (RH). After surgery, a right subdural hematoma caused epileptic status and severe aphasia. This post-surgical complication of a crossed aphasia confirmed the prior fMRI findings of RH language thus stressing the value of pre-surgical fMRI evaluations, even when surgery is planned in the RH of a right-handed patient.

Hemispherotomy and functional hemispherectomy: indications and outcome.

Peri-insular hemispherotomy is a disconnective procedure that enables functional isolation of single or multiple epileptogenic regions largely involving one hemisphere. This report is based on a consecutive series of 13 pediatric patients affected by refractory hemispheric epilepsy studied and operated on at the Neurological Institute "C. Besta" of Milan. In all patients seizures were focal with polymorphic features and daily frequency. Preoperative electro-clinical and MRI data were suggestive of Rasmussen's encephalitis in 6 cases, hemimegalencephaly in 2, hemispheric cortical malformation in 3, perinatal stroke in 2 cases. Mean age at surgery was 7.3 years. The postoperative course was good for all patients. Mean follow-up period was 4.5 years (range 2-7 years). After hemispherotomy, 8 patients were Engel Class I and five continued to have seizures and were classified as Engel Class II (1 case) III (3 cases) or IV (1 case). The outcome results varied according to the etiology; the best results were achieved in patients with Rasmussen encephalitis and perinatal vascular strokes with 75% classified in Engel Class I. Three patients underwent a second surgery because of persistent seizures and evidence of incomplete disconnection; two out of three patients had hemimegalencephaly, and did not improve; the third patient with perinatal stroke resulted seizure free. We conclude that hemispherotomy can be performed successfully to treat medically intractable hemispheric epilepsy, providing remarkable results in terms of seizure outcome and quality of life.

Functional MRI in malformations of cortical development: activation of dysplastic tissue and functional reorganization.

BACKGROUND AND PURPOSE: Functional neuroimaging and electrophysiological studies suggest that dysplastic neural tissue in malformations of cortical development may participate in task performance, and that functional organization can be altered beyond visible lesion boundaries. The aim of this work was to investigate cortical function in a heterogeneous group of patients with malformations of cortical development. METHODS: Twelve patients participated in the study, 2 for each of the following categories: subcortical, periventricular, and band heterotopia, unilateral and bilateral polymicrogyria, and focal cortical dysplasia. Functional magnetic resonance imaging was performed with finger tapping, somatosensory and visual stimulation, and language-related tasks. RESULTS: We found activations within the dysplastic tissue in subcortical heterotopia, band heterotopia, and polymicrogyria, but not in periventricular heterotopic nodules. In one of the patients with focal cortical dysplasia, language-related activation involved part of the lesion. Functional reorganization beyond visible lesion boundaries was seen, with different patterns, in 4 patients. CONCLUSIONS: In accordance with previous reports, our findings indicate that dysplastic neural tissue can be activated during task performance, and that in some patients, extensive functional reorganization occurs, highlighting the importance of functional magnetic resonance imaging in presurgical planning in those patients for whom epilepsy surgery is considered as an option.

Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival.

PURPOSE: Recent data suggest that methylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase (MGMT), by increasing the chemosensitivity of glioblastoma multiforme, is significantly associated with improved prognosis. Results in contradiction with these findings, however, are present in the literature and the clinical and genetic context framing MGMT methylation is poorly characterized. EXPERIMENTAL DESIGN: To address these issues, we have investigated the MGMT methylation status, clinical and magnetic resonance imaging characteristics, and relevant genetic features (loss of heterozygosity on 17p and 19q, EGFR amplification, and p53 mutations) in a retrospective study on 86 patients affected by glioblastoma multiforme: 72 patients had a clinical history indicating de novo insurgence of the tumor and the remaining 14 were secondary glioblastoma multiforme. RESULTS: MGMT methylation was detected by methylation-specific PCR in 41 of 86 cases (47.7%; Meth+). Progression-free survival and overall survival were significantly longer in Meth+ than in Meth- patients [10 versus 7 months (P=0.003, log-rank test) and 18 versus 14 months (P=0.0003, log-rank test), respectively]. Mixed-nodular enhancement at magnetic resonance imaging was significantly more frequent in Meth+ and secondary glioblastoma multiforme and ring enhancement in Meth- and primary glioblastoma multiforme (P<0.005). MGMT methylation was more present in secondary glioblastoma multiforme (P=0.006) and associated with loss of heterozygosity on 17p and/or 19q (P=0.005). CONCLUSIONS: These observations suggest that MGMT methylation is part of a genetic signature of glioblastomas that developed from lower-grade gliomas.

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.

Morphological neuroimaging of malformations of cortical development.

Malformations of cortical development are classified on the basis of imaging features and stages of cortical development. They are grouped by causes of the malformation: abnormal glial and neuronal proliferation, abnormal neuronal migration and abnormal cortical organisation. Focal or multifocal and generalised forms are recognised in each of these groups. In the first group, generalised forms include microlissencephalies. Among focal-multifocal abnormalities, neoplastic forms include ganglioglioma and dysembryoplastic neuroepithelial tumours. Non-neoplastic forms include focal cortical dysplasia and tuberous sclerosis. Malformations due to abnormal migration include lissencephalies; cortical heterotopias are recognised in both focal and generalised forms. Abnormal cortical organisation includes polymicrogyria, in generalised or focal forms, and schizencephalies among the focal forms.