FCD Type Research Articles

Application of preoperative MRI lesion identification algorithm in pediatric and young adult focal cortical dysplasia-related epilepsy

ObjectiveThe purpose of this study was to evaluate the performance and generalizability of an automated, interpretable surface-based MRI classifier for the detection of focal cortical dysplasia. MethodsThis was a retrospective cohort incorporating MRIs from the epilepsy surgery (FCD and MRI-negative) and neuroimaging (healthy controls) databases at Children's National Hospital (CNH), and a publicly-available FCD Type II dataset from Bonn, Germany. Clinical characteristics and outcomes were abstracted from patient records and/or existing databases. Subjects were included if they had 3T epilepsy-protocol MRI. Manually-segmented FCD masks were compared to the automated masks generated by the Multi-centre Epilepsy Lesion Detection (MELD) FCD detection algorithm. Sensitivity/specificity were calculated. ResultsFrom CNH, 39 FCD pharmacoresistant epilepsy (PRE) patients, 19 healthy controls, and 19 MRI-negative patients were included. From Bonn, 85 FCD Type II were included, of which 68 passed preprocessing. MELD had varying performance (sensitivity) in these datasets: CNH FCD-PRE (54 %); Bonn (68 %); MRI-negative (44 %). In multivariate regression, FCD Type IIB pathology predicted higher chance of MELD automated lesion detection. All four patients who underwent resection/ablation of MELD-identified clusters achieved Engel I outcome. SignificanceWe validate the performance of MELD automated, interpretable FCD classifier in a diverse pediatric cohort with FCD-PRE. We also demonstrate the classifier has relatively good performance in an independent FCD Type II cohort with pediatric-onset epilepsy, as well as simulated real-world value in a pediatric population with MRI-negative PRE.

Focal Cortical Dysplasia: Diagnosis, Classification, and Treatment Options

AbstractFocal cortical dysplasias (FCDs) include a spectrum of anomalies of cortical development that consist in one or more areas with altered lamination and in some cases, neurons of abnormal morphology. Clinically, these structural anomalies led to arise of epilepsy, which is more often a focal, drug-resistant type with onset in pediatric or adolescent age. Occasionally, other symptoms have been reported in patients with FCDs, such as headache, movement disorders, and cognitive impairment. According to International League against Epilepsy scheme of 2011, three main subtypes of FCD can be distinguished, based of anatomopathological feature, radiological signs, and clinical expression. Magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography, and neurophysiology are the cornerstones of diagnosis, although their negativity cannot exclude FCD in symptomatic patients, especially in FCD type I which often is elusive. In MRI, the main finding is the irregularity of the cortical–subcortical signal, specifically reduction of cortical thickness and absence of clear demarcation between gray and white matters, which is strongly diagnostic for FCD. Epilepsy related to FCD is difficult to manage and until now there is not a clear direction for treatment's rules. FCD shows poor response to antiepileptic drugs (AEDs), and there is no evidence of some AED that has proved more efficacy than others in patients with FCDs. Considering genetical and pathophysiological recent acquisitions, mammalian target of rapamycin inhibitors may play a fundamental role in future treatment of FCDs, but nowadays, surgery still remains the main weapon, with 50% of patients who undergo neurosurgery.

Negative MRI and a seizure onset zone close to eloquent areas in FCD type II: Application of MRg-LiTT after a SEEG re-evaluation in pediatric patients with a previous failed surgery

ObjectiveNegative MRI and an epileptogenic zone (EZ) adjacent to eloquent areas are two main issues that can be encountered during pre-surgical evaluation for epilepsy surgery. Focal Cortical Dysplasia type II (FCD type II) is the most common aetiology underlying a negative MRI.The objective of this study is to present three cases of pediatric patients exhibiting negative MRI and a seizure onset zone close to eloquent areas, who previously underwent traditional open surgery or SEEG-guided radiofrequency thermocoagulations (RF-TC). After seizure seizure recrudescence, pre-surgical SEEG was re-evaluated and Magnetic Resonance-guided laser interstitial thermal therapy (MRg-LiTT) was performed.We discuss the SEEG patterns, the planning of laser probes trajectories and the outcomes one year after the procedure. MethodsPediatric patients who underwent SEEG followed by MRg-LiTT for drug-resistant epilepsy associated with FCD type II at our Centre were included. Pre-surgical videoEEG (vEEG), stereoEEG (sEEG), and MRI were reviewed. Post-procedure clinical outcome (measured by Engel score) and complications rates were evaluated. ResultsThree patients underwent 3 MRg-LiTT procedures from January 2022 to June 2022. Epileptogenic zone was previously studied via SEEG in all the patients. All the three patients pre-surgical MRI was deemed negative. Mean age at seizure onset was 47 months (21–96 months), mean age at MRg-LiTT was 12 years (10 years 10 months – 12 years 9 months). Engel class Ia outcome was achieved in patients #2 and #3, Engel class Ib in patient #1. Mean follow-up length was of 17 months (13 months – 20 months). Complications occurred in one patient (patient #2, extradural hematoma). ConclusionsThe combined use of SEEG and MRg-LiTT in complex cases can lead to good outcomes both as a rescue therapy after failed surgery, but also as an alternative to open surgery after a successful SEEG-guided Radiofrequency Thermocoagulation (RF-TC). Specific SEEG patterns and a previous good outcome from RF-TC can be predictors of a favourable outcome.

WNT pathway in focal cortical dysplasia compared to perilesional nonlesional tissue in refractory epilepsies

BackgroundFocal cortical dysplasia (FCD) is a malformation of cortical development that causes medical refractory seizures, and one of the main treatments may be surgical resection of the affected area of the brain. People affected by FCD may present with seizures of variable severity since childhood. Despite many medical treatments available, only surgery can offer cure. The pathophysiology of the disease is not yet understood; however, it is known that several gene alterations may play a role. The WNT/β-catenin pathway is closely related to the control and balance of cell proliferation and differentiation in the central nervous system. The aim of this study was to explore genes related to the WNT/β-catenin pathway in lesional and perilesional brain tissue in patients with FCD type II.MethodsDysplastic and perilesional tissue from the primary dysplastic lesion of patients with FCD type IIa were obtained from two patients who underwent surgical treatment. The analysis of the relative expression of genes was performed by a qRT-PCR array (super array) containing 84 genes related to the WNT pathway.ResultsOur results suggest the existence of molecular alteration in some genes of the WNT pathway in tissue with dysplastic lesions and of perilesional tissue. We call this tissue of normal-appearing adjacent cortex (NAAC). Of all genes analyzed, a large number of genes show similar behavior between injured, perilesional and control tissues. However, some genes have similar characteristics between the perilesional and lesional tissue and are different from the control brain tissue, presenting the perilesional tissue as a molecularly altered material.ConclusionOur results suggest that the perilesional area after surgical resection of tissue with cortical dysplasia presents molecular changes that may play a role in the recurrence of seizures in these patients. The perilesional tissue should receive expanded attention beyond the somatic mutations described and associated with FCD, such as mTOR, for example, to new signaling pathways that may play a crucial role in seizure recurrence.

P20.02.B ELECTRO-CLINICAL, NEUROIMAGING FEATURES AND NEUROPATHOLOGICAL CHARACTERIZATION OF POLYMORPHOUS LOW-GRADE NEUROEPITHELIAL TUMOR OF THE YOUNG (PLNTY)

Abstract BACKGROUND Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) has been recently recognized by 2021 WHO Central nervous system classification. It is an epileptogenic tumor type, affecting mostly children and young adults, with peculiar radiological, and pathomolecular features. PLNTY is a very rare tumor, described in only 52 cases up to now. Herein, we describe 13 patients with electro-clinical and neuroimaging findings, associated to histopathological and molecular findings. MATERIAL AND METHODS We selected PLNTY patients from our Cancer Registry (Apr 2017-Dec 2022), and collected electro-clinical, radiological and histo-molecular data. Minimum follow-up was 6 months. Exams included EEG, long-term scalp video-EEG, pre-surgical brain computer tomography and Magnetic Brain Imaging (MRI). Immunohistochemistry included CD34, IDH1-R132H, GFAP, synaptophysin, ATRX, p53 and FGFR3. IDH1-2, BRAF (V600E) sequencing, Kiaa1549:BRAF, FGFR3:TACC3, FGFR2:kii1598 and FGFR2:CTNNA3 fusion analyses will be performed. RESULTS We describe 13 patients, median age 20.6 years (range 12.3-46.4). Most patients showed memory/executive impairment and had epilepsy, with an onset from 5 months-21 years before surgery. The main feature of seizures was a difficult localization and even lateralization, both semiologically and electrographically. Post-surgical seizure control was excellent.The tumors (n=11/13 temporal) presented as solid or solid-cystic cortical mass with no mass effect and unclear hedges. Calcifications were present in 4, and cysts in 6 cases. Microscopically the tumors showed infiltrative growth pattern, oligodendroglial-like cells, strong and often diffuse CD34 immunostaining, and frequent intra-tumoral calcifications. Malformation of cortical development, namely FCD type IIIB, was associated to PLNTY in 2 cases. Proliferation activity (MIB-1 LI) was very low (1%) in all cases except one (MIB-1 LI which reached 3%). CONCLUSION This study significantly extends the number of reported PLNTY associated to epilepsy, mostly characterized by bilateral interictal epileptiform discharges and difficult to lateralize seizures.The MRI features were heterogeneous and the differential diagnosis should include also dysplasia and glioneuronal tumors. PLNTY, despite its name, occurs also in adults, and electro-clinical and radiological diagnosis can be challenging. As recently described, PLNTY can show the MAPK pathway activating alterations, that are under investigation in our cohort to eventually clarify their role in the evolution of the disease. SUPPORT the study is partially supported by the Health Italian Minister (RC).

Distinct patterns of interictal intracranial EEG in focal cortical dysplasia type I and II

ObjectiveFocal cortical dysplasia (FCD) is the most common malformation causing refractory focal epilepsy. Surgical removal of the entire dysplastic cortex is crucial for achieving a seizure-free outcome. Precise presurgical distinctions between FCD types by neuroimaging are difficult, mainly in patients with normal magnetic resonance imaging findings. However, the FCD type is important for planning the extent of surgical approach and counselling. MethodsThis study included patients with focal drug-resistant epilepsy and definite histopathological FCD type I or II diagnoses who underwent intracranial electroencephalography (iEEG). We detected interictal epileptiform discharges (IEDs) and their recruitment into repetitive discharges (RDs) to compare electrophysiological patterns characterizing FCD types. ResultsPatients with FCD type II had a significantly higher IED rate (p < 0.005), a shorter inter-discharge interval within RD episodes (p < 0.003), sleep influence on decreased RD periodicity (p < 0.036), and longer RD episode duration (p < 0.003) than patients with type I. A Bayesian classifier stratified FCD types with 82% accuracy. ConclusionTemporal characteristics of IEDs and RDs reflect the histological findings of FCD subtypes and can differentiate FCD types I and II. SignificancePresurgical prediction of FCD type can help to plan a more tailored surgical approach in patients with normal magnetic resonance findings.

Transcriptome analyses of the cortex and white matter of focal cortical dysplasia type II: Insights into pathophysiology and tissue characterization.

Focal cortical dysplasia (FCD) is a common cause of pharmacoresistant epilepsy. According to the 2022 International League Against Epilepsy classification, FCD type II is characterized by dysmorphic neurons (IIa and IIb) and may be associated with balloon cells (IIb). We present a multicentric study to evaluate the transcriptomes of the gray and white matters of surgical FCD type II specimens. We aimed to contribute to pathophysiology and tissue characterization. We investigated FCD II (a and b) and control samples by performing RNA-sequencing followed by immunohistochemical validation employing digital analyses. We found 342 and 399 transcripts differentially expressed in the gray matter of IIa and IIb lesions compared to controls, respectively. Cholesterol biosynthesis was among the main enriched cellular pathways in both IIa and IIb gray matter. Particularly, the genes HMGCS1, HMGCR, and SQLE were upregulated in both type II groups. We also found 12 differentially expressed genes when comparing transcriptomes of IIa and IIb lesions. Only 1 transcript (MTRNR2L12) was significantly upregulated in FCD IIa. The white matter in IIa and IIb lesions showed 2 and 24 transcripts differentially expressed, respectively, compared to controls. No enriched cellular pathways were detected. GPNMB, not previously described in FCD samples, was upregulated in IIb compared to IIa and control groups. Upregulations of cholesterol biosynthesis enzymes and GPNMB genes in FCD groups were immunohistochemically validated. Such enzymes were mainly detected in both dysmorphic and normal neurons, whereas GPNMB was observed only in balloon cells. Overall, our study contributed to identifying cortical enrichment of cholesterol biosynthesis in FCD type II, which may correspond to a neuroprotective response to seizures. Moreover, specific analyses in either the gray or the white matter revealed upregulations of MTRNR2L12 and GPNMB, which might be potential neuropathological biomarkers of a cortex chronically exposed to seizures and of balloon cells, respectively.

Brain Somatic Variant in Ras-Like Small GTPase RALA Causes Focal Cortical Dysplasia Type II

PurposeIn our group’s previous study, we performed deep whole-exome sequencing and targeted amplicon sequencing in the postoperative brain tissue of epilepsy patients with focal cortical dysplasia type II (FCD II). We identified the first somatic variant of RALA in the brain tissue of a child with FCD type IIb. RALA encodes a small GTPase of the Ras superfamily. To date, the role of RALA in brain development is not yet known. In this study, we reported that the RALA somatic variant led to FCD type II through activation of the mammalian target of rapamycin (mTOR) pathways.Materials and MethodsHEK293T cells were transfected in vitro to analyze the expression of the RalA protein, as well as phosphorylated S6 (P-S6), one of the major markers of mTOR pathway activation, RalA GTPase activity, and the interaction between RalA and its downstream binding effectors. In vivo, wild-type, and mutant RALA plasmids were transfected into the local cortex of mice using in utero electroporation to evaluate the effect of RALA c.G482A on neuronal migration.ResultsThe RALA c.G482A mutation increased RalA protein expression, the abnormal activation of the mTOR pathways, RalA GTPase activity, and binding to downstream effectors. RALA c.G482A local transfection in the embryonic brain in utero induced abnormal cortical neuron migration in mice.ConclusionThis study demonstrated for the first time that the somatic gain-of-function variant of RALA activates the mTOR pathway and leads to neuronal migration disorders in the brain, facilitating the development of FCD II. Therefore, RALA brain somatic mutation may be one of the pathogenic mechanisms leading to FCD II, which is always related to drug-resistant epilepsy in children. However, more somatic variations of this gene are required to be confirmed in more FCD II patient brain samples.

Predictors of postoperative long-term seizure outcome in pediatric patients with focal cortical dysplasia type II at a German tertiary epilepsy center.

Focal cortical dysplasia (FCD) is a common cause of early-onset intractable epilepsy, and resection is a highly sufficient treatment option. In this study, the authors aimed to provide a retrospective analysis of pre- and postoperative factors and their impact on postoperative long-term seizure outcome. The postoperative seizure outcomes of 50 patients with a mean age of 8 ± 4.49 years and histologically proven FCD type II were retrospectively analyzed. Furthermore, pre- and postoperative predictors of long-term seizure freedom were assessed. The seizure outcome was evaluated based on the International League Against Epilepsy (ILAE) classification. Complete resection of FCD according to MRI criteria was achieved in 74% (n = 37) of patients. ILAE class 1 at the last follow-up was achieved in 76% (n = 38) of patients. A reduction of antiepileptic drugs (AEDs) to monotherapy or complete withdrawal was achieved in 60% (n = 30) of patients. Twelve patients (24%) had a late seizure recurrence, 50% (n = 6) of which occurred after reduction of AEDs. A lower number of AEDs prior to surgery significantly predicted a favorable seizure outcome (p = 0.013, HR 7.63). Furthermore, younger age at the time of surgery, shorter duration of epilepsy prior to surgery, and complete resection were positive predictors for long-term seizure freedom. The duration of epilepsy, completeness of resection, number of AEDs prior to surgery, and younger age at the time of surgery served as predictors of postoperative long-term seizure outcome, and, as such, may improve clinical practice when selecting and counseling appropriate candidates for resective epilepsy surgery. The study results also underscored that epilepsy surgery should be considered early in the disease course of pediatric patients with FCD type II.

Subtraction ictal SPECT co-registered to MRI (SISCOM) patterns in children with temporal lobe epilepsy

ObjectiveWe evaluated SISCOM patterns and their relationship with surgical outcome in children with temporal lobe epilepsy (TLE) who had undergone a temporal lobe surgery. MethodsThis was an observational study evaluating SISCOM patterns in 40 children with TLE. We classified SISCOM patterns into 4 categories; (i) unilateral anteromesial and/or anterolateral temporal pattern; (ii) unilateral anteromesial and/or anterolateral temporal plus posterior extension pattern; (iii) bilateral anteromesial and/or anterolateral temporal pattern; and (iv) atypical pattern. Determinants of SISCOM pattern and correlation between postoperative outcomes and SISCOM patterns were evaluated. ResultsPattern (i), (ii), (iii), and (iv) were identified in 10 (25%), 14 (35%), 0 (0%), and 16 (40%) patients, respectively. There was no significant correlation between patterns and postoperative outcomes. SISCOM patterns significantly associated with the presence of hippocampal sclerosis and type of focal cortical dysplasia (p-value = 0.048 and 0.036, respectively). Patients with HS had 5 times the odds of having unilateral temporal pattern, compared to patients with other neuropathology (OR = 5, 95% CI 0.92 to 27.08). Patients with FCD type 2 had 9.71 times the odds of having atypical pattern, compared to patients with other types of FCD (OR = 9.71, 95% CI 0.92 to 103.04). Lobar concordance of SISCOM and ictal and interictal scalp EEG significantly correlated with postoperative outcomes (p-value = 0.018 and 0.013, respectively). ConclusionThree SISCOM patterns were seen. Patients with HS had increased odds of having unilateral temporal pattern while patients with FCD type 2 had increased odds of having atypical pattern. However, there was no significant correlation between SISCOM patterns and postoperative outcomes. Lobar concordance of SISCOM and ictal and interictal scalp EEG significantly correlated with postoperative outcome. SignificanceThis study shows that the distribution of SISCOM patterns and their relationship with postoperative outcomes in children with TLE are different from adult population. Besides, SISCOM may add only limited diagnostic and prognostic information in children with drug-resistant TLE undergoing epilepsy surgery. Further evaluation to identify patient populations that may benefit from SISCOM is desirable.

Surgical outcome and prognostic factors in epilepsy patients with MR-negative focal cortical dysplasia.

ObjectiveFocal cortical dysplasia (FCD) represents a heterogeneous group of disorders of the cortical formation and is one of the most common causes of epilepsy. Magnetic resonance imaging (MRI) is the modality of choice for detecting structural lesions, and the surgical prognosis in patients with MR lesions is favorable. However, the surgical prognosis of patients with MR-negative FCD is unknown. We aimed to evaluate the long-term surgical outcomes and prognostic factors in MR-negative FCD patients through comprehensive presurgical data.MethodsWe retrospectively reviewed data from 719 drug-resistant epilepsy patients who underwent resective surgery and selected cases in which surgical specimens were pathologically confirmed as FCD Type I or II. If the epileptogenic focus and surgical specimens were obtained from brain areas with a normal MRI appearance, they were classified as MR-negative FCD. Surgical outcomes were evaluated at 2 and 5 years, and clinical, neurophysiological, and neuroimaging data of MR-negative FCD were compared to those of MR-positive FCD.ResultsFinally, 47 MR-negative and 34 MR-positive FCD patients were enrolled in the study. The seizure-free rate after surgery (Engel classification I) at postoperative 2 year was 59.5% and 64.7% in the MR-negative and positive FCD groups, respectively (p = 0.81). This rate decreased to 57.5% and 44.4% in the MR-negative and positive FCD groups (p = 0.43) at postoperative 5 years. MR-negative FCD showed a higher proportion of FCD type I (87.2% vs. 50.0%, p = 0.001) than MR-positive FCD. Unilobar cerebral perfusion distribution (odds ratio, OR 5.41) and concordance of interictal epileptiform discharges (OR 5.10) were significantly associated with good surgical outcomes in MR-negative FCD.ConclusionIn this study, MR-negative and positive FCD patients had a comparable surgical prognosis, suggesting that comprehensive presurgical evaluations, including multimodal neuroimaging studies, are crucial for obtaining excellent surgical outcomes even in epilepsy patients with MR-negative FCD.

Phosphorylation of S6 Protein as a Potential Biomarker in Surgically Treated Refractory Epilepsy

The tuberous sclerosis complex (TSC), focal cortical dysplasia IIB (FCD IIB), and hemimegalencephaly (HME) exhibit similar molecular features that are dependent on the hyperactivation of the mTOR pathway. They are all associated with refractory epilepsy and the need for surgical resection with varying outcomes. The phosphorylated protein S6 (pS6) is a downstream target of mTOR, whose increased expression might indicate mTOR hyperactivation, but which is also present when there is no alteration in the pathway (such as in FCD type I). We have performed immunohistochemical marking and quantification of pS6 in resected brain specimens of 26 patients clinically and histologically diagnosed with TSC, FCD IIB, or HME and compared this data to a control group of 25 patients, to measure the extent of pS6 positivity and its correlation with clinical aspects. Our results suggest that pS6 may serve as a reliable biomarker in epilepsy and that a greater percentage of pS6 marking can relate to more severe forms of mTOR-dependent brain anomalies.

Automatic Detection of Focal Cortical Dysplasia Type II in MRI: Is the Application of Surface-Based Morphometry and Machine Learning Promising?

Background and ObjectivesFocal cortical dysplasia (FCD) is a type of malformations of cortical development and one of the leading causes of drug-resistant epilepsy. Postoperative results improve the diagnosis of lesions on structural MRIs. Advances in quantitative algorithms have increased the identification of FCD lesions. However, due to significant differences in size, shape, and location of the lesion in different patients and a big deal of time for the objective diagnosis of lesion as well as the dependence of individual interpretation, sensitive approaches are required to address the challenge of lesion diagnosis. In this research, a FCD computer-aided diagnostic system to improve existing methods is presented.MethodsMagnetic resonance imaging (MRI) data were collected from 58 participants (30 with histologically confirmed FCD type II and 28 without a record of any neurological prognosis). Morphological and intensity-based features were calculated for each cortical surface and inserted into an artificial neural network. Statistical examinations evaluated classifier efficiency.ResultsNeural network evaluation metrics—sensitivity, specificity, and accuracy—were 96.7, 100, and 98.6%, respectively. Furthermore, the accuracy of the classifier for the detection of the lobe and hemisphere of the brain, where the FCD lesion is located, was 84.2 and 77.3%, respectively.ConclusionAnalyzing surface-based features by automated machine learning can give a quantitative and objective diagnosis of FCD lesions in presurgical assessment and improve postsurgical outcomes.

Robotic-Guided Stereoelectroencephalography for Refractory Epilepsy: Technique and Nuances.

Stereoelectroencephalography (SEEG) has become an integral part of epilepsy surgery, often used in the localization of the epileptogenic zone. It is an essential modality not only in the evaluation of nonlesional but also lesional drug refractory epilepsy, especially in the presence of anatomo-electro-clinical discordance. To describe our technique and the operative nuances involved in the performance of robotic SEEG placement. A 28-year lady with seizure onset at the age of 15 years presented with two types of seizures: one was associated with an aura of chest discomfort, palpitations along with oral and bilateral automatisms. There was associated speech and behavioral arrest along with ictal urinary incontinence. The other type has head turning to the right with secondary generalization lasting up to 1 min. Multimodality investigations showed bilateral temporal origin of seizures. SEEG evaluation revealed left amygdala and anterior temporal neocortical (ATL) origin of seizures. The patient underwent left ATL and amygdalectomy. Histopathology revealed focal cortical dysplasia (FCD type Ib). The patient became seizure free (ILAE Class 1) at 1-year follow up. Robotic-guided SEEG is a safe and accurate method of evaluating complex MRI negative epilepsy.

Unsupervised machine learning reveals lesional variability in focal cortical dysplasia at mesoscopic scale

ObjectiveFocal cortical dysplasia (FCD) is the most common epileptogenic developmental malformation and a prevalent cause of surgically amenable epilepsy. While cellular and molecular biology data suggest that FCD lesional characteristics lie along a spectrum, this notion remains to be verified in vivo. We tested the hypothesis that machine learning applied to MRI captures FCD lesional variability at a mesoscopic scale. MethodsWe studied 46 patients with histologically verified FCD Type II and 35 age- and sex-matched healthy controls. We applied consensus clustering, an unsupervised learning technique that identifies stable clusters based on bootstrap-aggregation, to 3 T multicontrast MRI (T1-weighted MRI and FLAIR) features of FCD normalized with respect to distributions in controls. ResultsLesions were parcellated into four classes with distinct structural profiles variably expressed within and across patients: Class-1 with isolated white matter (WM) damage; Class-2 combining grey matter (GM) and WM alterations; Class-3 with isolated GM damage; Class-4 with GM-WM interface anomalies. Class membership was replicated in two independent datasets. Classes with GM anomalies impacted local function (resting-state fMRI derived ALFF), while those with abnormal WM affected large-scale connectivity (assessed by degree centrality). Overall, MRI classes reflected typical histopathological FCD characteristics: Class-1 was associated with severe WM gliosis and interface blurring, Class-2 with severe GM dyslamination and moderate WM gliosis, Class-3 with moderate GM gliosis, Class-4 with mild interface blurring. A detection algorithm trained on class-informed data outperformed a class-naïve paradigm. SignificanceMachine learning applied to widely available MRI contrasts uncovers FCD Type II variability at a mesoscopic scale and identifies tissue classes with distinct structural dimensions, functional and histopathological profiles. Integrating in vivo staging of FCD traits with automated lesion detection is likely to inform the development of novel personalized treatments.

Features of the neuroradiological picture of ganglioglioma on the example of 20 clinical cases

To analyze the images obtained during pre-surgical neuroimaging in patients with gangliomas for the presence of specific signs and verification of the neoplastic process. The results of presurgical MRI (3.0, 1.5 Tesla) of 20 patients with gangliomas were analyzed to identify specific signs of a neuronal-glial tumor and verify the neoplastic process based on the results obtained and a review of the literature. In addition to high-resolution MRI (HR MRI), various protocol modifications were applied to patients with epileptogenic pathological substrates of unclear etiology, including tractography (DTI) and contrast-free MR perfusion (ASL). In 5 cases, a multi-modal study was performed that combined the results of CT, routine MRI, HR MRI, functional MRI (fMRI) in various combinations and PET CT. In 17 cases, patients underwent epileptic surgery. Three patients without epilepsy were operated on for a tumor diagnosed by radiological examination. In all 20 cases, gangliogliomas were verified, including 1 anaplastic, 1 infantile desmoplastic, and another patient had histological samples showing signs of a composite tumor. Combination with FCD IIIb was observed in 3 cases. Two patients had a double pathology (cases of tumors combination with lissencephaly and neuronal heterotopia) and another had a composite neuronal-glial tumor. In 15 cases, gangliogliomas showed neuroradiological features typical for dysembryoplastic neuroepithelial tumor (DNT) such as multicystic, nodular, and diffuse (dysplastic) described in the literature. In addition, in 9 cases, they had significant signs of neoplastic process such as contrast enhancement, continued growth and remodeling of the underlying bone. Verification of the neoplastic process based on the results of neuroradiological studies was difficult in 6 cases. In 2 cases, it was not possible to confirm the presence of neoplasm by radiological methods, and in 1 patient, the verification of the tumor during differential diagnosis took more than 8 years. The most common differential diagnosis was performed with DNT and FCD type IIb, which have a number of similar neuroradiological features.

Histological type of focal cortical dysplasia is associated with the risk of postsurgical seizure in children and adolescents.

AimFocal cortical dysplasia (FCD) is a common cause of refractory epilepsy in children and adolescents. Epilepsy surgery is a treatment option for FCD. This study aimed to investigate the relationship between postsurgical outcomes and FCD types according to the International League Against Epilepsy (ILAE) classification and assess prognostic factors in pediatric and adolescent epilepsy surgery.MethodsWe retrospectively analyzed 92 children and adolescents with a proven pathological diagnosis of FCD who underwent resective surgery at our epilepsy center between August 2012 and September 2015. The patients were followed up for at least 1 year to evaluate the surgical outcomes, and a multivariable regression analysis was performed to identify risk factors of seizure relapse.ResultsAfter surgery, 53.3% of the patients were completely seizure-free during the entire follow-up period. The FCD types, incomplete resection of the epileptic cortex, and use of intracranial electrode were independent risk factors of seizure recurrence. The patients with FCD type II had relatively favorable surgical outcomes compared to the patients with FCD type I. The difference in the postoperative outcome between patients with FCD types III and I was not significant.ConclusionThere is a significant association between FCD types and surgical outcomes in children and adolescents with epilepsy. These findings provide guidance for the optimization of surgical strategies.

Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia.

ObjectivesFocal cortical dysplasia (FCD) is a major cause of drug‐resistant focal epilepsy in children, and the clinicopathological classification remains a challenging issue in daily practice. With the recent progress in DNA methylation–based classification of human brain tumors we examined whether genomic DNA methylation and gene expression analysis can be used to also distinguish human FCD subtypes.Methods DNA methylomes and transcriptomes were generated from massive parallel sequencing in 15 surgical FCD specimens, matched with 5 epilepsy and 6 nonepilepsy controls.ResultsDifferential hierarchical cluster analysis of DNA methylation distinguished major FCD subtypes (ie, Ia, IIa, and IIb) from patients with temporal lobe epilepsy patients and nonepileptic controls. Targeted panel sequencing identified a novel likely pathogenic variant in DEPDC5 in a patient with FCD type IIa. However, no enrichment of differential DNA methylation or gene expression was observed in mechanistic target of rapamycin (mTOR) pathway–related genes.SignificanceOur studies extend the evidence for disease‐specific methylation signatures toward focal epilepsies in favor of an integrated clinicopathologic and molecular classification system of FCD subtypes incorporating genomic methylation.

Histopathologic substrate of drug-resistant epilepsy in older adults and the elderly undergoing surgery.

SummaryPatients 60 years or older are one of the highest risk age groups for development of epilepsy. Clinical and neuroimaging analysis has typically accounted for etiology in two‐thirds of these patients, while the data on histopathology are lacking. We provide the first analysis of the histopathological substrates underlying drug‐resistant epilepsy (DRE) in older adults/elderly patients who underwent resective epilepsy surgery (RES) at Cleveland Clinic. A total of 78 patients (mean age ± standard deviation: 64.7 ± 3.7 years; 59% female) were included in the study. The most common pathologies included hippocampal sclerosis (HS; 35.9%; all visible on magnetic resonance imaging [MRI]), focal cortical dysplasia (FCD; 25.6%) and remote infarct/ischemic changes (12.8%). Underlying pathology did not differ significantly between the patients achieving a good seizure outcome (Engel class I; 77% [47 of 61 patients]) and the rest of the cohort. With one exception, all MRI‐negative cases had FCD type Ib. A receiver‐operating characteristic (ROC) curve analysis found a significant association (P = 0.002) between seizure‐onset age and HS, whereby the odds of its presence were reduced by 4% for every 1 year increase in the age at seizure onset. The model showed that the age cutoff for seizure onset predicting HS was 43 years, with a negative predictive value of 81.6%. None of the 14 patients with late‐onset epilepsy (≥60 years of age) were found to have HS; they mostly had acquired lesions. Our study provides histopathologic evidence for the diminished role of late‐onset HS in DRE in older adults/elderly who undergo RES.

A comprehensive clinico-pathological and genetic evaluation of bottom-of-sulcus focal cortical dysplasia in patients with difficult-to-localize focal epilepsy.

We comprehensively studied the clinical presentation, stereo-EEG and MRI findings, histopathological diagnosis, and brain somatic mutations in a retrospective series of drug-resistant patients with difficult-to-localize epilepsy due to focal cortical dysplasia at the bottom of a sulcus (BOS-FCD). We identified 10 patients with BOS-FCD from the Cleveland Clinic epilepsy surgery database submitted for intracranial video-EEG monitoring. Brain MRI, including voxel-based morphometric analysis and surgical tissue submitted for histopathology, was reviewed. Paraffin tissue samples from five patients were made available for targeted next-generation sequencing. Postsurgical follow-up was available in nine patients. BOS-FCD was identified in the superior frontal sulcus in six patients, inferior frontal sulcus in one patient, central sulcus in one patient, and intraparietal sulcus in two patients. All patients had stereotyped seizures. Intracranial EEG recordings identified ictal onset at the BOS-FCD in all 10 patients, whereas ictal scalp EEG had a localizing value in only six patients. Complete resection was achieved by lesionectomy or focal corticectomy in nine patients. Histopathologically, six patients had FCD type IIb and three had FCD type IIa. Next-generation sequencing analysis of DNA extracted from lesion-enriched (micro-dissected) tissue from five patients with FCD type II led to the identification of a germline frameshift insertion in DEPDC5, introducing a premature stop in one patient. Eight out of nine patients with available follow-up were completely seizure-free (Engel Class IA) after a mean follow-up period of six years. Our results confirm previous studies classifying difficult-to-localize BOS-FCD into the emerging spectrum of FCD ILAE type II mTORopathies. Further studies with large patient numbers and ultra-deep genetic testing may help to bridge the current knowledge gap in genetic aetiologies of FCD.