[Focal cortical dysplasia: visual assessment of MRI and MR morphometry data]. / Fokal'naya kortikal'naya displaziya: sravnitel'nyi analiz vizual'noi otsenki dannykh magnitno-rezonansnoi tomografii i magnitno-rezonansnoi morfometrii.

OBJECTIVE: Assessing the diagnostic significance of MR morphometry in determining the localization of focal cortical dysplasias (FCD). MATERIAL AND METHODS: The study included 13 children after surgery for drug-resistant epilepsy caused by FCD type II and stable postoperative remission of seizures (Engel class IA, median follow-up 56 months). We analyzed the results of independent expert assessment of native MR data by three radiologists (HARNESS protocol) and MR morphometry data regarding accuracy of FCD localization. We considered 2 indicators, i.e. local cortical thickening and gray-white matter blurring. RESULTS: FCD detection rate was higher after MR morphometry compared to visual analysis of native MR data using the HARNESS protocol. MR morphometry also makes it possible to more often identify gray-white matter blurring as a sign often missed by radiologists (p<0.05). CONCLUSION: MR morphometry is an additional non-invasive method for assessing the localization of FCD.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Somatic mutations involving TSC 1 and TSC2 genes in two children with focal cortical dysplasia.

BACKGROUND: The role of PI3K/AKT/mTOR pathway hyperactivation in localized brain overgrowth is evolving. We describe two patients with focal cortical dysplasia (FCD) who demonstrated somatic mutations in TSC1 and TSC2 genes in the dysplastic brain tissue but not peripheral blood. METHODS: Paired whole-exome sequencing was performed on genomic DNA extracted from blood and excised brain tissue in two children with FCD who underwent excision of dysplastic tissue. RESULTS: Patient 1, a 14-year boy, had drug-resistant focal epilepsy with onset at 20 months. His brain MRI showed abnormalities suggestive of FCD in the left superior and middle frontal lobes. Patient 2 presented at the age of 10 years with pharmaco-resistant focal epilepsy (onset at six years). His MRI suggested FCD in the left insular lobe. Both patients underwent surgical excision of FCD, and excised tissues were pathologically confirmed to have type IIb FCD. For patient 1, a missense mutation (c.64C > T; p.Arg22Trp) was detected in the TSC1 gene in DNA of dysplastic brain tissue but not peripheral blood lymphocytes. Similarly, for patient 2, a frameshift mutation (c.4258_4261delCAGT; p.Ser1420GlyfsTer55) in the TSC2 gene was identified in the brain tissue but not blood. Both gene variants are likely pathogenic and cause mTOR pathway activation. CONCLUSION: Our report of TSC1/TSC2 somatic mutations in patients with non-syndromic FCD suggests that localized hyperactivation of the mTOR pathway can cause focal malformations during cortical development and presents pharmacological targets for precision therapy in FCD management.

Radiofrequency thermocoagulation of the sulcus bottom in type II focal cortical dysplasia-related epilepsy with tapered implantation of electrodes: a case report.

We report a 15-year-old male patient with recurrent epileptic seizures for 12 years. Oral multiple drugs do not work well to his condition. MRI FLAIR scans revealed focal cortical dysplasia type II in the right parietal lobe. The diagnosis of the patient was drug-refractory epilepsy, FCD-related secondary epilepsy. According to the shape of the FCD lesion, electrodes were implanted in a tapered pattern along the bottom of the sulcus to completely destroy the focus. Magnetic resonance imaging at 6 months after surgery revealed that the FCD at the sulcus bottom was completely destroyed. After 26 months of follow-up, the patient had undergone no epileptic seizures, reaching Engel class I. For FCD that are located deep in the brain and adjacent to functional areas, craniotomy has a high risk. And stereoelectroencephalography-guided radiofrequency thermocoagulation may be a preferred treatment.

One-Stage, Limited-Resection Epilepsy Surgery for Bottom-of-Sulcus Dysplasia.

OBJECTIVE: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD). METHODS: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG. RESULTS: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication. CONCLUSION: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures.

Awake Epilepsy Surgery in Patients with Focal Cortical Dysplasia.

BACKGROUND: Awake craniotomy (AC) and direct electric stimulation emerged together with epilepsy surgery >80 years ago. The goal of our study was to evaluate the benefits of awake surgery in patients with drug-resistant epilepsy caused by focal cortical dysplasia (FCD) affecting eloquent areas. METHODS: Our material included 95 patients with drug-resistant epilepsy and FCD, who were operated on between January 2009 and December 2018. These 95 patients were assigned into 3 groups: AC; general anesthesia (GA) with intraoperative neuromonitoring; and GA without intraoperative neuromonitoring. We investigated the following variables: age at surgery, lesion side, eloquent cortex involvement, brain mapping success rate, epilepsy surgery success rate, intraoperative complications, postoperative complications, and intraoperative changes of the preoperative resection plan according to results of the brain mapping by direct electric stimulation. RESULTS: We found statistically significant differences between the AC and GA groups in the mean age at operation, lesion side, eloquent localization, and postoperative transient neurologic deficit. Seizure outcome in the AC was satisfactory (71% complete seizure control) and comparable to the seizure outcome in the GA groups. Our preoperative plan was changed because of functional constraints in 6 patients (43%) operated on during AC. CONCLUSIONS: AC during epilepsy surgery for FCD in eloquent areas may change the preoperative plan. The good rate of postoperative seizure control and the absence of permanent postoperative neurologic deficit in our series is the main proof that AC is a useful tool in patients with FCD involving the eloquent cortex.

Dysmorphic neurons as cellular source for phase-amplitude coupling in Focal Cortical Dysplasia Type II.

OBJECTIVE: Reliable localization of the epileptogenic zone is necessary for successful epilepsy surgery. Neurophysiological biomarkers include ictal onsets and interictal spikes. Furthermore, the epileptic network shows oscillations with potential localization value and pathomechanistic implications. The cellular origin of such markers in invasive EEG in vivo remains to be clarified. METHODS: In the presented pilot study, surgical brain samples and invasive EEG recordings of seven patients with surgically treated Focal Cortical Dysplasia (FCD) type II were coregistered using a novel protocol. Dysmorphic neurons and balloon cells were immunohistochemically quantified. Evaluated markers included seizure onset, spikes, and oscillatory activity in delta, theta, gamma and ripple frequency bands, as well as sample entropy and phase-amplitude coupling between delta, theta, alpha and beta phase and gamma amplitude. RESULTS: Correlations between histopathology and neurophysiology provided evidence for a contribution of dysmorphic neurons to interictal spikes, fast gamma activity and ripples. Furthermore, seizure onset and phase-amplitude coupling in areas with dysmorphic neurons suggests preserved connectivity is related to seizure initiation. Balloon cells showed no association. CONCLUSIONS: Phase-amplitude coupling, spikes, fast gamma and ripples are related to the density of dysmorphic neurons and localize the seizure onset zone. SIGNIFICANCE: The results of our pilot study provide a new powerful tool to address the cellular source of abnormal neurophysiology signals to leverage current and novel biomarkers for the localization of epileptic activity in the human brain.

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.

Ictal and interictal source imaging on intracranial EEG predicts epilepsy surgery outcome in children with focal cortical dysplasia.

OBJECTIVE: To localize the seizure onset zone (SOZ) and irritative zone (IZ) using electric source imaging (ESI) on intracranial EEG (iEEG) and assess their clinical value in predicting epilepsy surgery outcome in children with focal cortical dysplasia (FCD). METHODS: We analyzed iEEG data from 25 children with FCD-associated medically refractory epilepsy (MRE) who underwent surgery. We performed ESI on ictal onset to localize SOZ (ESI-SOZ) and on interictal discharges to localize IZ (ESI-IZ). We tested whether resection of ESI-SOZ and ESI-IZ predicted good surgical outcome (Engel 1). We further compared the prediction performance of ESI-SOZ and ESI-IZ to those of SOZ and IZ defined using conventional methods, i.e. by identifying iEEG-contacts showing ictal onsets (conventional-SOZ) or being the most interictally active (conventional-IZ). RESULTS: The proximity of ESI-SOZ (p = 0.043, odds-ratio = 3.9) and ESI-IZ (p = 0.011, odds-ratio = 7.04) to resection has higher effect on patients' outcome than proximity of conventional-SOZ (p = 0.17, odds-ratio = 1.7) and conventional-IZ (p = 0.038, odds-ratio = 2.6). Resection of ESI-SOZ and ESI-IZ presented higher discriminative power in predicting outcome (68% and 60%) than conventional-SOZ and conventional-IZ (48% and 53%). CONCLUSIONS: Localizing SOZ and IZ via ESI on iEEG offers higher predictive value compared to conventional-iEEG interpretation. SIGNIFICANCE: iEEG-ESI may help surgical planning and facilitate prognostic assessment of children with FCD-associated MRE.

Sleep related epilepsy in focal cortical dysplasia type 2: Insights from sleep recordings in presurgical evaluation.

OBJECTIVE: To determine the relationship between seizure onset, sleep stage and focal cortical dysplasia type 2 (FCD2) location in sleep related epilepsy (SRE). METHODS: We reviewed scalp video-EEG data of 77 patients with SRE among 130 surgically treated patients with histologically confirmed FCD2. Seizure onset was classified as occurring during NREM, REM and after arousal. RESULTS: Sleep recordings were available for 65 patients (37 males, 7-49 years old). FCD2 was located in frontal lobe in 46 (71%) and in extra-frontal regions in 19, including the temporal lobe in 6. MRI was negative/doubtful in 35 cases. Interictal rhythmic/pseudorhythmic spike rate increased from 31% during waking to 65% during sleep. Seizure onset occurred from NREM in 46 cases (71%), mostly from stage 2, and after arousal in 14 (22%). Seizures occurring from NREM/REM sleep were significantly more frequent in frontal (89%) compared to extra-frontal location (42%), whilst arousal preceded seizure onset more often in extra-frontal (58%) compared to frontal location (7%). CONCLUSIONS: NREM seizure onset is the most common ictal pattern in SRE due to frontal FCD2 whereas preceding arousal points to extra-frontal regions. SIGNIFICANCE: Sleep recordings may help for FCD2 localisation and suggest topography dependent impact on sleep related epileptic networks.

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.

Clinical features and surgical outcomes in young children with focal cortical dysplasia type II.

AIMS: To investigate clinical characteristics and surgery outcomes of young children with focal cortical dysplasia (FCD) type II. METHODS: Young children (onset age ≤6 years) with FCDII who underwent epileptic surgery in Children Epilepsy Center of Peking University First Hospital in 2014-2018 were followed up for at least 6 months after surgery. RESULTS: One hundred and twelve children with FCDII were included, with median age of onset 0.9 years (0.01-5.9), who underwent surgery at 4.1 years old (0.8-16.2). Focal seizures were most frequent (90.2%) and epileptic spasms presented in 23 (20.5%) cases. Epileptic encephalopathy was not uncommon (12.5%), associated with earlier epilepsy onset and higher rate of bilateral onset on ictal EEG (OR = 0.213, 9.059; P = .041, .004). At the last follow-up, 88.4% achieved seizure-free. Before surgery, 49.1% showed moderate/severe developmental delay, associated with earlier seizure onset and higher rate of history of epileptic encephalopathy (OR = 0.740, 5.160, P = .023, .042). For 48 children with preoperatively moderate/severe developmental delay, DQ rank at 6 months postsurgery was improved in only four cases. CONCLUSION: For young children with FCDII, they tend to present with epileptic encephalopathies and show moderate/severe developmental delay before surgery. The seizure outcome was favorable after surgery. For children with preoperatively moderate/severe developmental delay, developmental outcome at 6 months after surgery was not satisfactory.

Changes in vascular density in resected tissue of 97 patients with mild malformation of cortical development, focal cortical dysplasia or TSC-related cortical tubers.

Recent studies suggested a possible association between malformations of cortical development and microvascular density. In this study we aimed to further elucidate the relation between microvascular density and cortical developmental abnormalities in a cohort of 97 patients with epilepsy and histologically proven mild malformation of cortical development (mMCD), focal cortical dysplasia (FCD) or tuberous sclerosis complex (TSC). Surgical tissue samples were analyzed with quantitative measures of vessel density, T-cell response, microglial activation and myelin content. Subsequently, the results were compared to an age- and localization matched control group. We observed an increase in microvasculature in white matter of TSC cortical tubers, which is linked to inflammatory response. No increase was seen in mMCD or FCD subtypes compared to controls. In mMCD/FCD and tubers, lesional cortex and white matter showed increased vascular density compared to perilesional tissues. Moreover, cortical vessel density increased with longer epilepsy duration and older age at surgery while in controls it decreased with age. Our findings suggest for that the increase in white matter vascular density might be pathology-specific rather than a consequence of ongoing epileptic activity. Increased cortical vessel density with age and with longer epilepsy duration in mMCD/FCD's and tubers, however, could be a consequence of seizures.

A Surgical Case of Complete Resection of the Focal Cortical and Subcortical Dysplasia in the Motor Cortex.

BACKGROUND: Focal cortical dysplasias (FCDs) are highly epileptogenic and frequently associated with medically refractory focal epilepsy. FCDs are frequently located in the frontal lobe, making its complete resection highly challenging when in proximity to the motor cortex. CASE DESCRIPTION: We report a case of a 25-year-old woman with medically refractory epilepsy secondary to a focal cortical dysplasia in the motor cortex and extending deeply into the subcortical white matter. A detailed presurgical evaluation and invasive electroencephalographic monitoring performed at our epilepsy monitoring unit, along with the use of motor mapping, functional magnetic resonance imaging, diffusion tensor imaging, and the Stealth navigation system resulted in the complete resection of the lesion without a permanent postoperative motor deficit. The patient remained seizure-free at a 63-month follow-up while being maintained on a single antiepileptic drug. CONCLUSION: A detailed presurgical evaluation, accurate mapping of the functional and dysplastic cortex, and a well-planned tailored and complete surgical resection of the cortical dysplasia can result in a favorable outcome with relatively little risk of postoperative neurologic deficit.

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.