mTOR-therapy and targeted treatment opportunities in mTOR-related epilepsies associated with cortical malformations.

Dysregulation of the mTOR pathway is now well documented in several neurodevelopmental disorders associated with epilepsy. Mutations of mTOR pathway genes are involved in tuberous sclerosis complex (TSC) as well as in a range of cortical malformations from hemimegalencephaly (HME) to type II focal cortical dysplasia (FCD II), leading to the concept of "mTORopathies" (mTOR pathway-related malformations). This suggests that mTOR inhibitors (notably rapamycin (sirolimus), and everolimus) could be used as antiseizure medication. In this review, we provide an overview of pharmacological treatments targeting the mTOR pathway for epilepsy based on lectures from the ILAE French Chapter meeting in October 2022 in Grenoble. There is strong preclinical evidence for the antiseizure effects of mTOR inhibitors in TSC and cortical malformation mouse models. There are also open studies on the antiseizure effects of mTOR inhibitors, as well as one phase III study showing the antiseizure effect of everolimus in TSC patients. Finally, we discuss to which extent mTOR inhibitors might have properties beyond the antiseizure effect on associated neuropsychiatric comorbidities. We also discuss a new way of treatment on the mTOR pathways.

A Case of a Solitary Cortical Tuber with No Other Manifestations of Tuberous Sclerosis Complex Mimicking Focal Cortical Dysplasia Type II with Calcification.

Cortical tubers are one of the typical intracranial manifestations of tuberous sclerosis complex (TSC). Multiple cortical tubers are easy to diagnose as TSC; however, a solitary cortical tuber without any other cutaneous or visceral organ manifestations can be confused with other conditions, particularly focal cortical dysplasia. We report a surgical case of refractory epilepsy caused by a solitary cortical tuber mimicking focal cortical dysplasia type II, and describe the radiological, electrophysiological, and histopathological findings of our case.

Focal thalamocortical circuit abnormalities in sleep related epilepsy caused by focal cortical dysplasia type II.

Purpose To investigate the variations of the thalamocortical circuit between the focal cortical dysplasia (FCD) type II patients with sleep-related epilepsy (SRE) and those without SRE (non-SRE). Methods Patients with epilepsy who had histologically proven FCD type II were enrolled. Those without diffusion tensor image and 3-dimensional (3D) T1 MRI sequences were excluded. Thalamocortical structural connectivity to lesion and non-lesion regions was quantified using probabilistic tractography. Fractional anisotropy (FA) and mean diffusivity (MD) were computed. Results A total of 30 consecutive patients were included. Among them, 18 patients (60%) had SRE. Analysis of covariance showed that smaller lesion size was significantly associated with SRE (p=0.048). Compared to patients with non-SRE, patients with SRE showed a significant decrease in FA of thalamocortical projections to the lesion region (p=0.007). No difference was observed in the thalamocortical connectivity to the non-lesion region between patients with SRE and non-SRE. Among the patients with SRE, a significant decrease in FA of thalamocortical projections to the lesion region was noted compared with the contralateral homotopic non-lesion region (p=0.026). Conclusion The data provide evidence of disparity in thalamocortical projections to the lesion regions between SRE and non-SRE. This might indicate the underlying pathophysiology or neuroanatomical substrates of SRE related to the FCD type II.

Sirolimus for epileptic seizures associated with focal cortical dysplasia type II.

OBJECTIVE: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. METHODS: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. RESULTS: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. INTERPRETATION: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.

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.

A Single-Arm Open-Label Clinical Trial on the Efficacy and Safety of Sirolimus for Epileptic Seizures Associated with Focal Cortical Dysplasia Type II: A Study Protocol.

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.

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.

Isolated cortical tuber in an infant with genetically confirmed tuberous sclerosis complex 1 presenting with symptomatic West syndrome.

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disorder caused by mutations in either TSC1 on chromosome 16 or TSC2 on chromosome 9, clinically characterized mainly by facial angiofibroma, epilepsy, and intellectual disability. Cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytoma are characteristic central nervous system lesions among 11 major features in the current clinical diagnostic criteria for TSC. We encountered an unusual case of genetically confirmed TSC1 presenting with symptomatic West syndrome due to an isolated cortical dysplasia in the left occipital lobe of a six-month-old male infant who did not meet the clinical diagnostic criteria for TSC. The patient underwent left occipital lesionectomy at age 11 months and has been seizure-free for nearly six years since then. Histological examination of the resection specimen revealed cortical neuronal dyslamination with abundant dysmorphic neurons and ballooned cells, consistent with focal cortical dysplasia (FCD) type IIb. However, the lesion was also accompanied by unusual features, including marked calcifications, dense fibrillary gliosis containing abundant Rosenthal fibers, CD34-positive glial cells with abundant long processes confined to the dysplastic cortex, and multiple nodular lesions occupying the underlying white matter, consisting exclusively of ballooned cell and/or balloon-like astrocytes with focal calcifications. Genetic testing for TSC1 and TSC2 using the patient's peripheral blood revealed a germline heterozygous mutation in exon 7 (NM_000368.5: c.526dupT, p.Tyr176fs) in TSC1. Isolated FCD with unusual features such as calcification, dense fibrillary gliosis, Rosenthal fibers and/or subependymal nodule-like lesions in the white matter may indicate the possibility of a cortical tuber even without a clinical diagnosis of TSC. Identification of such histopathological findings has significant implications for early and accurate diagnosis and treatment of TSC, and is likely to serve as an important supplementary feature for the current clinical diagnostic criteria for TSC.

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.

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.

Interpreting the Tests of Focal Cortical Dysplasia for Epilepsy Surgery Referral.

OBJECTIVE: Focal cortical dysplasia (FCD) is a common cause of refractory, focal onset epilepsy in children. Interictal, scalp electroencephalograph (EEG) markers have been associated with these pathologies and epilepsy surgery may be an option for some patients. We aim to study how scalp EEG and magnetic resonance imaging (MRI) markers of FCD affect referral of these patients for surgical evaluation. METHODS: A single-center, retrospective review of children with focal onset epilepsy. Patients were included if they were between 1 month and 18 years of age, had focal onset seizures, prolonged scalp EEG monitoring, and an MRI conducted after 2 years of age. Statistics were carried out using the chi-squared and student's t-test, as well as a logistic regression model. RESULTS: Sixty-eight patients were included in the study. Thirty-seven of these patients were referred to a comprehensive pediatric epilepsy program (CPEP) for surgical evaluation, and of these 22% showed FCD EEG markers, 32% FCD MRI markers, and 10% had both. These markers were also present in patients not referred to a CPEP. The MRI markers were significantly associated with CPEP referral, whereas EEG markers were not. Neither marker type was associated with epilepsy surgery. CONCLUSION: This study found that children with focal onset epilepsy were more likely to be referred for surgical evaluation if they were medically refractory, or were diagnosed with FCD or tumor on MRI. Scalp EEG markers of FCD were not associated with CPEP referral. The online tool CASES may be a useful physician guide for identifying appropriate children for epilepsy surgery referral.

Interpréter les tests de détection de la dysplasie corticale focale en vue d'une évaluation préopératoire du traitement de l'épilepsie.Objectif: La dysplasie corticale focale (DCF) constitue une des causes communes des crises convulsives partielles réfractaires chez l'enfant. À la suite d'EEG effectués au niveau du cuir chevelu, des marqueurs de l'activité épileptique interictale ont été associés avec ce trouble pour lequel une intervention chirurgicale peut constituer, dans le cas de certains patients, une option. Nous voulons nous pencher sur la façon dont ces marqueurs et les marqueurs utilisés lors d'examens d'IRM pour la DCF peuvent affecter l'aiguillage de ces patients en vue d'une évaluation préopératoire. Méthodes: Dans un seul établissement hospitalier, nous avons effectué une analyse rétrospective de cas d'enfants chez qui sont apparues des crises convulsives partielles. Pour être inclus, les patients devaient être âgés de 1 mois à 18 ans, avoir été victimes de telles crises convulsives, avoir bénéficié de surveillance prolongée par EEG et avoir subi un examen d'IRM après l'âge de deux ans. Nous avons enfin effectué une analyse statistique à l'aide d'un modèle de régression logistique et des tests du X2 et de Student. Résultats: Au total, nous avons inclus soixante-huit patients dans cette étude. Trente-sept d'entre eux ont été redirigés vers un programme pédiatrique complet de traitement de l'épilepsie (comprehensive pediatric epilepsy program) en vue d'une évaluation préopératoire. Sur ces trente-sept patients, on a observé chez 22 % d'entre eux les marqueurs électroencéphalographiques associés à la DCF ; ce pourcentage atteignait 32 % dans le cas des marqueurs de la DCF utilisés en imagerie ; enfin, on a pu détecter ces deux types de marqueurs chez 10 % de ces trente-sept patients. Fait à souligner, ces marqueurs étaient aussi présents chez des patients n'ayant pas été orientés vers le type de programme cité ci-dessus. En outre, les marqueurs utilisés en imagerie se sont avérés étroitement associés au fait d'orienter des patients vers ce programme tandis que les marqueurs électroencéphalographiques ne l'étaient pas. Finalement, aucun de ces types de marqueurs n'a pu être associé à une intervention chirurgicale visant à traiter l'épilepsie. Conclusion: Cette étude a donc permis de constater que les enfants atteints de crises convulsives partielles étaient plus susceptibles d'être orientés en vue d'une évaluation préopératoire si leur trouble était de nature réfractaire ou s'ils avaient reçu un diagnostic de DCF ou de tumeur cancéreuse à la suite d'un examend'IRM. Les marqueurs électroencéphalographiques de la DCF n'ont pas été associés à un aiguillage vers un programme pédiatrique complet de traitement de l'épilepsie. Il se pourrait à cet égard que l'outil en ligne CASES soit un guide utile pour les médecins souhaitant identifier les enfants convenant à un aiguillage en vue d'un traitement chirurgical de l'épilepsie.

Focal Cortical Dysplasia and Refractory Epilepsy: Role of Multimodality Imaging and Outcome of Surgery.

BACKGROUND AND PURPOSE: Focal cortical dysplasia (FCD) is one of the most common causes of drug resistant epilepsy. Our aim was to evaluate the role of presurgical noninvasive multimodality imaging techniques in selecting patients with refractory epilepsy and focal cortical dysplasia for epilepsy surgery and the influence of the imaging modalities on long-term seizure freedom. MATERIALS AND METHODS: We performed a retrospective analysis of data of 188 consecutive patients with FCD and refractory epilepsy with at least 2 years of postsurgery follow-up. Predictors of seizure freedom and the sensitivity of neuroimaging modalities were analyzed. RESULTS: MR imaging showed clear-cut FCD in 136 (72.3%) patients. Interictal FDG-PET showed focal hypo-/hypermetabolism in 144 (76.6%); in 110 patients in whom ictal SPECT was performed, focal hyperperfusion was noted in 77 (70.3%). Focal resection was the most common surgery performed in 112 (59.6%). Histopathology revealed FCD type I in 102 (54.3%) patients. At last follow-up, 124 (66.0%) were seizure-free. Complete resection of FCD and type II FCD were predictors of seizure freedom. Localization of FCD on either MR imaging or PET or ictal SPECT had the highest sensitivity for seizure freedom at 97.5%. Among individual modalities, FDG-PET had the highest sensitivity (78.2%), followed by MR imaging (75.8%) and ictal SPECT (71.8%). The sensitivity of MR imaging to localize type I FCD (60.8%) was significantly lower than that for type II FCD (84.8%, P < .001). Among 37 patients with subtle MR imaging findings and a focal FDG-PET pattern, 30 patients had type I FCD. CONCLUSIONS: During presurgical multimodality evaluation, localization of the extent of the epileptogenic zone in at least 2 imaging modalities helps achieve seizure freedom in about two-thirds of patients with refractory epilepsy due to FCD. FDG-PET is the most sensitive imaging modality for seizure freedom, especially in patients with type I FCD.

A case of focal cortical dysplasia type Ib atypically showing reversible intensity changes on magnetic resonance imaging which could be affected by epileptic discharge activity.

Focal cortical dysplasia (FCD) was first described as a distinct neuropathological entity in 1971 by Taylor and colleagues. FCD is thought to be an embryological migration disorder and is thus considered a non-progressive, unchangeable disease throughout life. A 9-year-old right-handed boy was referred from a local hospital for medically intractable epileptic seizures. Serial magnetic resonance images (MRI) showed intensity changes that indicated exacerbation and remission. After presurgical evaluations including intracranial video-electroencephalogram monitoring, we performed a lesionectomy aided by MRI and epileptic focus resection. He has been free from seizures for more than 3 years. Neuropathological findings showed FCD type Ib. We surgically treated a patient with FCD, which showed MRI intensity changes indicating exacerbation and remission. Although FCD type Ib is generally invisible on MRI, in this patient, changes in intensity on MRI made FCD type Ib visible.

Dynamics of seizure-induced behavioral and autonomic arousal.

PURPOSE: Arousal is the most primitive, powerful instinct with survival benefit present in all vertebrates. Even though the arousal systems are classically viewed as "ascending" brainstem phenomena, there is a "descending" cortical feedback system that maintains consciousness. In this study, we provide electrophysiological confirmation that seizures localized to the anterior cingulum can behaviorally manifest as paroxysms of arousal from sleep. METHODS: Temporal dynamics of arousal induced by anterior cingulate seizures were analyzed by using multiple modalities including stereoelectroencephalography (phase lag index and phase amplitude coupling), lead-1 ECG (point-process heart rate variability analysis) and diffusion tractography (DTI). RESULTS: The ictal arousal was associated with an increase in synchronization in the alpha band and an increase in local theta or alpha-gamma phase-amplitude coupling. In comparison to seizures that lacked clinical manifestations, ictal arousal was associated with an increase in heart rate but not heart rate variability. Finally, DTI demonstrated degeneration in white fiber tracts passing between the anterior cingulum and anterior thalamus ipsilateral to the epileptogenic cortex. The patient underwent resection of the anterior cingulum, and histopathology confirmed focal cortical dysplasia type II. CONCLUSION: Anterior cingulate seizures inducing behavioral arousal have identifiable autonomic and EEG signatures.

Epilepsy surgery for focal cortical dysplasia: Seizure and quality of life (QOLIE-89) outcomes.

AIM: Surgery for drug resistant epilepsy (DRE) with focal cortical dysplasia (FCD) often requires multiple non-invasive as well as invasive pre-surgical evaluations and innovative surgical strategies. There is limited data regarding surgical management of people with FCD as the underlying substrate for DRE among the low and middle-income countries (LAMIC) including India. METHODOLOGY: The presurgical evaluation, surgical strategy and outcome of 52 people who underwent resective surgery for DRE with FCD between January 2008 and December 2016 were analyzed. The 2011 classification proposed by Blumcke et al., was used for histo-pathological categorization. The Engel classification was used for defining the seizure outcome. The surgical outcome was correlated with the preoperative clinical presentation, video encephalogram (VEEG) recording, magnetic resonance imaging (MRI), invasive monitoring, surgical findings as well as histopathology and the quality of life in epilepsy (QOLIE)- 89 scores. RESULTS: Fifty-two patients underwent resective surgery for FCD (mean age at onset of seizure: 7.94 ± 6.23 years; duration of seizures prior to surgery: 12.95 ± 9.56 years; and, age at surgery: 20.88 ± 12.51 years). The following regional distribution was found; temporal-24 (language-13), frontal-15 (motor cortex- 5), parietal-5 (sensory cortex-4), occipital-1 and multilobar-7. Forty-seven percent of the cases had FCD in the right hemisphere and 53% had FCD in the left hemisphere. Invasive monitoring was performed for identification of the epileptogenic zone (EZ) as well as eloquent cortex in 7 cases and an intra-operative electro-corticography (ECoG) was used in 32 cases. Histopathology revealed the following distribution; FCD IA-4, IB- 1, IC-5, IIA-8, IIB-18, IIIA-13, IIIB -1, IIIC-1 and IIID-1. After a median follow up of 3.7 years after surgery, 84% of patients had Engel's Ia outcome. QOLIE-89 scores improved from 38.33 ± 4.7 (31.14-49.03) before surgery to 75.21 ± 8.44 (56.49-90.49) after surgery (P < 0.001). The younger age of the patient (<20 years) at surgery (P = 0.013), a lower pre-operative score (<9) on seizure severity scale (P = 0.012), focal discharges without propagation on ictal VEEG (P < 0.001), absence of acute post-operative seizures (P < 0.001) and Type II FCD (P = 0.045) were the significant predictors for a favorable seizure outcome. CONCLUSION: Surgical management of people with DRE and FCD is possible in countries with limited resources. Meticulous pre-surgical evaluation to localize the epileptogenic zone and complete resection of the focus and lesion can lead to the cure or control of epilepsy; and, improvement in the quality of life was observed along with seizure-free outcome.

Long-term seizure outcome in pediatric patients with focal cortical dysplasia undergoing tailored and standard surgical resections.

PURPOSE: Focal cortical dysplasia (FCD) is the major cause of focal intractable epilepsy in childhood. Here we analyze the factors influencing the success of surgical treatment in a large cohort of children with histologically ascertained FCD. METHOD: A retrospective study of the effects of FCD type, surgical intervention, and age at surgery in a pediatric cohort. RESULTS: A total of 113 patients (71 male; mean age at surgery 10.3 years; range 0-18) were analyzed; 45 had undergone lesionectomy, 42 lobectomy, 18 multi-lobectomy, and eight hemispherotomy. Complete seizure control (Engel Ia) was achieved in 56% after two years, 52% at five years, and 50% at last follow-up (18-204 months). Resections were more extensive in younger patients (40% of the surgeries affecting more than one lobe in patients aged nine years or younger vs. 22% in patients older than nine years). While resections were more limited in older children, their long-term outcome tended to be superior (42% seizure freedom in patients aged nine years or younger vs. 56% in patients older than nine years). The outcome in FCD I was not significantly inferior to that in FCD II. CONCLUSIONS: Our data confirm the long-term efficacy of surgery in children with FCD and epilepsy. An earlier age at surgery within this cohort did not predict a better long-term outcome, but it involved less-tailored surgical approaches. The data suggest that in patients with an unclear extent of the dysplastic area, later resections may offer advantages in terms of the precision of surgical-resection planning.

Challenges in managing epilepsy associated with focal cortical dysplasia in children.

Focal cortical dysplasia (FCD) is the most common cause of intractable focal epilepsy in children, in whom seizures are most commonly pharmacoresistant from onset. This review summarizes the current understandings of the epidemiology, natural history, and the proposed mechanisms of epileptogenisis in FCD. Advances in neuroimaging techniques have enhanced the recognition of this pathology, which can be subtle. Illustrative neurophysiology and imaging examples are provided to help the clinicians identify diagnostic evidence of suspected FCD. Given the refractory course to pharmacologic management, alternative options such as ketogenic diet, resective surgery or neuromodulation can be considered. Recognition of FCD pathology in children with early onset epilepsy should prompt timely evaluations for resective surgery, which may render a significant number of patients seizure-free and improve neurocognitive outcome.