Epilepsy surgery below the age of 5 years: Are we still in time to preserve developmental and intellectual functions?

OBJECTIVE: The aim of this study is to describe the pre- and post-operative developmental and intellectual functions in a cohort of patients who underwent surgery for drug-resistant epilepsy (DRE) before the age of 5 years. METHOD: We retrospectively reviewed the medical records and neurodevelopmental assessments of a cohort of 80 surgically treated pediatric patients with DRE. We included patients if they had at least one pre- and one post-surgical neuropsychological assessments; 27 met the inclusion criteria. We evaluated Developmental Quotient (DQ) and Intelligence Quotient (IQ) before and after surgery. We identified two groups based on psychological evaluation outcome: Group 1, with stable or improved developmental and intellectual functions, and Group 2, experiencing developmental and intellectual loss. RESULTS: The mean age at seizure onset was 1.2 ± 1.0 years, and the mean age at surgery was 2.9 ± 1.2 years. At the last follow-up (mean 4 years, SD ± 2), 19/27 (70%) patients were seizure- and drug-free; 18/27 patients (67%) fit in Group 1, and 9/27 (33%) fit in Group 2. The mean age at surgery was 2.6 years (SD ± 1.1; range 1.2-5.1) in Group 1 and 3.4 years in Group 2 (SD ± 1.1; range 1.6-5.0). Group 1 had a lower pre-operative DQ/IQ total score than Group 2 (median DQ/IQ respectively 82 vs 108, p = 0.05). Between pre- and post-assessments, we found that in Group 1, Performance scores improved (82.7 vs 102, p = 0.001), while in Group 2, the Total and Verbal scores worsened (respectively 108 vs 75, p = 0.008, and 100 vs 76, p = 0.021). SIGNIFICANCE: Our study's results emphasize the positive impact of surgery before the age of 5 years on developmental and intellectual outcomes. Despite limitations such as a small sample size, lack of a control group, and diverse etiologies, our findings support the crucial role of early intervention in preserving or enhancing developmental and intellectual functions in young patients with DRE. PLAIN LANGUAGE SUMMARY: This retrospective study, conducted at the Bambino Gesù Children Hospital in Italy, reports neuropsychological and developmental and/or cognitive data for children undergoing early epilepsy surgery (before the age of 5). It found that children with lower developmental or cognitive profiles gained the highest scores on post-operative neuropsychological evaluations. This study provides information on the potential benefits of early surgery in shortening the duration of epilepsy, preventing or arresting deterioration, and enhancing plasticity and recovery.

Trends, outcomes, and complications of surgery for lesional epilepsy in infants and toddlers: A multicenter study.

OBJECTIVE: To assess seizure and developmental outcomes, their predictors, and complications in 160 children who, between 1998 and 2022, underwent surgery for lesional epilepsy with curative intent before the age of 3 years. To compare trends in epilepsy surgery in this age group before and after the year 2014. METHODS: Retrospective multicenter study. Descriptive and univariate analyses, and multivariable models for all outcomes. RESULTS: These 160 patients (76 F; 47.5%) underwent 169 surgeries (age at surgery 20.4 ± 9.4 months). At the last follow-up (77 ± 57.4 months), 121 patients (75.6%) were in Engel class I, 106 (66.2%) of whom were in Engel class Ia. Antiseizure medications were stopped in 84 patients (52.5%). Complications requiring reoperations were observed in 16 patients (10%; 9.5% of surgeries) and unexpected permanent deficits in 12 (7.5%; 7.1% of surgeries). Postoperative cognitive functions remained unchanged in 56 patients (44.4%), improved in 51 (40.5%), and worsened in 19 (15.1%). Multivariable analyses showed that the probability of achieving Engel class Ia was lower when the duration of epilepsy was longer, patients underwent preoperative video-EEG, and unexpected postoperative permanent deficits occurred. Cognitive improvement after surgery was associated with lower preoperative seizure frequency, better preoperative developmental level, and a longer postoperative follow-up. FCDII and tumors were the histopathologies carrying a higher probability of achieving seizure freedom, while polymicrogyria was associated with a lower probability of cognitive improvement. The number of patients operated on after 2014 was higher than before (61.3% vs. 38.7%), with stable outcomes. SIGNIFICANCE: Epilepsy surgery is effective and safe in infants and toddlers, although the complication rate is higher than seen in older patients. Shorter duration of epilepsy, lower seizure frequency, no need for video-EEG, tumors, and some malformations of cortical development are robust predictors of seizure and cognitive outcome that may be exploited to increase earlier referral. PLAIN LANGUAGE SUMMARY: This study analyzed the results of epilepsy surgery in 160 children who had been operated on before the age of 3 years at four Italian centers between 1998 and 2022. At the last follow-up (77 ± 57.4 months), 121 patients (75.6%) were free from disabling seizures, of which 106 (66.2%) were completely seizure-free since surgery. Major surgical complications occurred in 28 patients (17.5%), which is higher than observed with epilepsy surgery in general, but similar to hemispheric/multilobar surgery. Postoperative cognitive function remained unchanged in 56 patients (44.4%), improved in 51 (40.5%), and worsened in 19 (15.1%). Epilepsy surgery is effective and safe in infants and toddlers.

Surgical and radiosurgical treatment of hypothalamic hamartoma: The Italian experience between 2011 and 2021.

OBJECTIVE: To investigate the Italian experience on the surgical and radiosurgical treatment of drug-resistant epilepsy due to hypothalamic hamartoma (HH) in the period 2011-2021 in six Italian epilepsy surgery centers, and to compare safety and efficacy profiles of the different techniques. METHODS: We collected pseudo-anonymized patient's data with at least 12 months of follow-up. Surgical outcome was defined according to Engel classification of seizure outcome. Univariate analysis was performed to assess the risk of post-operative seizures, categorized in dichotomous variable as favorable and unfavorable; explanatory variables were considered. Mann-Whitney or Chi-squared test were used to assess the presence of an association between variables (p < 0.05). RESULTS: Full presurgical and postoperative data about 42 patients from 6 epilepsy surgery centers were gathered. Engel class I was reached in the 65.8% and 66.6% of patients with gelastic and non-gelastic seizures, respectively. Other than daily non-gelastic seizures were associated with seizure freedom (p = 0.01), and the radiological type presented a trend toward significance (p = 0.12). SIGNIFICANCE: Endoscopic disconnection and laser interstitial thermal therapy are effective in the treatment of HH-related epilepsy, with a tolerable safety profile. Both gelastic and non-gelastic seizures can be treated, also in patients with a long history of seizures. PLAIN LANGUAGE SUMMARY: This study collected data about 42 patients with HH-related epilepsies. Endoscopic disconnection and laser therapy are both effective and safe in the treatment of hypothalamic hamartoma-related epilepsies.

Hypothalamic Hamartoma related epilepsy: A systematic review exploring clinical, neuropsychological, and psychiatric outcome after surgery.

The post-surgical outcome for Hypothalamic Hamartoma (HH) related epilepsy in terms of seizure freedom (SF) has been extensively studied, while cognitive and psychiatric outcome has been less frequently reported and defined. This is a systematic review of English language papers, analyzing the post-surgical outcome in series of patients with HH-related epilepsy (≥5 patients, at least 6 months follow-up), published within January 2002-December 2022. SF was measured using Engel scale/equivalent scales. We looked at the outcome related to different surgical techniques, and HH types according to Delalande classification. We evaluated the neuropsychological and neuropsychiatric status after surgery, and the occurrence of post-surgical complications. Forty-six articles reporting 1318 patients were included, of which ten pediatric series. SF was reported in 686/1222 patients (56,1%). Delalande classification was reported in 663 patients from 24 studies, of which 70 were type I HH (10%), 320 were type II HH (48%), 189 were type III HH (29%) and 84 were type IV HH (13%). The outcome in term of SF was reported in 243 out of 663 patients. SF was reported in 12 of 24 type I HH (50%), 80 of 132 type II HH (60,6%), 32 of 59 type III HH (54,2%) and 12 of 28 type IV HH (42,9%). SF was reached in 129/262 (49,2%) after microsurgery, 102/199 (51,3%) after endoscopic surgery, 46/114 (40,6%) after gamma knife surgery, 245/353 (69,4%) after radiofrequency thermocoagulation, and 107/152 (70,4%) after MRI-guided laser interstitial thermal therapy. Hyperphagia/weight gain were the most reported surgical complications. Others were electrolyte alterations, diabetes insipidus, hypotiroidism, transient hyperthermia/poikilothermia. The highest percentage of memory deficits was reported after microsurgery, while hemiparesis and cranial nerves palsy were reported after microsurgery or endoscopic surgery. Thirty studies reported developmental delay/intellectual disability in 424/819 (51,7%) patients. 248/346 patients obtained a global improvement (72%), 70/346 were stable (20%), 28/346 got worse (8%). 22 studies reported psychiatric disorders in 257/465 patients (55,3%). 78/98 patients improved (80%), 13/98 remained stable (13%), 7/98 got worse (7%). Most of the patients had non-structured cognitive/psychiatric assessments. Based on the available data, the surgical management in patients with HH related epilepsy should be individualized, aiming to reach not only the best epilepsy result, but also the optimal cognitive and psychiatric outcome.

The value of linear and non-linear quantitative EEG analysis in paediatric epilepsy surgery: a machine learning approach.

Epilepsy surgery is effective for patients with medication-resistant seizures, however 20-40% of them are not seizure free after surgery. Aim of this study is to evaluate the role of linear and non-linear EEG features to predict post-surgical outcome. We included 123 paediatric patients who underwent epilepsy surgery at Bambino Gesù Children Hospital (January 2009-April 2020). All patients had long term video-EEG monitoring. We analysed 1-min scalp interictal EEG (wakefulness and sleep) and extracted 13 linear and non-linear EEG features (power spectral density (PSD), Hjorth, approximate entropy, permutation entropy, Lyapunov and Hurst value). We used a logistic regression (LR) as feature selection process. To quantify the correlation between EEG features and surgical outcome we used an artificial neural network (ANN) model with 18 architectures. LR revealed a significant correlation between PSD of alpha band (sleep), Mobility index (sleep) and the Hurst value (sleep and awake) with outcome. The fifty-four ANN models gave a range of accuracy (46-65%) in predicting outcome. Within the fifty-four ANN models, we found a higher accuracy (64.8% ± 7.6%) in seizure outcome prediction, using features selected by LR. The combination of PSD of alpha band, mobility and the Hurst value positively correlate with good surgical outcome.

Structural networking of the developing brain: from maturation to neurosurgical implications.

Modern neuroscience agrees that neurological processing emerges from the multimodal interaction among multiple cortical and subcortical neuronal hubs, connected at short and long distance by white matter, to form a largely integrated and dynamic network, called the brain "connectome." The final architecture of these circuits results from a complex, continuous, and highly protracted development process of several axonal pathways that constitute the anatomical substrate of neuronal interactions. Awareness of the network organization of the central nervous system is crucial not only to understand the basis of children's neurological development, but also it may be of special interest to improve the quality of neurosurgical treatments of many pediatric diseases. Although there are a flourishing number of neuroimaging studies of the connectome, a comprehensive vision linking this research to neurosurgical practice is still lacking in the current pediatric literature. The goal of this review is to contribute to bridging this gap. In the first part, we summarize the main current knowledge concerning brain network maturation and its involvement in different aspects of normal neurocognitive development as well as in the pathophysiology of specific diseases. The final section is devoted to identifying possible implications of this knowledge in the neurosurgical field, especially in epilepsy and tumor surgery, and to discuss promising perspectives for future investigations.

Connectome-based approaches in pediatric epilepsy surgery: "State-of-the art" and future perspectives.

Modern epilepsy science has overcome the traditional interpretation of a strict region-specific origin of epilepsy, highlighting the involvement of wider patterns of altered neuronal circuits. In selected cases, surgery may constitute a valuable option to achieve both seizure freedom and neurocognitive improvement. Although epilepsy is now considered as a brain network disease, the most relevant literature concerning the "connectome-based" epilepsy surgery mainly refers to adults, with a limited number of studies dedicated to the pediatric population. In this review, the Authors summarized the main current available knowledge on the relevance of WM surgical anatomy in epilepsy surgery, the post-surgical modifications of brain structural connectivity and the related clinical impact of such modifications within the pediatric context. In the last part, possible implications and future perspectives of this approach have been discussed, especially concerning the optimization of surgical strategies and the predictive value of the epilepsy network analysis for planning tailored approaches, with the final aim of improving case selection, presurgical planning, intraoperative management, and postoperative results.

Updated clinical recommendations for the management of tuberous sclerosis complex associated epilepsy.

Children with tuberous sclerosis complex (TSC), may experience a variety of seizure types in the first year of life, most often focal seizure sand epileptic spasms. Drug resistance is seen early in many patients, and the management of TSC associated epilepsy remain a major challenge for clinicians. In 2018 clinical recommendations for the management of TSC associated epilepsy were published by a panel of European experts. In the last five years considerable progress has been made in understanding the neurobiology of epileptogenesis and three interventional randomized controlled trials have changed the therapeutic approach for the management of TSC associated epilepsy. Pre-symptomatic treatment with vigabatrin may delay seizure onset, may reduce seizure severity and reduce the risk of epileptic encephalopathy. The efficacy of mTOR inhibition with adjunctive everolimus was documented in patients with TSC associated refractory seizures and cannabidiol could be another therapeutic option. Epilepsy surgery has significantly improved seizure outcome in selected patients and should be considered early in all patients with drug resistant epilepsy. There is a need to identify patients who may have a higher risk of developing epilepsy and autism spectrum disorder (ASD). In the recent years significant progress has been made owing to the early identification of risk factors for the development of drug-resistant epilepsy. Better understanding of the mechanism underlying epileptogenesis may improve the management for TSC-related epilepsy. Developmental neurobiology and neuropathology give opportunities for the implementation of concepts related to clinical findings, and an early genetic diagnosis and use of EEG and MRI biomarkers may improve the development of pre-symptomatic and disease-modifying strategies.

Vertical Hemispherotomy: Contribution of Advanced Three-Dimensional Modeling for Presurgical Planning and Training.

Vertical hemispherotomy is an effective treatment for many drug-resistant encephalopathies with unilateral involvement. One of the main factors influencing positive surgical results and long-term seizure freedom is the quality of disconnection. For this reason, perfect anatomical awareness is mandatory during each step of the procedure. Although previous groups attempted to reproduce the surgical anatomy through schematic representations, cadaveric dissections, and intraoperative photographs and videos, a comprehensive understanding of the approach may still be difficult, especially for less experienced neurosurgeons. In this work, we reported the application of advanced technology for three-dimensional (3D) modeling and visualization of the main neurova-scular structures during vertical hemispherotomy procedures. In the first part of the study, we built a detailed 3D model of the main structures and landmarks involved during each disconnection phase. In the second part, we discussed the adjunctive value of augmented reality systems for the management of the most challenging etiologies, such as hemimegalencephaly and post-ischemic encephalopathy. We demonstrated the contribution of advanced 3D modeling and visualization to enhance the quality of anatomical representation and interaction between the operator and model according to a surgical perspective, optimizing the quality of presurgical planning, intraoperative orientation, and educational training.

Phase-amplitude coupling between low- and high-frequency activities as preoperative biomarker of focal cortical dysplasia subtypes.

OBJECTIVE: To evaluate whether ictal phase-amplitude coupling (PAC) between high-frequency activity and low-frequency activity could be used as a preoperative biomarker of Focal Cortical Dysplasia (FCD) subtypes. We hypothesize that FCD seizures present unique PAC characteristics that may be linked to their specific histopathological features. METHODS: We retrospectively examined 12 children with FCD and refractory epilepsy who underwent successful epilepsy surgery. We identified ictal onsets recorded with stereo-EEG. We estimated the strength of PAC between low-frequencies and high-frequencies for each seizure by means of modulation index. Generalized mixed effect models and receiver operating characteristic (ROC) curve analysis were used to test the association between ictal PAC and FCD subtypes. RESULTS: Ictal PAC was significantly higher in patients with FCD type II compared to type I, only on SOZ-electrodes (p < 0.005). No differences in ictal PAC were found on non-SOZ electrodes. Pre-ictal PAC registered on SOZ electrodes predicted FCD histopathology with a classification accuracy > 0.9 (p < 0.05). CONCLUSIONS: The correlations between histopathology and neurophysiology provide evidence for the contribution of ictal PAC as a preoperative biomarker of FCD subtypes. SIGNIFICANCE: Developed into a proper clinical application, such a technique may help improve clinical management and facilitate the prediction of surgical outcome in patients with FCD undergoing stereo-EEG monitoring.

Interpretable surface-based detection of focal cortical dysplasias: a Multi-centre Epilepsy Lesion Detection study.

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted 'gold-standard' subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.

Current role of surgery for tuberous sclerosis complex-associated epilepsy.

Tuberous sclerosis complex (TSC) is a rare multisystem, autosomal dominant neurocutaneous syndrome in which epilepsy is the most common of several neurological and psychiatric manifestations. Around two thirds of patients develop drug-resistant epilepsy for whom surgical resection of epileptogenic foci is indicated when seizures remain inadequately controlled following trial of two antiseizure medications. The challenge with presurgical and surgical approaches with patients with TSC is overcoming the complexity from the number of tubers and the multiplex epileptogenic network forming the epileptogenic zone. Data suggest that seizure freedom is achieved by 55%-60% of patients, but predictive factors for success have remained elusive, which makes for unconfident selection of surgical candidates. This article presents three different cases as illustrations of the potential challenges faced when assessing the suitability of TSC patients for epilepsy surgery.

Knowledge and attitudes of neurologists toward epilepsy surgery: an Italian survey.

The current study, conceived with the contribution of the Commission for Epilepsy Surgery of the Italian League Against Epilepsy (LICE) and the Epilepsy Study Group of the Italian Neurological Society (SIN), aimed to assess potential physician-related barriers to refer subjects for epilepsy surgery. All the members of SIN and LICE were invited by email to complete a 28-item online questionnaire. The survey items included: (1) individual and medical practice characteristics, (2) knowledge of current indications to select candidates for epilepsy surgery, (3) factors potentially affecting the attitude toward epilepsy surgery. Overall, 210 physicians completed the survey. More than half (63.3%) of the participants showed proper knowledge of the ILAE drug-resistance. Definition and almost two-thirds of them (71.9%) considered themselves adequately informed about indications, risks, and benefits of epilepsy surgery. Surgery was regarded as a valid option to be used as early as possible by 84.8% of the interviewees, and 71% of them estimated its complication rate to be low. However, more than half (63%) of the respondents reportedly referred patients for surgery only after the failure of 3-5 antiseizure medications. Overestimation of risks/complications of surgery and inadequate healthcare resources were identified as the main factor contrasting the patient referral for surgery by 43% and 40.5% of the participants, respectively. In conclusion, this survey confirms the existence of knowledge gap within both physicians and the healthcare system, as well as an educational need regarding epilepsy surgery. Further researches are warranted to define learning outcomes and optimize educational tools.

Short and Long-Term Toxicity in Pediatric Cancer Treatment: Central Nervous System Damage.

Neurotoxicity caused by traditional chemotherapy and radiotherapy is well known and widely described. New therapies, such as biologic therapy and immunotherapy, are associated with better outcomes in pediatric patients but are also associated with central and peripheral nervous system side effects. Nevertheless, central nervous system (CNS) toxicity is a significant source of morbidity in the treatment of cancer patients. Some CNS complications appear during treatment while others present months or even years later. Radiation, traditional cytotoxic chemotherapy, and novel biologic and targeted therapies have all been recognized to cause CNS side effects; additionally, the risks of neurotoxicity can increase with combination therapy. Symptoms and complications can be varied such as edema, seizures, fatigue, psychiatric disorders, and venous thromboembolism, all of which can seriously influence the quality of life. Neurologic complications were seen in 33% of children with non-CNS solid malign tumors. The effects on the CNS are disabling and often permanent with limited treatments, thus it is important that clinicians recognize the effects of cancer therapy on the CNS. Knowledge of these conditions can help the practitioner be more vigilant for signs and symptoms of potential neurological complications during the management of pediatric cancers. As early detection and more effective anticancer therapies extend the survival of cancer patients, treatment-related CNS toxicity becomes increasingly vital. This review highlights major neurotoxicities due to pediatric cancer treatments and new therapeutic strategies; CNS primary tumors, the most frequent solid tumors in childhood, are excluded because of their intrinsic neurological morbidity.

Networking of the Human Cerebellum: From Anatomo-Functional Development to Neurosurgical Implications.

In the past, the cerebellum was considered to be substantially involved in sensory-motor coordination. However, a growing number of neuroanatomical, neuroimaging, clinical and lesion studies have now provided converging evidence on the implication of the cerebellum in a variety of cognitive, affective, social, and behavioral processes as well. These findings suggest a complex anatomo-functional organization of the cerebellum, involving a dense network of cortical territories and reciprocal connections with many supra-tentorial association areas. The final architecture of cerebellar networks results from a complex, highly protracted, and continuous development from childhood to adulthood, leading to integration between short-distance connections and long-range extra-cerebellar circuits. In this review, we summarize the current evidence on the anatomo-functional organization of the cerebellar connectome. We will focus on the maturation process of afferent and efferent neuronal circuitry, and the involvement of these networks in different aspects of neurocognitive processing. The final section will be devoted to identifying possible implications of this knowledge in neurosurgical practice, especially in the case of posterior fossa tumor resection, and to discuss reliable strategies to improve the quality of approaches while reducing postsurgical morbidity.

Can Presurgical Interhemispheric EEG Connectivity Predict Outcome in Hemispheric Surgery? A Brain Machine Learning Approach.

OBJECTIVES: Hemispherotomy (HT) is a surgical option for treatment of drug-resistant seizures due to hemispheric structural lesions. Factors affecting seizure outcome have not been fully clarified. In our study, we used a brain Machine Learning (ML) approach to evaluate the possible role of Inter-hemispheric EEG Connectivity (IC) in predicting post-surgical seizure outcome. METHODS: We collected 21 pediatric patients with drug-resistant epilepsy; who underwent HT in our center from 2009 to 2020; with a follow-up of at least two years. We selected 5-s windows of wakefulness and sleep pre-surgical EEG and we trained Artificial Neuronal Network (ANN) to estimate epilepsy outcome. We extracted EEG features as input data and selected the ANN with best accuracy. RESULTS: Among 21 patients, 15 (71%) were seizure and drug-free at last follow-up. ANN showed 73.3% of accuracy, with 85% of seizure free and 40% of non-seizure free patients appropriately classified. CONCLUSIONS: The accuracy level that we reached supports the hypothesis that pre-surgical EEG features may have the potential to predict epilepsy outcome after HT. SIGNIFICANCE: The role of pre-surgical EEG data in influencing seizure outcome after HT is still debated. We proposed a computational predictive model, with an ML approach, with a high accuracy level.

Hemispherotomy in Infants with Hemimegalencephaly: Long-Term Seizure and Developmental Outcome in Early Treated Patients.

Hemimegalencephaly (HME) is a rare brain congenital malformation, consisting in altered neuronal migration and proliferation within one hemisphere, which is responsible for early onset drug-resistant epilepsy. Hemispherotomy is an effective treatment option for patients with HME and drug-resistant epilepsy. Surgical outcome may be variable among different surgical series, and the long-term neuropsychological trajectory has been rarely defined using a standardized neurocognitive test. We report the epileptological and neuropsychological long-term outcomes of four consecutive HME patients, operated on before the age of three years. All patients were seizure-free and drug-free, and the minimum follow-up duration was of five years. Despite the excellent post-surgical seizure outcome, the long-term developmental outcome is quite variable between patients, ranging from mild to severe intellectual disabilities. Patients showed improvement mainly in communication skills, while visuo-perceptive and coordination abilities were more impaired. Epileptological outcome seems to be improved in early treated patients; however, neuropsychological outcome in HME patients may be highly variable despite early surgery.

The Role of KRAS Mutations in Cortical Malformation and Epilepsy Surgery: A Novel Report of Nevus Sebaceous Syndrome and Review of the Literature.

The rare nevus sebaceous (NS) syndrome (NSS) includes cortical malformations and drug-resistant epilepsy. Somatic RAS-pathway genetic variants are pathogenetic in NS, but not yet described within the brain of patients with NSS. We report on a 5-year-old boy with mild psychomotor delay. A brown-yellow linear skin lesion suggestive of NS in the left temporo-occipital area was evident at birth. Epileptic spasms presented at aged six months. EEG showed continuous left temporo-occipital epileptiform abnormalities. Brain MRI revealed a similarly located diffuse cortical malformation with temporal pole volume reduction and a small hippocampus. We performed a left temporo-occipital resection with histopathological diagnosis of focal cortical dysplasia type Ia in the occipital region and hippocampal sclerosis type 1. Three years after surgery, he is seizure-and drug-free (Engel class Ia) and showed cognitive improvement. Genetic examination of brain and skin specimens revealed the c.35G > T (p.Gly12Val) KRAS somatic missense mutation. Literature review suggests epilepsy surgery in patients with NSS is highly efficacious, with 73% probability of seizure freedom. The few histological analyses reported evidenced disorganized cortex, occasionally with cytomegalic neurons. This is the first reported association of a KRAS genetic variant with cortical malformations associated with epilepsy, and suggests a possible genetic substrate for hippocampal sclerosis.

Infra-Occipital Supra-Tentorial Approach for Resection of Low-Grade Tumor of the Left Lingual Gyrus: 2-Dimensional Operative Video.

Surgical treatment of lesions involving the postero-medial occipito-temporal region is challenging because of high risk of morbidity due to damage or excessive retraction of critical neuro-vascular structures, especially within the dominant hemisphere.1-3 Here, we describe the case of a 17-yr-old patient who underwent resection of an epileptogenic low-grade tumor located within the left-dominant lingual gyrus. Seizures were characterized, as a first symptom, by right-sided simple visual hallucination that pointed to the left pericalcarine region, corresponding to the lesion location. No signs of primary involvement of anterior temporo-mesial structures (hippocampus/amygdala) were found. As the anatomo-electroclinical correlation was concordant, direct tumor removal was indicated through an infra-occipital supratentorial approach. This route allowed direct access to the target through a safe extra-axial corridor, which limits intraparenchymal dissection until the tumor margin is identified and avoids critical vascular structures, such as the vein of Labbé.4,5 An external cerebrospinal fluid (CSF) drainage was used to facilitate brain relaxation, minimizing brain and venous retraction and, consequently, reducing the risk of postoperative neurological complications, especially for vision. Postoperative magnetic resonance imaging (MRI) demonstrated no surgical complications. Pathological examination revealed a ganglioglioma. At 9-mo follow-up, the neurological examination was normal, antiepileptic therapy was stopped, and the patient was seizure-free. The video describes the main surgical steps, using both intraoperative videos and advanced 3-dimensional modeling of neuroimaging pictures. Informed consent was obtained for surgery and video recording.