Vertical Parasagittal Hemispherotomy in a Pediatric Case of Epilepsy Due to Rasmussen Encephalitis: 2-Dimensional Operative Video.

Hemispherotomy is an effective disconnection technique for the treatment of different forms of drug-resistant epilepsy due to encephalopathies with unilateral hemispheric involvement.1-8 We describe the case of a 6-year-old child affected by Rasmussen encephalitis who underwent right vertical parasagittal hemispherotomy.9 The goal of the procedure was to isolate the basal ganglia region by interrupting the interhemispheric and intrahemispheric white matter connectivity. The main surgical steps include the transcortical approach to the lateral ventricle, the posterior callosotomy, the fimbria-fornix incision, the laterothalamic vertical incision, the anterior callosotomy, the frontobasal disconnection, and the transcaudate lateral incision to the anterior temporal horn.7,10 At 10-month follow-up, the patient was seizure free with a stable left hemiparesis. The antiepileptic therapy was progressively interrupted. The video describes the main surgical steps, using both intraoperative videos and advanced three-dimensional modeling of neuroimaging pictures. Patient' parents consented to the procedure. The participants and any identifiable individuals consented to publication of his/her image. Approval from the ethics committee was acquired.

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.

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.

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.

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.

Seizure outcomes and safety profiles of surgical options for epilepsy associated to hypothalamic hamartomas. A systematic review and meta-analysis.

PURPOSE: Several surgical options are available for treating hypothalamic hamartoma-related epilepsy but their respective efficacy and safety profiles are poorly defined. METHODS: A literature search identified English-language articles reporting series of patients (minimum 3 patients with a follow-up ≥12 months) operated on by either microsurgery, endoscopic surgery, radiosurgery, radiofrequency thermocoagulation or laser interstitial thermal therapy for hypothalamic hamartoma-related epilepsy. The unit of analysis was each selected study. Pooled rates of seizure freedom and of neurological and endocrinological complications were analyzed using meta-analysis to calculate both fixed and random effects. The results of meta-analyses were compared. RESULTS: Thirty-nine studies were included. There were 568 and 514 participants for seizure outcome and complication analyses, respectively. The pairwise comparison showed that: i) the proportion of seizure-free cases was significantly lower for radiosurgery as compared to microsurgery, radiofrequency thermocoagulation and laser ablation, and significantly lower for endoscopic surgery as compared to radiofrequency thermocoagulation; ii) the proportion of permanent hypothalamic dysfunction was significantly higher for microsurgery as compared to all other techniques, and significantly lower for endoscopic surgery as compared to radiofrequency thermocoagulation and laser ablation; iii) the incidence of permanent neurological disorders was significantly higher for microsurgery as compared to endoscopic surgery, radiosurgery and radiofrequency thermocoagulation, and significantly lower for radiosurgery as compared to laser ablation. CONCLUSIONS: Minimally invasive surgical techniques, including endoscopic surgery, radiofrequency thermocoagulation and laser ablation, represent an acceptable compromise between efficacy and safety in the treatment of hypothalamic hamartoma-related epilepsy. Microsurgery and radiosurgery should be considered in carefully selected cases.

Magnetic resonance imaging based neurosurgical planning on hololens 2: A feasibility study in a paediatric hospital.

Objective: The goal of this work is to show how to implement a mixed reality application (app) for neurosurgery planning based on neuroimaging data, highlighting the strengths and weaknesses of its design. Methods: Our workflow explains how to handle neuroimaging data, including how to load morphological, functional and diffusion tensor imaging data into a mixed reality environment, thus creating a first guide of this kind. Brain magnetic resonance imaging data from a paediatric patient were acquired using a 3 T Siemens Magnetom Skyra scanner. Initially, this raw data underwent specific software pre-processing and were subsequently transformed to ensure seamless integration with the mixed reality app. After that, we created three-dimensional models of brain structures and the mixed reality environment using Unity™ engine together with Microsoft® HoloLens 2™ device. To get an evaluation of the app we submitted a questionnaire to four neurosurgeons. To collect data concerning the performance of a user session we used Unity Performance Profiler. Results: The use of the interactive features, such as rotating, scaling and moving models and browsing through menus, provided by the app had high scores in the questionnaire, and their use can still be improved as suggested by the performance data collected. The questionnaire's average scores were high, so the overall experiences of using our mixed reality app were positive. Conclusion: We have successfully created a valuable and easy-to-use neuroimaging data mixed reality app, laying the foundation for more future clinical uses, as more models and data derived from various biomedical images can be imported.

Calcium phosphate and titanium cranioplasty after total angular craniopagus separation.

Craniopagus separation requires careful planning and a multi-staged surgical approach, managed by a multidisciplinary team. Despite growing experience on surgical management, the long-term restoration of the cranial defect has been rarely discussed so far. Several alloplastic materials have been proposed as effective and safe solutions for cranioplasty even for pediatric patients, allowing for bone generation, good aesthetic results, and low complication rates. We report, for the first time, on a separated craniopagus child who underwent successful implant of a tailor-made system based on the combination of calcium phosphate ceramic reinforced with a titanium mesh.

The arcuate fasciculus: Combining structure and function into surgical considerations.

BACKGROUND: Two Centuries from today, Karl Friedrich Burdach attributed the nomenclature "arcuate fasciculus" to a white matter (WM) pathway connecting the frontal to the temporal cortices by arching around the Sylvian fissure. Although this label remained essentially unvaried, the concepts related to it and the characterization of the structural properties of this bundle evolved along with the methodological progress of the past years. Concurrently, the functional relevance of the arcuate fasciculus (AF) classically restricted to the linguistic domain has extended to further cognitive abilities. These features make it a relevant structure to consider in a large variety of neurosurgical procedures. OBJECTIVE: Herein, we build on our previous review uncovering the connectivity provided by the Superior Longitudinal System, including the AF, and provide a handy representation of the structural organization of the AF by considering the frequency of defined reports in the literature. By adopting the same approach, we implement an account of which functions are mediated by this WM bundle. We highlight how this information can be transferred to the neurosurgical field by presenting four surgical cases of glioma resection requiring the evaluation of the relationship between the AF and the nearby structures, and the safest approaches to adopt. CONCLUSIONS: Our cumulative overview reports the most common wiring patterns and functional implications to be expected when approaching the study of the AF, while still considering seldom descriptions as an account of interindividual variability. Given its extension and the variety of cortical territories it reaches, the AF is a pivotal structure for different cognitive functions, and thorough understanding of its structural wiring and the functions it mediates is necessary for preserving the patient's cognitive abilities during glioma resection.

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.

The structural connectivity of the human angular gyrus as revealed by microdissection and diffusion tractography.

The angular gyrus (AG) has been described in numerous studies to be consistently activated in various functional tasks. The angular gyrus is a critical connector epicenter linking multiple functional networks due to its location in the posterior part of the inferior parietal cortex, namely at the junction between the parietal, temporal, and occipital lobes. It is thus crucial to identify the different pathways that anatomically connect this high-order association region to the rest of the brain. Our study revisits the three-dimensional architecture of the structural AG connectivity by combining state-of-the-art postmortem blunt microdissection with advanced in vivo diffusion tractography to comprehensively describe the association, projection, and commissural fibers that connect the human angular gyrus. AG appears as a posterior "angular stone" of associative connections belonging to mid- and long-range dorsal and ventral fibers of the superior and inferior longitudinal systems, respectively, to short-range parietal, occipital, and temporal fibers, including U-shaped fibers in the posterior transverse system. Thus, AG is at a pivotal dorso-ventral position reflecting its critical role in the different functional networks, particularly in language elaboration and spatial attention and awareness in the left and right hemispheres, respectively. We also reveal striatal, thalamic, and brainstem connections and a typical inter-hemispheric homotopic callosal connectivity supporting the suggested AG role in the integration of sensory input for modulating motor control and planning. The present description of AG's highly distributed wiring diagram may drastically improve intraoperative subcortical testing and post-operative neurologic outcomes related to surgery in and around the angular gyrus.

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.

Surgical management of pediatric intracranial CCM: a 10-year single center experience.

BACKGROUND: Cerebral cavernous malformations (CCMs) are low-flow vascular malformations made up of dilated vascular spaces without intervening parenchyma that can occur throughout the central nervous system. CCMs can occur sporadically or in familial forms. Presentation is diverse, ranging from asymptomatic discoveries to drug-resistant epilepsy and hemorrhages. METHODS: We describe the surgical management of CCMs in pediatric patients at Bambino Gesù Children's Hospital in Rome over the last 10 years. The cases have been stratified based on the clinical presentation and the relevant literature is discussed accordingly. RESULTS: We discuss the rationale and technique used in these cases based on their presentation, as well as the generally positive outcomes we achieved with early surgical management, use of intra-operative ultrasound (ioUS) and intraoperative neuromonitoring. CONCLUSIONS: Surgical management of pediatric CCMs is a safe and effective strategy, low rates of postoperative morbidity and partial resection were observed.