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Objective: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder associated with refractory early‐onset epilepsy. Current evidence supports surgery as the intervention most likely to achieve long‐term seizure freedom, but no specific guidelines are available on TSC pre‐surgical workup. This critical review assesses which TSC patients are suitable for surgical treatment, when pre‐surgical evaluation should start, and what degree of surgical resection is optimal for postsurgical outcome. Methods: We searched for publications from 2000 to 2020 in Pubmed and Embase using the terms “tuberous sclerosis,” “epilepsy,” and “epilepsy surgery”. To evaluate postsurgical seizure outcome, we selected only studies with at least one year of follow‐up. Results: Overall, we collected data on 1,026 patients from 34 studies. Age at surgery ranged from one month to 54 years. Mean age at surgery was 8.41 years. Of the diagnostic non‐invasive pre‐surgical tools, MRI and video‐EEG were considered most appropriate. Promising data for epileptogenic tuber detection is provided from invasive SEEG studies. Data on surgery and related outcome were available for 769 patients. Seizure freedom was seen in 64.4% of patients who underwent tuberectomy, 68.9% treated with lobectomy and 65.1% with multilobar resection. The most effective surgical approach was lobectomy, even though more recently tuberectomy associated with the resection of the perituberal area seems to be the best approach to reach seizure freedom. Published postsurgical seizure freedom rates in patients with TSC were between 65% and 75%, but reduced to 48%‐57% over longer follow‐up periods. Early surgery might positively affect neurodevelopmental trajectory in some patients, even though data on cognitive outcome are still to be confirmed with longitudinal studies. Significance: Considering the strong correlation between epilepsy duration and neurocognitive outcome, all patients with TSC ought to be referred early to a dedicated epilepsy centre for individually tailored pre‐surgical evaluation by a multi‐disciplinary epilepsy surgery team.

Hippocampal sclerosis (HS) may be associated with focal cortical dysplasia IIIa (FCD IIIa) in patients undergoing surgery for temporal lobe epilepsy (TLE).

Separation of craniopagus twins is a complicated procedure with ethical and technical considerations; a multimodal imaging presurgical assessment ensures a more comprehensive evaluation of such twins’ anatomy.

Epilepsy is characterized by specific alterations in network organization. The main parameters at the basis of epileptogenic network formation are alterations of cortical thickness, development of pathologic hubs, modification of hub distribution, and white matter alterations. The effect is a reinforcement of brain connectivity in both the epileptogenic zone and the propagation zone. Moreover, the epileptogenic network is characterized by some specific neurophysiologic biomarkers that evidence the tendency of the network itself to shift from an interictal state to an ictal one. The recognition of these features is crucial in planning epilepsy surgery.

Berardinelli‐Seip syndrome, or congenital generalized lipodystrophy type 2 (CGL2), is characterized by a lack of subcutaneous adipose tissue and precocious metabolic syndrome with insulin resistance, resulting in diabetes, dyslipidaemia, hepatic steatosis, cardiomyopathy, and acanthosis nigricans. Most reported mutations are associated with mild, non‐progressive neurological impairment. We describe the clinical and EEG data of a patient with progressive myoclonus epilepsy (PME), CGL2, and progressive neurological impairment, carrying a homozygous BSCL2nonsense mutation. The patient had epilepsy onset at the age of two, characterized by monthly generalized tonic‐clonic seizures. By the age of three, he presented with drug‐resistant ongoing myoclonic absence seizures, photosensitivity, progressive neurological degeneration, and moderate cognitive delay. Molecular analysis of the BSCL2gene yielded a homozygous c.(1076dupC) p.(Glu360*) mutation. Application of a vagus nerve stimulator led to temporary improvement in seizure frequency, general neurological condition, and EEG background activity. Specific BSCL2mutations may lead to a peculiar CGL2 phenotype characterized by PME and progressive neurodegeneration. Application of a vagus nerve stimulator, rarely used for PMEs, may prove beneficial, if only temporarily, for both seizure frequency and general neurological condition.

The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome in which glioma is one of the prevalent tumors. Gliomagenesis in NF1 results in a heterogeneous spectrum of low- to high-grade neoplasms occurring during the entire lifespan of patients. The pattern of genetic and epigenetic alterations of glioma that develops in NF1 patients and the similarities with sporadic glioma remain unknown. Here, we present the molecular landscape of low- and high-grade gliomas in patients affected by NF1 (NF1-glioma). We found that the predisposing germline mutation of the NF1gene was frequently converted to homozygosity and the somatic mutational load of NF1-glioma was influenced by age and grade. High-grade tumors harbored genetic alterations of TP53and CDKN2A, frequent mutations of ATRXassociated with Alternative Lengthening of Telomere, and were enriched in genetic alterations of transcription/chromatin regulation and PI3 kinase pathways. Low-grade tumors exhibited fewer mutations that were over-represented in genes of the MAP kinase pathway. Approximately 50% of low-grade NF1-gliomas displayed an immune signature, T lymphocyte infiltrates, and increased neo-antigen load. DNA methylation assigned NF1-glioma to LGm6, a poorly defined Isocitrate Dehydrogenase 1wild-type subgroup enriched with ATRXmutations. Thus, the profiling of NF1-glioma defined a distinct landscape that recapitulates a subset of sporadic tumors.

Hypothalamic hamartomas (HHs) are intrinsically epileptogenic lesions associated to medically intractable focal epilepsy mainly characterized by gelastic and focal seizures. Intralesional recording with deep electrodes has documented the presence of ictal discharge arising from inside the lesion. Nevertheless interictal and ictal scalp EEG is poorly informative and non-localizing in a great deal of cases. HH disconnection leads to seizure remission in most cases. To describe the intralesional EEG recordings and to compare them with concomitant scalp EEG and with previous cases reported in literature. We reviewed the medical records of 17 children affected by drug-resistant focal epilepsy associated to HH. We recorded intralesional electrical activity during stereo-endoscopic disconnection in three cases and during deep brain stimulation implantation in one. We also correlated it with the simultaneous scalp-EEG recording. Acute intralesional recordings in our cases confirmed the presence of epileptiform abnormalities intermingled with low-voltage activity, mostly on the same side of the HH attachment. Paroxysmal activity recorded inside the HH was always evident. Mapping of HH epileptogenic activity could be useful to confirm the usefulness of disconnection procedure. This should consider on-site recording from the HH and if abnormalities are detected safely proceed to disconnection of the HH.

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.

Vagal nerve stimulation (VNS) has been approved for treatment of refractory depression (or treatment-resistant deperssion) and bipolar disorder in Europe and Canada since 2001 and in United States since 2004 by the Food and Drug Administration. Several lines of evidence support an effective antidepressant effect with such treatment modality, outcomes being mainly evaluated with Hamilton Rating Scale for Depression (HRSD). We here report a series of nine patients with severe treatment-resistant deperssion. They all underwent surgical intervention of implantation of left vagal nerve electrode at our institute. The preoperative psychiatric status and postoperative clinical outcome were both evaluated with the 21-item version of the HRSD (HRSD21). Five out of nine patients, having at least one-year follow-up, were responders (?50 reduction of HRSD scoring) and four of these also were remitters (HRSD < 10). One patient with bipolar II disorder and one patient with melancholic depression did not significantly benefit from the procedure; the latter three patients have follow-ups shorter than three months and one of them meets the remittance criteria; nonetheless, for the other two , HRSD21score is gradually decreasing with time.

Both clinical and biological features have been reported as prognostic factors in low-grade gliomas. Among these, histotype, tumor size, enhancement, age and genetic pattern. Microvessel density (MVD) has been correlated to clinical outcome in astrocytomas, but its impact in oligodendrogliomas and mixed tumors is not sure. The pro-angiogenic chemokine stromal cell-derived factor (SDF-1/CXCL12) and its receptor CXC chemokine receptor 4 (CXCR4) have been described in low-grade gliomas, with a correlation between CXCL12 expression and shorter time to progression (TTP). The intermediate filament Nestin is expressed in proliferating vessels. Platelet-derived growth factor B (PDGF-B) and its receptor PDGFR-β are also involved in angiogenesis and malignant progression in gliomas. The aim of this study was to retrospectively investigate the MVD and immunohistochemical expression of CXCL12, CXCR4, PDGF-B, PDGFR-β and Nestin in 40 patients (11 oligodendrogliomas and 29 oligoastrocytomas). In our study, oligodendroglioma histotype was associated with a trend to a more prolonged TTP than mixed tumors (P = 0.12). Age younger than 32, pre-surgery lack of enhancement at CT/MRI and total versus partial resection were not associated with longer TTP. Positivity for CXCL12 on tumor/endothelial cells was the only factor associated with a significantly shorter TTP (P = 0.011). Positivity for CXCL12 in tumor cells was predictive of a shorter survival time (P = 0.014). Since CXCL12 is not only related to angiogenesis, but also exerts an anti-apoptotic effect that may contribute to tumor progression/endothelial escape from apoptotic mechanisms, expression of CXCL12 by these tumors might add prognostic information to available clinical and bio-molecular indexes.

Malignant gliomas are associated with risk of thromboembolism, but the molecular link between tumor and peripheral pro-coagulant status has not been elucidated. Vascular Endothelial Growth Factor (VEGF), tissue-type Plasminogen Activator (tPA), Plasminogen Activator Inhibitor-1 (PAI-1) and lipoprotein (lp) (a) influence the pro-coagulant status. To assess whether the presence of the tumor influenced the peripheral levels of VEGF, tPA, PAI-1 and lp(a), we studied the expression and secretion of VEGF, tPA, PAI-1 and lp(a) in glioma specimens, in peripheral blood and in primary glioma-derived cultures. We also measured lp(a), VEGF, tPA and PAI-1 in the peripheral circulation of patients, before and after surgery for glioma.VEGF, tPA and PAI-1 were expressed in glioma specimens. Glioma cells were indeed a major source of tPA and PAI-1; these molecules were significantly more expressed in glioma than in patient’s blood cells. Lp(a) was rarely expressed in glioma specimens and not expressed in blood cells. In glioma, VEGF, tPA and PAI-1 were localized mainly in tumor cells; tPA was localized also in the extracellular matrix and PAI-1 in tumor vascular lumen. Glioma cells were indeed able to produce and release VEGF, tPA and PAI-1. After surgery, peripheral levels of VEGF and PAI-1 were increased, while tPA and lp(a) were unchanged.The great amount of VEGF, tPA and PAI-1 produced by glioma could influence peripheral levels of these molecules. The partial resection of the tumor by surgery was not able to decrease plasma levels of these molecules.

The relative ineffectiveness of current therapies for malignant gliomas has led to the need for novel therapeutics. Therapies based on biologic modifiers are among a variety of cancer treatments currently in use or under experimental evaluation and have shown great promise, especially since several potent stimulators of the immune system have been cloned and are now available for clinical use. Early attempts at glioma therapy based on biologic modifiers, however, have failed to demonstrate significant effectiveness. In this review, we select and summarize the results of preclinical and clinical studies published during the past two years that focus on immunotherapy and biologic modifiers for treating gliomas. Despite limited clinical success, we conclude that an increased understanding of molecular biology and immunology from recent studies may pave the way for more effective approaches.

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