Refractory Status Epilepticus in Genetic Epilepsy-Is Vagus Nerve Stimulation an Option?

Refractory and super-refractory status epilepticus (RSE, SRSE) are severe conditions that can have long-term neurological consequences with high morbidity and mortality rates. The usefulness of vagus nerve-stimulation (VNS) implantation during RSE has been documented by anecdotal cases and in systematic reviews; however, the use of VNS in RSE has not been widely adopted. We successfully implanted VNS in two patients with genetic epilepsy admitted to hospital for SRSE; detailed descriptions of the clinical findings and VNS parameters are provided. Our patients were implanted 25 and 58 days after status epilepticus (SE) onset, and a stable remission of SE was observed from the seventh and tenth day after VNS implantation, respectively, without change in anti-seizure medication. We used a fast ramp-up of stimulation without evident side effects. Our results support the consideration of VNS implantation as a safe and effective adjunctive treatment for SRSE

β-arrestin1-mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renewal of SHH medulloblastoma cancer stem cells

Background Aberrant Sonic Hedgehog/Gli (Hh/Gli) signaling pathway is a critical regulator of Sonic hedgehog medulloblastoma (SHH-MB). Cancer stem cells (CSCs), thought to be largely responsible for tumor initiation, maintenance, dissemination and relapse, have been identified in SHH-MB. Since we previously demonstrated that Hh/Gli signaling controls CSCs features in SHH-MB and that in these tumors miR-326 is down regulated, here we investigated whether there is a functional link between Hh/Gli signaling and miR-326. Methods We evaluated β-arrestin1 (Arrb1) and its intragenic miR-326 levels in CSCs derived from SHH-MB. Subsequently, we modulated the expression of Arrb1 and miR-326 in CSCs in order to gain insight into their biological role. We also analyzed the mechanism by which Arrb1 and miR-326 control Hh/Gli signaling and self-renewal, using luciferase and protein immunoprecipitation assays. Results Low levels of Arrb1 and miR-326 represent a feature of CSCs derived from SHH-MB. We observed that re-expression of Arrb1 and miR-326 inhibits Hh/Gli signaling pathway at multiple levels, which cause impaired proliferation and self-renewal, accompanied by down regulation of Nanog levels. In detail, miR-326 negatively regulates two components of the Hh/Gli pathway the receptor Smoothened (Smo) and the transcription factor Gli2, whereas Arrb1 suppresses the transcriptional activity of Gli1, by potentiating its p300-mediated acetylation. Conclusions Our results identify a new molecular mechanism involving miR-326 and Arrb1 as regulators of SHH-MB CSCs. Specifically, low levels of Arrb1 and miR-326 trigger and maintain Hh/Gli signaling and self-renewal

The miR-139-5p regulates proliferation of supratentorial paediatric low-grade gliomas by targeting the PI3K/AKT/mTORC1 signalling

Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma

BACKGROUND: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). METHODS: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. RESULTS: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. CONCLUSIONS: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports

The inferior fronto-occipital fascicle: a century of controversies from anatomy theaters to operative neurosurgery.

International audienceINTRODUCTION: Since its first description in the early 19 th century, the inferior frontooccipital fascicle (IFOF) and its anatomo-functional features were neglected in the neuroscientific literature for the last century. In the last decade, the rapid development of in vivo imaging for the reconstruction of white matter (WM) connectivity (i.e., tractography) and the consequent interest in more traditional ex vivo methods (postmortem dissection) have allowed a renewed debate about course, termination territories, anatomical relationships, and functional roles of this fascicle. EVIDENCE ACQUISITION: We reviewed the main current knowledge concerning the structural and functional anatomy of the IFOF and possible implications in neurosurgical practice. EVIDENCE SYNTHESIS: The IFOF connects the occipital cortex, the temporo-basal areas, the superior parietal lobule, and the pre-cuneus to the frontal lobe, passing through the ventral third of subinsular WM of the external capsule. This wide distribution of cortical terminations provides multimodal integration between several functional networks, including language, non-verbal semantic processing, object identification, visuo-spatial processing and planning, reading, facial expression recognition, memory and conceptualization, emotional and neuropsychological behavior. This anatomo-functional organization has important implication also in neurosurgical practice, especially when approaching the frontal, insular, temporo-parieto-occipital regions and the ventricular system. CONCLUSIONS: The IFOF is the most extensive associative bundle of the human connectome. Its multi-layer organization reflects important implications in many aspects of brain functional processing. Accurate awareness of IFOF functional anatomy and integration between multimodal datasets coming from different sources has crucial implications for both neuroscientific knowledge and quality of neurosurgical treatments

NS-03ROBOT-ASSISTED STEREOTACTIC BIOPSY IN DIPG

Recent advancements in molecular characterization of diffuse intrinsic pontine gliomas (DIPG) have favored the reintroduction of stereotactic biopsy to obtain tumor samples. Acceptable morbidity has been documented in experienced Centers performing biopsies in clinical trials. Transcerebellar transpeduncular approach has been proposed as a safer and easier way to perform pontine biopsies with favorable risk profile (5-10% of new neurological deficit). From January 2015 to January 2016 six biopsies were performed using the Rosa robotic arm system using a transfrontal precoronary approach. Whenever feasible target was chosen in high diffusion restriction areas or contrast enhancing areas on MRI imaging and fused with CT scan images to maximize precision. Four to six samples were obtained from each procedure allowing histological characterization and H3K27 mutation identification in all cases. We were able to save freshly frozen samples for biological characterization to guide target therapy in all cases. We observed transient worsening of diplopia in two patients, returning to baseline within 1 month. No bleeding was documented at early CT scan and reaching of planned target was observed in all cases. We confirm an acceptable risk profile of DIPG biopsy in experienced hands. Transfrontal approach has the theoretical advantage to be parallel to white matter long tracts of the pons, however a longer needle track is required. Further advantages are supine position during the procedure and possibility to use robotic systems with submillimetric precision and high stability of biopsy needle. These procedures should better be performed at selected Centers offering clinical trials for DIP

NS-01PEDIATRIC INTRAOPERATIVE NEUROPHYSIOLOGICAL MONITORING IN POSTERIOR FOSSA SURGERY

Intraoperative neurophysiological monitoring (IOM) has recently become a promising tool in neurosurgery. Experiences in children are scattered and the real contribution of this technique to extent of resection and post-operative neurological impairment prevention has not be fully determined yet. We describe our experience in 33 consecutive posterior fossa surgical procedures (30 patients, 19 males and 11 females) in the last two years. Standard monitoring setting included trans-cranial motor evoked potentials (tcMEP), somatosensory evoked potentials (SEP), continuous electromyography (EMG) and brainstem evoked potentials (BAEPs). Relevant IOM information was recorded and correlated to tumor characteristics, intraoperative modifications of surgical strategy, post-operative neurological deficits. Spontaneous EMG activations were observed in 100% of brainstem lesion, in 80% of those infiltrating the floor of the IV ventricle and in less than 50% of cerebellar hemispheric ones. Brainstem infiltration was found to be highly predictive for transient EMG activation (94% in infiltrating vs 37% in non-infiltrating lesions). Transient EMG activation was highly predictive of early post-operative neurological impairment (84% at 72 hours) but did not correlate with long term neurological deficits (35% at 3 months). MEP modifications were only found in presence of brainstem infiltration and resulted in modification of surgical strategy. 75% of patients showing potential drops were found to suffer early motor impairment after surgery. SEP modifications were also rare (12%) but correlated to early post-operative sensibility/motor deficit (75%). No significant variation of BAEPs was observed in our study. No specific IOM pattern was observed in the two patients with post-operative posterior fossa syndrome

Surgery for drug-resistant tuberous sclerosis complex-associated epilepsy: who, when, and what

Objective. Tuberous sclerosis complex (TSC) is a m ultisystem 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 multidisciplinary epilepsy surgery team