Pilot Trial on Awake Surgery for Low-Grade Arteriovenous Malformations in Speech Area and Systematic Review of the Literature.

OBJECTIVE: One of the pressing constraints in the treatment of arteriovenous malformations (AVM) is the potential development of new neurologic deficits, mainly when the AVM is in an eloquent area. The risk of ischemia when an en passage arterial supply is present is not negligible. In this regard, awake surgery holds promise in increasing the safety of low-grade AVM resection. METHODS: We conducted a pilot trial on 3 patients with low-grade AVMs affecting speech areas to evaluate the safety of awake craniotomy using Conscious Sedation. Each feeder was temporarily clipped before the section. Also, we performed a systematic review to analyze the existing data about the impact of awake surgery in eloquent AVM resection. RESULTS: None of the 3 patients presented with neurologic deficits after the procedure. Awake craniotomy was useful in 1 case, as it allowed the detection of speech arrest during the temporal clipping of 1 of the feeders. This vessel was identified as an en passage vessel, closer to the nidus. The second attempt revealed the feeder of the AVM, which was sectioned. Systematic review yielded 7 studies meeting our inclusion criteria. Twenty-six of 33 patients included in these studies presented with AVM affecting speech area. Only 2 studies included the motor evoked potentials. Six studies used direct cortical and subcortical stimulation. In all studies the asleep-awake-asleep technique was used. CONCLUSIONS: Awake craniotomies are safe procedures and may be helpful in avoiding ischemic complications in low-grade AVMs, either affecting eloquent areas and/or when en passage feeders are present.

Plasma ctDNA Monitoring of a PTCH1-Mutant Metastatic Adult Medulloblastoma Showing a Durable Benefit With Vismodegib.

Adult medulloblastoma (MB) is a rare disease affecting 0.6 persons per million adults over 19 years of age. The SHH-activated/TP53-wild type is the most common subtype, accounting for 60% of adult MBs, being characterized by mutations in PTCH1, SMO, or the TERT promoter. Several small studies demonstrate objective but short-lived responses to SMO inhibitors such as vismodegib or sonidegib. Like other oncogene-addicted solid tumors, detection of the corresponding drivers through liquid biopsy could aid in the molecular diagnosis and monitoring of the disease through less invasive procedures. However, most studies have only evaluated cerebrospinal fluid as the ctDNA reservoir, and very limited evidence exists on the role of liquid biopsy in plasma in patients with primary central nervous system tumors, including MB. We present the case of a 26-year-old patient with a recurrent MB, in which next-generation sequencing (FoundationOne CDx) revealed a mutation in PTCH1, allowing the patient to be treated with vismodegib in second line, resulting in a durable benefit lasting for 1 year. Using an in-house digital PCR probe, the PTCH1 mutation could be tracked in ctDNA during treatment with first-line chemotherapy and while on treatment with vismodegib, demonstrating a precise correlation with the radiological and clinical behavior of the disease.

Patients awaiting surgery for neurosurgical diseases during the first wave of the COVID-19 pandemic in Spain: a multicentre cohort study.

OBJECTIVES: The large number of infected patients requiring mechanical ventilation has led to the postponement of scheduled neurosurgical procedures during the first wave of the COVID-19 pandemic. The aims of this study were to investigate the factors that influence the decision to postpone scheduled neurosurgical procedures and to evaluate the effect of the restriction in scheduled surgery adopted to deal with the first outbreak of the COVID-19 pandemic in Spain on the outcome of patients awaiting surgery. DESIGN: This was an observational retrospective study. SETTINGS: A tertiary-level multicentre study of neurosurgery activity between 1 March and 30 June 2020. PARTICIPANTS: A total of 680 patients awaiting any scheduled neurosurgical procedure were enrolled. 470 patients (69.1%) were awaiting surgery because of spine degenerative disease, 86 patients (12.6%) due to functional disorders, 58 patients (8.5%) due to brain or spine tumours, 25 patients (3.7%) due to cerebrospinal fluid (CSF) disorders and 17 patients (2.5%) due to cerebrovascular disease. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was mortality due to any reason and any deterioration of the specific neurosurgical condition. Second, we analysed the rate of confirmed SARS-CoV-2 infection. RESULTS: More than one-quarter of patients experienced clinical or radiological deterioration. The rate of worsening was higher among patients with functional (39.5%) or CSF disorders (40%). Two patients died (0.4%) during the waiting period, both because of a concurrent disease. We performed a multivariate logistic regression analysis to determine independent covariates associated with maintaining the surgical indication. We found that community SARS-CoV-2 incidence (OR=1.011, p<0.001), degenerative spine (OR=0.296, p=0.027) and expedited indications (OR=6.095, p<0.001) were independent factors for being operated on during the pandemic. CONCLUSIONS: Patients awaiting neurosurgery experienced significant collateral damage even when they were considered for scheduled procedures.

Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome-associated glioma.

Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted.

Detection of IDH1 Mutations in Plasma Using BEAMing Technology in Patients with Gliomas.

Molecular testing using blood-based liquid biopsy approaches has not been widely investigated in patients with glioma. A prospective single-center study enrolled patients with gliomas ranging from grade II to IV. Peripheral blood (PB) was drawn at different timepoints for circulating tumour DNA (ctDNA) monitoring. Next-generation sequencing (NGS) was used for the study of isocitrate dehydrogenase 1 (IDH1) mutations in the primary tumor. Beads, Emulsion, Amplification and Magnetics (BEAMing) was used for the study of IDH1 mutations in plasma and correlated with the NGS results in the tumor. Between February 2017 and July 2018, ten patients were enrolled, six with IDH1-mutant and four with IDH1 wild-type gliomas. Among the six IDH-mutant gliomas, three had the same IDH1 mutation detected in plasma (50%), and the IDH1-positive ctDNA result was obtained in patients either at diagnosis (no treatment) or during progressive disease. While the false-negative rate reached 86% (18/21), 15 out of the 18 (83%) plasma-negative results were from PB collected from the six IDH-mutant patients at times at which there was no accompanying evidence of tumor progression, as assessed by MRI. There were no false-positive cases in plasma collected from patients with IDH1 wild-type tumors. BEAMing detected IDH1 mutations in the plasma of patients with gliomas, with a modest clinical sensitivity (true positivity rate) but with 100% clinical specificity, with complete agreement between the mutant loci detected in tumor and plasma. Larger prospective studies should be conducted to expand on these findings, and further explore the clearance of mutations in PB from IDH1-positive patients in response to therapy.

State of the Art and Future Direction in Diagnosis, Molecular Biology, Genetics, and Treatment of Brain Arteriovenous Malformations.

Brain arteriovenous malformations (bAVMs) are uncommon and represent a heterogeneous group of lesions. Although these 2 facts have delayed research on this topic, knowledge about the pathophysiology, diagnosis, and treatment of bAVMs has evolved in recent years. We conducted a review of the literature to update the knowledge about diagnosis, molecular biology, genetic, pathology, and treatment by searching for the following terms: "Epidemiology AND Natural History," "risk of hemorrhage," "intracranial hemorrhage," "diagnosis," "angiogenesis," "molecular genetics," "VEGF," "KRAS," "radiosurgery," "endovascular," "microsurgery," or "surgical resection." Our understanding of bAVMs has significantly evolved in recent years. The latest investigations have helped in defining some molecular pathways involved in the pathology of bAVM. Although there is still more to learn and discover, describing these pathways will allow the creation of targeted treatments that could improve the prognosis of patients with bAVMs.

Neurosurgical emergency management during the lockdown period in health care regions in Spain with different COVID-19 impact: lessons learned to improve outcomes on the future waves.

BACKGROUND: COVID-19 has overloaded health care systems, testing the capacity and response in every European region. Concerns were raised regarding the impact of resources' reorganization on certain emergency pathology management. The aim of the present study was to assess the impact of the outbreak (in terms of reduction of neurosurgical emergencies) during lockdown in different regions of Spain. METHODS: We analyzed the impact of the outbreak in four different affected regions by descriptive statistics and univariate comparison with same period of two previous years. These regions differed in their incidence level (high/low) and in the time of excess mortality with respect to lockdown declaration. That allowed us to analyze their influence on the characteristics of neurosurgical emergencies registered for every region. RESULTS: 1185 patients from 18 neurosurgical centers were included. Neurosurgical emergencies that underwent surgery dropped 24.41% and 28.15% in 2020 when compared with 2019 and 2018, respectively. A higher reduction was reported for the most affected regions by COVID-19. Non-traumatic spine experienced the most significant decrease in number of cases. Life-threatening conditions did not suffer a reduction in any health care region. CONCLUSIONS: COVID-19 affected dramatically the neurosurgical emergency management. The most significant reduction in neurosurgical emergencies occurred on those regions that were hit unexpectedly by the pandemic, as resources were focused on fighting the virus. As a consequence, life-threating and non-life-threatening conditions' mortality raised. Results in regions who had time to prepare for the hit were congruent with an organized and sensible neurosurgical decision-making.

Impact of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients: a nationwide study in Spain.

OBJECTIVE: To assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain. SETTINGS: The initial flood of COVID-19 patients overwhelmed an unprepared healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied. PARTICIPANTS: This was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020. INTERVENTIONS: An exploratory factorial analysis was performed to select the most relevant variables of the sample. PRIMARY AND SECONDARY OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection. RESULTS: Sixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/105 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade ≥3 (OR 2.5) and preoperative GCS 3-8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/105 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated. CONCLUSIONS: Perioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/105 people/week) was a statistically independent predictor of mortality. TRIAL REGISTRATION NUMBER: CEIM 20/217.

Does Endovascular Treatment with Curative Intention Have Benefits for Treating High-Grade Arteriovenous Malformation versus Radiosurgery? Efficacy, Safety, and Cost-Effectiveness Analysis.

BACKGROUND: The treatment of high-grade arteriovenous malformations (AVMs) remains challenging. Microsurgery provides a rapid and complete occlusion compared with other options but is associated with undesirable morbidity and mortality. The aim of this study was to compare the occlusion rates, incidence of unfavorable outcomes, and cost-effectiveness of embolization and stereotactic radiosurgery (SRS) as a curative treatment for high-grade AVMs. METHODS: A retrospective series of 57 consecutive patients with high-grade AVM treated with embolization or SRS, with the aim of achieving complete occlusion, was analyzed. Demographic, clinical, and angioarchitectonic variables were collected. Both treatments were compared for the occlusion rate and procedure-related complications. In addition, a cost-effectiveness analysis was performed. RESULTS: Thirty patients (52.6%) were men and 27 (47.4%) were women (mean age, 39 years). AVMs were unruptured in 43 patients (75.4%), and ruptured in 14 patients (24.6%). The presence of deep venous drainage, nidus volume, perforated arterial supply, and eloquent localization was more frequent in the SRS group. Complications such as hemorrhage or worsening of previous seizures were more frequent in the embolization group. No significant differences were observed in the occlusion rates or in the time necessary to achieve occlusion between the groups. The incremental cost-effectiveness ratio for endovascular treatment versus SRS was $53.279. CONCLUSIONS: Both techniques achieved similar occlusion rates, but SRS carried a lower risk of complications. Staged embolization may be associated with a greater risk of hemorrhage, whereas SRS was shown to have a better cost-effectiveness ratio. These results support SRS as a better treatment option for high-grade AVMs.

Klippel-Trenaunay-Weber Syndrome Associated with Multiple Cerebral Arteriovenous Malformations: Usefulness of Gamma Knife Stereotactic Radiosurgery in This Syndrome.

BACKGROUND: Klippel-Trenaunay-Weber syndrome (KTWS) is characterized by the presence of a combined vascular malformation of capillaries, veins, and lymphatic vessels; congenital venous abnormalities; and limb hypertrophy. Its association with neurovascular abnormalities is infrequent, and the presence of intracranial arteriovenous malformations (AVMs) is extremely rare. CASE DESCRIPTION: We report a case of a 48-year-old male diagnosed with KTWS who spontaneously presented with a cerebral hemorrhage. Computed tomography scan and angio-computed tomography studies revealed bleeding associated with AVM rupture. In the conventional arteriography study, 10 small (<1 cm) AVMs were observed. The patient presented a good clinical recovery. These multiple small lesions were not considered susceptible to surgical or endovascular treatments. Therefore all lesions were treated with Gamma Knife stereotactic radiosurgery since it attains the highest dose drop and minimal irradiation of the healthy parenchyma. One year after the treatment, the lesions have shrunk. CONCLUSIONS: Cerebral AVMs are extremely rare in KTWS cases; however, their presence can have serious consequences if they are treated. We find it advisable to include brain imaging tests, such as nuclear magnetic resonance imaging, to diagnose and monitor KTWS. Furthermore, a Gamma Knife may be useful when multiple AVMs are present.

Primary bilateral fronto-temporoparietal decompressive craniectomy-An alternative treatment for severe traumatic brain injury: Case report and technical note.

Bilateral fronto-temporoparietal decompressive craniectomy provides bigger area of the decompression that decreases the brain tissue herniation; therefore, it leads to a decrease in the neuronal stretching effect that is probably related to functional outcomes.