A modern approach to olfactory groove meningiomas

J Neurosurg 140:1215–1222, 2024

Management of olfactory groove meningiomas (OGMs) has changed significantly with the advances in extended endoscopic endonasal approaches (EEAs), which is an excellent approach for patients with anosmia since it allows early devascularization and minimizes retraction on the frontal lobes. Craniotomy is best suited for preservation of olfaction. However, not infrequently, a tumor presents after extending outside the reach of an EEA and a solely transcranial approach would require manipulation and retraction of the frontal lobes. These OGMs may best be treated by a staged EEA-craniotomy approach. In this study the authors’ goal was to present their case series of patients with OGMs treated with their surgical approach algorithm.

METHODS The authors conducted an IRB-approved, nonrandomized historic cohort including all consecutive cases of OGMs treated surgically between 2010 and 2020. Patient demographic information, presenting symptoms, operative details, and complications data were collected. Preoperative and postoperative tumor and T2/FLAIR intensity volumes were calculated using Visage Imaging software.

RESULTS Thirty-one patients with OGMs were treated (14 craniotomy only, 11 EEA only, and 6 staged). There was a significant difference in the distribution of patients presenting with anosmia and visual disturbance by approach. Tumor size was significantly correlated with preoperative vasogenic edema. Gross-total resection was achieved in 90% of cases, with near-total resection occurring twice with EEA and once with a staged approach. T2/FLAIR hyperintensity completely resolved in 90% of cases and rates did not differ by approach. Complication rates were not significantly different by approach and included 4 CSF leaks (p = 0.68).

CONCLUSIONS A staged approach for the management of large OGMs with associated anosmia and significant lateral extension is a safe and effective option for surgical management. Through utilization of the described algorithm, the authors achieved a high rate of GTR, and this strategy may be considered for large OGMs.

Use of 5-ALA fluorescence–guided surgery versus white-light conventional microsurgery for the resection of newly diagnosed glioblastomas (RESECT study): a French multicenter randomized phase III study

J Neurosurg 140:987–1000, 2024

Only one phase III prospective randomized study, published in 2006, has assessed the performance of 5-aminolevulinic acid (5-ALA) fluorescence–guided surgery (FGS) for glioblastoma resection. The aim of the RESECT study was to compare the onco-functional results associated with 5-ALA fluorescence and with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care.

METHODS This was a phase III prospective randomized single-blinded study, involving 21 French neurosurgical centers, comparing 5-ALA FGS with white-light conventional microsurgery in patients with glioblastoma managed according to the current standards of care, including neuronavigation use and postoperative radiochemotherapy. Randomization was performed in a 1:1 ratio stratified by institution. 5-ALA (20 mg/kg) or placebo (ascorbic acid) was administered orally 3–5 hours before the incision. The primary endpoint was the rate of gross-total resection (GTR) blindly assessed by an independent committee. Patients without a confirmed pathological diagnosis of glioblastoma or with unavailable postoperative MRI studies were excluded from the per-protocol analysis.

RESULTS Between March 2013 and August 2016, a total of 171 patients were assigned to the 5-ALA fluorescence group (n = 88) or to the placebo group (n = 83). Twenty-four cases were excluded because the WHO histological criteria of grade 4 glioma were not met. The proportion of GTR was significantly higher in the 5-ALA fluorescence group (53/67, 79.1%) than in the placebo group (33/69, 47.8%; p = 0.0002). After adjustment for age, preoperative Karnofsky Performance Scale score, and tumor location, GTR was still associated with 5-ALA fluorescence (OR 4.13 [95% CI 1.94–8.79]). The mean 7-day postoperative Karnofsky Performance Scale score (≥ 80% in 49/71, 69.0% [5-ALA group]; 50/71, 70.4% [placebo group], p = 0.86) and the proportion of patients with a worsened neurological status 3 months postoperatively (9/68, 13.2% [5-ALA group]; 9/70, 12.9% [placebo group], p = 0.95) were similar between groups. Adverse events related to 5-ALA intake were rare and consisted of photosensitization in 4/87 (4.6%) patients and hepatic cytolysis in 1/87 (1.1%) patients. The 6-month PFS (70.2% [95% CI 57.7%–79.6%] and 68.4% [95% CI 55.7%–78.1%]; p =0.39) and 24-month OS (30.1% [95% CI 18.9%–42.0%] and 37.7% [95% CI 25.8%–49.5%]; p = 0.89) did not significantly differ. In multivariate analysis, GTR was an independent predictor of PFS (hazard ratio 0.56 [95% CI 0.36–0.86], p =0.008) and OS (hazard ratio 0.65 [95% CI 0.42–1.01], p = 0.05). The use of 5-ALA FGS generates a significant extra cost of 2732.36€ (95% CI 1658.40€–3794.11€).

CONCLUSIONS The authors found that 5-ALA FGS is an easy-to-use, cost-effective, and minimally time-consuming technique that safely optimizes the extent of resection in patients harboring glioblastoma amenable to a large resection.

Asleep triple-modality motor mapping for perirolandic gliomas: an update on outcomes

J Neurosurg 140:1029–1037, 2024

Maximal safe resection of gliomas near motor pathways is facilitated by intraoperative mapping. Here, the authors review their results with triple-modality asleep motor mapping with motor evoked potentials and bipolar and monopolar stimulation for cortical and subcortical mapping during glioma surgery in an expanded cohort.

METHODS This was a retrospective analysis of patients who underwent resection of a perirolandic glioma near motor pathways. Clinical and neuromonitoring data were extracted from the electronic medical records for review. All patients with new or worsened postoperative motor deficits were followed for at least 6 months. Regression analyses were performed to assess factors associated with a persistent motor deficit.

RESULTS Between January 2018 and December 2021, 160 operations were performed in 151 patients with perirolandic glioma. Sixty-four patients (40%) had preoperative motor deficits, and the median extent of resection was 98%. Overall, patients in 38 cases (23.8%) had new or worse immediate postoperative deficits by discharge, and persistent deficits by 6 months were seen in 6 cases (3.8%), all in patients with high-grade gliomas. There were no new persistent deficits in low-grade glioma patients (0%). The risk factors for a persistent deficit included an insular tumor component (OR 8.6, p = 0.01), preoperative motor weakness (OR 8.1, p = 0.03), intraoperative motor evoked potential (MEP) changes (OR 36.5, p < 0.0001), and peri–resection cavity ischemia (OR 7.5, p = 0.04). Most persistent deficits were attributable to ischemic injury despite structural preservation of the descending motor tracts. For patients with persistent motor deficits, there were 3 cases (50%) in which a change in MEP was noted but subsequent subcortical monopolar stimulation still elicited a response in the corresponding muscle groups, suggesting axonal activation distal to a point of injury.

CONCLUSIONS Asleep triple motor mapping results in a low rate of permanent deficits, especially for low-grade gliomas. Peri–resection cavity ischemia continues to be a significant risk factor for permanent deficit despite maintaining appropriate distance for subcortical tracts based on monopolar feedback.

Sodium fluorescein uptake by the tumor microenvironment in human gliomas and brain metastases

J Neurosurg 140:958–967, 2024

Intravenous sodium fluorescein (SF) is increasingly used during surgery of gliomas and brain metastases to improve tumor resection. Currently, SF is believed to permeate the brain regions where the blood-brain barrier (BBB) is damaged and to accumulate in the extracellular space but not in tumor or healthy cells, making it possible to demarcate tumor margins to guide resection. By evaluating the immune contexture of a number of freshly resected gliomas and brain metastases from patients undergoing SF-guided surgery, the authors recurrently observed fluorescence-positive cells. Therefore, the aim of this study was to determine if SF accumulates inside the cells of the tumor microenvironment (TME), and if so, in which type of cells, and whether incorporation can also be observed in the leukocytes of peripheral blood.

METHODS Freshly resected tumor specimens were dissociated to single cells and analyzed by multiparametric flow cytometry. Peripheral blood leukocytes, macrophages, and a glioma cell line were treated with SF in vitro, and their cell uptake was assessed by multiparametric and imaging flow cytometry and by confocal microscopy.

RESULTS The ex vivo and in vitro analyses revealed that SF accumulates intracellularly in leukocytes as well as in tumor cells, but with a high variability of incorporation in the different cell subsets analyzed. Myeloid cells showed the highest level of fluorescence. In vitro uptake experiments showed that SF accumulation increases over time. The imaging analyses confirmed the internalization of the compound inside the cells.

CONCLUSIONS SF is not just a marker of BBB damage, but its intracellular detection suggests that it selectively accumulates intracellularly. Future efforts should target the mechanisms of its differential uptake by the different TME cell types in depth.

Minimally invasive keyhole approach for supramaximal frontal glioma resections

J Neurosurg 140:949–957, 2024

The authors aimed to review the frontal lobe’s surgical anatomy, describe their keyhole frontal lobectomy technique, and analyze the surgical results.

METHODS Patients with newly diagnosed frontal gliomas treated using a keyhole approach with supramaximal resection (SMR) from 2016 to 2022 were retrospectively reviewed. Surgeries were performed on patients asleep and awake. A human donor head was dissected to demonstrate the surgical anatomy. Kaplan-Meier curves were used for survival analysis.

RESULTS Of the 790 craniotomies performed during the study period, those in 47 patients met our inclusion criteria. The minimally invasive approach involved four steps: 1) debulking the frontal pole; 2) subpial dissection identifying the sphenoid ridge, olfactory nerve, and optic nerve; 3) medial dissection to expose the falx cerebri and interhemispheric structures; and 4) posterior dissection guided by motor mapping, avoiding crossing the inferior plane defined by the corpus callosum. A fifth step could be added for nondominant lesions by resecting the inferior frontal gyrus. Perioperative complications were recorded in 5 cases (10.6%). The average hospital length of stay was 3.3 days. High-grade gliomas had a median progression-free survival of 14.8 months and overall survival of 23.9 months.

CONCLUSIONS Keyhole approaches enabled successful SMR of frontal gliomas without added risks. Robust anatomical knowledge and meticulous surgical technique are paramount for obtaining successful resections.

Nonenhancing motor eloquent gliomas: navigated transcranial magnetic stimulation oncobiological signature

J Neurosurg 140:909–919, 2024

Preoperative grading of nonenhancing motor eloquent gliomas is hampered by a lack of specific imaging surrogates. Tumor grading is crucial for the informed consent discussion before tumor resection. In this paper, the authors hypothesized that navigated transcranial magnetic stimulation (nTMS)–derived metrics could provide significant information to distinguish between high- and low-grade motor eloquent gliomas that present as nonenhancing tumors and therefore contribute to improving patient counseling, timing of treatment, preoperative planning, and intraoperative strategies.

METHODS The authors conducted a retrospective single-center cohort study of patients admitted for tumor surgery between January 2018 and April 2022 with a nonenhancing motor eloquent glioma and preoperative bilateral nTMS mapping. nTMS data including resting motor threshold (RMT), interhemispheric RMT ratio (iRMTr), Cortical Excitability Score (CES), area and volume of cortical activation, and motor evoked potential (MEP) characteristics were obtained and integrated with demographic and clinical data.

RESULTS Thirty patients met the inclusion criteria, and 10 healthy participants were recruited for comparison. Seizures were the most common presenting symptom (25 patients) and WHO grade 3 the most common tumor grade (21 patients). The area and volume of functional cortical activation of both the abductor pollicis brevis and first dorsal interosseous muscles were decreased in healthy participants compared with patients with WHO grade 3 glioma (p < 0.05). An abnormal iRMTr for the lower limbs (16.7% [1/6] WHO grade 2, 76.2% [16/21] WHO grade 3, 100% [3/3] WHO grade 4; p = 0.015) and a higher CES (maximal abnormal CES: 0% [0/6] WHO grade 2, 38% [8/21] WHO grade 3, 66.7% [2/3] WHO grade 4; p = 0.010) were associated with the prediction of high-grade lesions. A total of 7280 MEPs were analyzed. A significant increase in the amplitude and a significant decrease in latency in the MEPs for the first dorsal interosseous and abductor digiti minimi muscles (p < 0.0001) were identified in healthy participants compared with WHO grade 3 glioma patients.

CONCLUSIONS Nonenhancing motor eloquent gliomas have a different impact on both anatomical and functional reorganization of motor areas according to their WHO grading.

Intraoperative in vivo confocal laser endomicroscopy imaging at glioma margins: can we detect tumor infiltration?

J Neurosurg 140:357–366, 2024

Confocal laser endomicroscopy (CLE) is a US Food and Drug Administration–cleared intraoperative real-time fluorescence-based cellular resolution imaging technology that has been shown to image brain tumor histoarchitecture rapidly in vivo during neuro-oncological surgical procedures. An important goal for successful intraoperative implementation is in vivo use at the margins of infiltrating gliomas. However, CLE use at glioma margins has not been well studied.

METHODS Matching in vivo CLE images and tissue biopsies acquired at glioma margin regions of interest (ROIs) were collected from 2 institutions. All images were reviewed by 4 neuropathologists experienced in CLE. A scoring system based on the pathological features was implemented to score CLE and H&E images from each ROI on a scale from 0 to 5. Based on the H&E scores, all ROIs were divided into a low tumor probability (LTP) group (scores 0–2) and a high tumor probability (HTP) group (scores 3–5). The concordance between CLE and H&E scores regarding tumor probability was determined. The intraclass correlation coefficient (ICC) and diagnostic performance were calculated.

RESULTS Fifty-six glioma margin ROIs were included for analysis. Interrater reliability of the scoring system was excellent when used for H&E images (ICC [95% CI] 0.91 [0.86–0.94]) and moderate when used for CLE images (ICC [95% CI] 0.69 [0.40–0.83]). The ICCs (95% CIs) of the LTP group (0.68 [0.40–0.83]) and HTP group (0.68 [0.39–0.83]) did not differ significantly. The concordance between CLE and H&E scores was 61.6%. The sensitivity and specificity values of the scoring system were 79% and 37%. The positive predictive value (PPV) and negative predictive value were 65% and 53%, respectively. Concordance, sensitivity, and PPV were greater in the HTP group than in the LTP group. Specificity was higher in the newly diagnosed group than in the recurrent group.

CONCLUSIONS CLE may detect tumor infiltration at glioma margins. However, it is not currently dependable, especially in scenarios where low probability of tumor infiltration is expected. The proposed scoring system has excellent intrinsic interrater reliability, but its interrater reliability is only moderate when used with CLE images. These results suggest that this technology requires further exploration as a method for consistent actionable intraoperative guidance with high dependability across the range of tumor margin scenarios. Specific-binding and/or tumor-specific fluorophores, a CLE image atlas, and a consensus guideline for image interpretation may help with the translational utility of CLE.

Decoding the clinical effects of low-grade glioma–induced cortical excitability

J Neurosurg 140:18–26, 2024

Patients with low-grade glioma (LGG) in eloquent regions often present with seizures, and findings on detailed neuropsychological testing are often abnormal. This study evaluated the association between cortical excitability, seizures, and cognitive function in patients with LGG.

METHODS LGG patients who underwent transcranial magnetic stimulation (TMS) from January 2021 to December 2022 were studied. Cortical excitability was measured using the resting motor thresholds (RMTs) of the upper and lower extremities. Early postoperative seizures served as the seizure endpoint. Neuropsychological assessment was completed prior to surgery contemporaneous with the TMS studies.

RESULTS A total of 31 patients were analyzed for seizure outcome. Median (interquartile range [IQR]) upper-extremity RMT was 39% (34%–46%) of maximum stimulator output, and the median (IQR) lower-extremity RMT was 69% (51%79%). Lower-extremity RMT was higher in patients with early postoperative seizures, especially in those with motor region tumors (p = 0.02); however, RMT was not associated with seizures at presentation or long-term seizure control. A total of 26 patients completed neuropsychological assessment. There were significant negative correlations between upper-extremity RMT and psychomotor processing speed (Wechsler Adult Intelligence Scale–Fourth Edition [WAIS-IV] Processing Speed Index r = −0.42, p = 0.031; WAIS-IV Coding r = −0.41, p = 0.036; WAIS-IV Symbol Search r = −0.39, p = 0.048), executive function (Trail Making Test Part B r = −0.41, p = 0.036), and hand dexterity (Grooved Pegboard Test r = −0.50, p = 0.047).

CONCLUSIONS RMT was positively correlated with early postoperative seizure risk and negatively correlated with psychomotor processing speed, executive function, and hand dexterity. These findings support the theory of local and regional resting oscillatory network dysfunction from a glioma-brain network.

Unique molecular, clinical, and treatment aspects of gliomas in adolescents and young adults

J Neurosurg 139:1619–1627, 2023

Adolescent and young adult (AYA) patients with glioma have historically had poorer outcomes than similar patients of younger or older age, a disparity thought to be attributable to the social and economic challenges faced by this group in the transition from childhood to adult life, delays in diagnosis, low participation of AYA patients in clinical trials, and the lack of standardized treatment approaches specific to this patient group.

Recent work from many groups has informed a revision of the World Health Organization classification schema for gliomas to identify biologically divergent pediatric and adult-type tumors, both types of which may occur in AYA patients, and revealed exciting opportunities for the use of targeted therapies for many of these patients. In this review, the authors focus on the glioma types of specific concern to practitioners caring for AYA patients and the factors that should be considered in the development of multidisciplinary teams to facilitate their care.

Neuroendoscopic transventricular transchoroidal approach for access to the posterior zone of the third ventricle or pineal region

Neurosurgical Review (2023) 46:323

The endoscopic transventricular transchoroidal approach facilitates entry into the posterior part of the third ventricle, allowing a visualization field from the foramen of Monro to the pineal region through this anatomical corridor. Combined surgery to treat the target lesion and possible endoscopic third ventriculostomy (ETV) can be performed through a single burr hole.

A detailed description of this surgical technique is given, and a series of cases from our center is presented. This retrospective study included patients with lesions in the pineal region or posterior zone of the third ventricle who underwent surgery between 2004 and 2022 in our center for tumor biopsy or endoscopic cyst fenestration. In nine cases, the transchoroidal approach was performed. Demographic and clinical variables were collected: sex, age at diagnosis, clinical presentation, characteristics of the lesion, pathological diagnosis, characteristics of the procedure, complications, subsequent treatments, evolution, follow-up time, and degree of success of the endoscopic procedure. The mean and range of the quantitative variables and frequency of the qualitative variables were analyzed, together with the statistical significance (p < 0.05). Surgical planning was carried out by performing a preoperative MRI, calculating the ideal entry point and trajectory for each case. The preoperative planning of the surgical technique is described in detail.

Of our sample, 55.6% were women, with a mean age of 35 years (7–78). The most common clinical presentation was intracranial hypertension (55.6%), with or without a focus. Eight patients presented hydrocephalus at diagnosis. The most frequent procedure was endoscopic biopsy with ETV (66.7%). The pathological diagnosis varied widely. Procedure-related complications included one case of self-limited bleeding of the choroidal fissure at its opening and one intraventricular hemorrhage due to tumor bleeding in the postoperative period. Non-procedure-related complications comprised two ETV failures and one case of systemic infection, while late complications included one case of disease progression and one case of radionecrosis. Four patients died, one due to poor neurological evolution after post-surgical tumor bleeding and three due to causes unrelated to the procedure. The rest of the patients had a favorable evolution and were asymptomatic or stable.

The transchoroidal approach through a single burr hole is a feasible and safe option for access to the posterior part of the third ventricle. Proper planning of each case is necessary to avoid complications.

Surgical, functional, and oncological considerations regarding awake resection for giant diffuse lower-grade glioma of more than 100 cm3

J Neurosurg 139:934–943, 2023

Surgery for giant diffuse lower-grade gliomas (LGGs) is challenging, and very few data have been reported on this topic in the literature. In this article, the authors investigated surgical, functional, and oncological aspects in patients who underwent awake resection for large LGGs with a volume > 100 cm3.

METHODS The authors retrospectively reviewed a consecutive cohort of patients who underwent surgery in an awake condition for an LGG (WHO grade 2 with possible foci of grade 3 transformation) with a volume > 100 cm3.

RESULTS A total of 108 patients were included, with a mean age of 36.1 ± 8.5 years. The mean presurgical LGG volume was 136.7 ± 34.5 cm3. In all but 2 patients a disconnection resective surgery up to functional boundaries was possible thanks to active patient collaboration during the awake period. At 3 months of follow-up, all but 1 patient had a normal neurological examination, with a mean Karnofsky Performance Status (KPS) score of 89.8 ± 10.36. In all patients with preoperative epilepsy, there was postoperative control or significant reduction of seizure events. Moreover, 85.1% of patients returned to work. The mean extent of resection (EOR) was 88.9% ± 7.0%, with a mean residual tumor volume (RTV) of 16.3 ± 12.0 cm3 (median RTV 15 cm3). Pathological examination revealed 73 grade 2 gliomas (67.6%; 26 oligodendrogliomas and 47 astrocytomas) and 35 gliomas with foci of grade 3 (32.4%; 19 oligodendrogliomas and 16 astrocytomas). During the postoperative period, 93.6% of patients underwent adjuvant chemotherapy with a median interval between surgery and first chemotherapy of 14 months (IQR 2–26 months), and 55% of patients had radiotherapy with a median interval of 38.5 months (IQR 18–59.8 months). At the last follow-up, 69.7% of patients were still alive with a median follow-up of 62 months (IQR 36–99 months). Overall survival (OS) rates at 1, 5, and 10 years were 100% (95% CI 0.99–1), 80% (95% CI 0.72–0.9), and 58% (95% CI 0.45–0.73), respectively. The median OS was 138 months. In multivariable Cox regression analysis, RTV was established as the only independent prognostic factor for survival.

CONCLUSIONS With the application of rigorous surgical methodology based on functional-guided resection, resection of giant LGGs (volume > 100 cm3) can be reproducibly achieved during surgery with patients under awake mapping with both favorable functional results (< 1% permanent neurological worsening) and favorable long-term oncological outcomes (median OS > 11 years, with a more significant benefit when the RTV is < 15 cm3).

A proposed classification system for presigmoid approaches: a scoping review

J Neurosurg 139:965–971, 2023

The “presigmoid corridor” covers a spectrum of approaches using the petrous temporal bone either as a target in treating intracanalicular lesions or as a route to access the internal auditory canal (IAC), jugular foramen, or brainstem. Complex presigmoid approaches have been continuously developed and refined over the years, leading to great heterogeneity in their definitions and descriptions. Owing to the common use of the presigmoid corridor in lateral skull base surgery, a simple anatomy-based and self-explanatory classification is needed to delineate the operative perspective of the different variants of the presigmoid route. Herein, the authors conducted a scoping review of the literature with the aim of proposing a classification system for presigmoid approaches.

METHODS The PubMed, EMBASE, Scopus, and Web of Science databases were searched from inception to December 9, 2022, following the PRISMA Extension for Scoping Reviews guidelines to include clinical studies reporting the use of “stand-alone” presigmoid approaches. Findings were summarized based on the anatomical corridor, trajectory, and target lesions to classify the different variants of the presigmoid approach.

RESULTS Ninety-nine clinical studies were included for analysis, and the most common target lesions were vestibular schwannomas (60/99, 60.6%) and petroclival meningiomas (12/99, 12.1%). All approaches had a common entry pathway (i.e., mastoidectomy) but were differentiated into two main categories based on their relationship to the labyrinth: translabyrinthine or anterior corridor (80/99, 80.8%) and retrolabyrinthine or posterior corridor (20/99, 20.2%). The anterior corridor comprised 5 variations based on the extent of bone resection: 1) partial translabyrinthine (5/99, 5.1%), 2) transcrusal (2/99, 2.0%), 3) translabyrinthine proper (61/99, 61.6%), 4) transotic (5/99, 5.1%), and 5) transcochlear (17/99, 17.2%). The posterior corridor consisted of 4 variations based on the target area and trajectory in relation to the IAC: 6) retrolabyrinthine inframeatal (6/99, 6.1%), 7) retrolabyrinthine transmeatal (19/99, 19.2%), 8) retrolabyrinthine suprameatal (1/99, 1.0%), and 9) retrolabyrinthine trans-Trautman’s triangle (2/99, 2.0%).

CONCLUSIONS Presigmoid approaches are becoming increasingly complex with the expansion of minimally invasive techniques. Descriptions of these approaches using the existing nomenclature can be imprecise or confusing. Therefore, the authors propose a comprehensive classification based on the operative anatomy that unequivocally describes presigmoid approaches simply, precisely, and efficiently.

Pseudoprogression versus true progression in glioblastoma: what neurosurgeons need to know

J Neurosurg 139:748–759, 2023

Management of patients with glioblastoma (GBM) is complex and involves implementing standard therapies including resection, radiation therapy, and chemotherapy, as well as novel immunotherapies and targeted small-molecule inhibitors through clinical trials and precision medicine approaches. As treatments have advanced, the radiological and clinical assessment of patients with GBM has become even more challenging and nuanced.

Advances in spatial resolution and both anatomical and physiological information that can be derived from MRI have greatly improved the noninvasive assessment of GBM before, during, and after therapy.

Identification of pseudoprogression (PsP), defined as changes concerning for tumor progression that are, in fact, transient and related to treatment response, is critical for successful patient management. These temporary changes can produce new clinical symptoms due to mass effect and edema. Differentiating this entity from true tumor progression is a major decision point in the patient’s management and prognosis.

Providers may choose to start an alternative therapy, transition to a clinical trial, consider repeat resection, or continue with the current therapy in hopes of resolution. In this review, the authors describe the invasive and noninvasive techniques neurosurgeons need to be aware of to identify PsP and facilitate surgical decision-making.

The transfrontal isthmus approach for insular glioma surgery

J Neurosurg 139:20–28, 2023

The classic transopercular or transsylvian approach to insular gliomas removes the tumor laterally through the insular cortex. This study describes a new anteroposterior approach through the frontal isthmus for insular glioma surgery.

METHODS The authors detailed the surgical techniques for resection of insular gliomas through the transfrontal isthmus approach. Fifty-nine insular gliomas with at least Berger-Sanai zone I involvement were removed with the new approach, and extent of resection and postoperative neurological outcomes were assessed.

RESULTS Fifty-nine patients were enrolled in the study, including 35 men and 24 women, with a mean (range) age 44.3 (19–75) years. According to the Berger-Sanai classification system, the most common tumor was a giant glioma (67.8%), followed by involvement of zones I and IV (18.6%). Twenty-two cases were Yaşargil type 3A/B, and 37 cases were Yaşargil type 5A/B. The average angle between the lateral plane of the putamen and sagittal line was 33.53°, and the average width of the isthmus near the anterior insular point was 33.33 mm. The average angle between the lateral plane of the putamen and the sagittal line was positively correlated with the width of the isthmus near the anterior insular point (r = 0.935, p < 0.0001). The median (interquartile range [IQR]) preoperative tumor volume was 67.82 (57.64–92.19) cm 3 . Of 39 low-grade gliomas, 26 (66.67%) were totally resected; of 20 high-grade gliomas, 19 (95%) were totally resected. The median (IQR) extent of resection of the whole group was 100% (73.7%–100%). Intraoperative diffusion-weighted imaging showed no cases of middle cerebral artery– or lenticulostriate artery–related stroke. Extent of insular tumor resection was positively correlated with the angle of the lateral plane of the putamen and sagittal line (r = −0.329, p = 0.011) and the width of the isthmus near the anterior insular point (r = −0.267, p = 0.041). At 3 months postoperatively, muscle strength grade exceeded 4 in all cases, and all patients exhibited essentially normal speech. The median (IQR) Karnofsky performance score at 3 months after surgery was 90 (80–90).

CONCLUSIONS The transfrontal isthmus approach changes the working angle from lateral-medial to anterior-posterior, allowing for maximal safe removal of insular gliomas.

Precuneal gliomas promote behaviorally relevant remodeling of the functional connectome

J Neurosurg 138:1531–1541, 2023

The precuneus hosts one of the most complex patterns of functional connectivity in the human brain. However, due to the extreme rarity of neurological lesions specifically targeting this structure, it remains unknown how focal damage to the precuneus may impact resting-state functional connectivity (rsFC) at the brainwide level. The aim of this study was to investigate glioma-induced rsFC modulations and to identify patterns of rsFC remodeling that accounted for the maintenance of cognitive performance after awake-guided surgical excision.

METHODS In a unique series of patients with IDH1-mutated low-grade gliomas (LGGs) infiltrating the precuneus who were treated at a single neurosurgical center (Montpellier University Medical Center, 2014–2021), the authors gauged the dynamic modulations induced by tumors on rsFC in comparison with healthy participants. All patients received a preoperative resting-state functional MRI and underwent operation guided by awake cognitive mapping. Connectome multivariate pattern analysis (MVPA), seed-network analysis, and graph theoretical analysis were conducted and correlated to executive neurocognitive scores (i.e., phonological and semantic fluencies, Trail-Making Test [TMT] parts A and B) obtained 3 months after surgery.

RESULTS Seventeen patients with focal precuneal infiltration were selected (mean age 38.1 ± 11.2 years) and matched to 17 healthy participants (mean age 40.5 ± 10.4 years) for rsFC analyses. All patients underwent awake cognitive mapping, allowing total resection (n = 3) or subtotal resection (n = 14), with a mean extent of resection of 90.6% ± 7.3%. Using MVPA (cluster threshold: p–false discovery rate corrected < 0.05, voxel threshold: p-uncorrected < 0.001), remote hotspots with significant rsFC changes were identified, including both insulas, the anterior cingulate cortex, superior sensorimotor cortices, and both frontal eye fields. Further seed-network analyses captured 2 patterns of between-network redistribution especially involving hyperconnectivity between the salience, visual, and dorsal attentional networks. Finally, the global efficiency of the salience-visual-dorsal attentional networks was strongly and positively correlated to 3-month postsurgical scores (n = 15) for phonological fluency (r 15 = 0.74, p = 0.0027); TMT-A (r 15 = 0.65, p = 0.012); TMTB (r 15 = 0.70, p = 0.005); and TMT-B-A (r 15 = 0.62, p = 0.018).

CONCLUSIONS In patients with LGGs infiltrating the precuneus, remote and distributed functional connectivity modulations in the preoperative setting are associated with better maintenance of cognitive performance after surgery. These findings provide a new vision of the mechanistic principles underlying neural plasticity and cognitive compensation in patients with LGGs.

Contralateral subfrontal approach for tuberculum sellae meningioma

J Neurosurg 138:598–609, 2023

Tuberculum sellae meningiomas (TSMs) present a burdensome surgical challenge because of their adjacency to vital neurovascular structures. The contralateral subfrontal approach provides an outstanding corridor for removing a TSM with an excellent visual outcome and limited complications. The authors present their long-term surgical experience in treating TSMs via the contralateral subfrontal approach and discuss patient selection, surgical techniques, and clinical outcomes.

METHODS Between 2005 and 2021, the authors used the contralateral subfrontal approach in 74 consecutive patients presenting with TSMs. The surgical decision-making process and surgical techniques are described, and the clinical outcomes were retrospectively analyzed.

RESULTS The mean patient age was 54.4 years, with a female predominance (n = 61, 82%). Preoperatively, 61 patients (82%) had vision symptoms and 73 (99%) had optic canal invasion by tumor. Gross-total resection was achieved in almost all patients (n = 70, 95%). The visual function improvement and stabilization rate was 91% (67/74). Eight patients (11%) showed a worsening of visual function on the less-compromised (approach-side) optic nerve. There was no occurrence of cerebrospinal fluid leakage. Four patients (5%) experienced recurrences after the initial operation (mean follow-up duration 63 months). There were no deaths in this study.

CONCLUSIONS The contralateral subfrontal approach provides a high chance of complete tumor removal and visual improvement with limited complications and recurrences, especially when the tumor is in a unilateral or midline location causing unilateral visual symptoms or bilateral asymmetrical visual symptoms, regardless of tumor size or encasement of major vessels. With the appropriate patient selection, surgical technique, and familiarity with surrounding neurovascular structures, this approach is reliable for TSM surgery.

Intraoperative confocal laser endomicroscopy: prospective in vivo feasibility study of a clinical-grade system for brain tumors

J Neurosurg 138:587–597, 2023

The authors evaluated the feasibility of using the first clinical-grade confocal laser endomicroscopy (CLE) system using fluorescein sodium for intraoperative in vivo imaging of brain tumors.

METHODS A CLE system cleared by the FDA was used in 30 prospectively enrolled patients with 31 brain tumors (13 gliomas, 5 meningiomas, 6 other primary tumors, 3 metastases, and 4 reactive brain tissue). A neuropathologist classified CLE images as interpretable or noninterpretable. Images were compared with corresponding frozen and permanent histology sections, with image correlation to biopsy location using neuronavigation. The specificities and sensitivities of CLE images and frozen sections were calculated using permanent histological sections as the standard for comparison. A recently developed surgical telepathology software platform was used in 11 cases to provide real-time intraoperative consultation with a neuropathologist.

RESULTS Overall, 10,713 CLE images from 335 regions of interest were acquired. The mean duration of the use of the CLE system was 7 minutes (range 3–18 minutes). Interpretable CLE images were obtained in all cases. The first interpretable image was acquired within a mean of 6 (SD 10) images and within the first 5 (SD 13) seconds of imaging; 4896 images (46%) were interpretable. Interpretable image acquisition was positively correlated with study progression, number of cases per surgeon, cumulative length of CLE time, and CLE time per case (p ≤ 0.01). The diagnostic accuracy, sensitivity, and specificity of CLE compared with frozen sections were 94%, 94%, and 100%, respectively, and the diagnostic accuracy, sensitivity, and specificity of CLE compared with permanent histological sections were 92%, 90%, and 94%, respectively. No difference was observed between lesion types for the time to first interpretable image (p = 0.35). Deeply located lesions were associated with a higher percentage of interpretable images than superficial lesions (p = 0.02). The study met the primary end points, confirming the safety and feasibility and acquisition of noninvasive digital biopsies in all cases. The study met the secondary end points for the duration of CLE use necessary to obtain interpretable images. A neuropathologist could interpret the CLE images in 29 (97%) of 30 cases.

CONCLUSIONS The clinical-grade CLE system allows in vivo, intraoperative, high-resolution cellular visualization of tissue microstructure and identification of lesional tissue patterns in real time, without the need for tissue preparation.

Pineal cyst: results of long-term MRI surveillance and analysis of growth and shrinkage rates

J Neurosurg 138:113–119, 2023

OBJECTIVE Pineal cyst (PC) is a relatively common true cyst in the pineal gland. Its long-term natural course remains ill defined. This study aims to evaluate the long-term natural history of PC and examine MRI risk factors for cyst growth and shrinkage to help better define which patients might benefit from surgical intervention.

METHODS The records and MRI of 409 consecutive patients with PC were retrospectively examined (nonsurgical cohort). Cyst growth and shrinkage were defined as a ≥ 2-mm increase and decrease in cyst diameter in any direction, respectively. In addition to size, MRI signal intensity ratios were analyzed.

RESULTS The median radiological follow-up period was 10.7 years (interquartile range [IQR] 6.4–14.3 years). The median change in maximal diameter was −0.6 mm (IQR −1.5 to 1.3 mm). During the observation period, cyst growth was confirmed in 21 patients (5.1%). Multivariate logistic regression analysis revealed that only age (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.93–0.99, p < 0.01) was significantly associated with cyst growth. No patient required resection during the observation period. Cyst shrinkage was confirmed in 57 patients (13.9%). Multivariate analysis revealed that maximal diameter (OR 1.22, 95% CI 1.12–1.35, p < 0.01) and cyst CSF T2 signal intensity ratio (OR 9.06, 95% CI 1.38–6.62 × 101, p = 0.02) were significantly associated with cyst shrinkage.

CONCLUSIONS Only 5% of PCs, mainly in patients younger than 50 years of age, have the potential to grow, while cyst shrinkage is more likely to occur across all age groups. Younger age is associated with cyst growth, while larger diameter and higher signal intensity on T2-weighted imaging are associated with shrinkage. Surgery is rarely needed for PCs, despite the possibility of a certain degree of growth.

Natural history of meningiomas: a serial volumetric analysis of 240 tumors

J Neurosurg 137:1639–1649, 2022

The management of asymptomatic intracranial meningiomas is controversial. Through the assessment of growth predictors, the authors aimed to create the basis for practicable clinical pathways for the management of these tumors.

METHODS The authors volumetrically analyzed meningiomas radiologically diagnosed at their institution between 2003 and 2015. The primary endpoint was growth of tumor volume. The authors used significant variables from the multivariable regression model to construct a decision tree based on the exhaustive Chi-Square Automatic Interaction Detection (CHAID) algorithm.

RESULTS Of 240 meningiomas, 159 (66.3%) demonstrated growth during a mean observation period of 46.9 months. On multivariable logistic regression analysis, older age (OR 0.979 [95% CI 0.958–1.000], p = 0.048) and presence of calcification (OR 0.442 [95% CI 0.224–0.872], p = 0.019) had a negative predictive value for tumor growth, while T2-signal iso-/hyperintensity (OR 4.415 [95% CI 2.056–9.479], p < 0.001) had a positive predictive value. A decision tree model yielded three growth risk groups based on T2 signal intensity and presence of calcifications. The median tumor volume doubling time (Td) was 185.7 months in the low-risk, 100.1 months in the intermediate-risk, and 51.7 months in the highrisk group (p < 0.001). Whereas 0% of meningiomas in the low- and intermediate-risk groups had a Td of ≤ 12 months, the percentage was 8.9% in the high-risk group (p = 0.021).

CONCLUSIONS Most meningiomas demonstrated growth during follow-up. The absence of calcifications and iso-/ hyperintensity on T2-weighted imaging offer a practical way of stratifying meningiomas as low, intermediate, or high risk. Small tumors in the low- or intermediate-risk categories can be monitored with longer follow-up intervals.

Adult diffuse intrinsic pontine glioma: clinical, radiological, pathological, molecular features, and treatments of 96 patients

J Neurosurg 137:1628–1638, 2022

Unlike its pediatric counterpart, adult diffuse intrinsic pontine glioma (DIPG) remains largely unelucidated. In this study, the authors examined the clinical, radiological, pathological, molecular, and clinical aspects of 96 adult DIPGs.

METHODS The National Brain Tumor Registry of China (April 2013–December 2019) was used to collect data on radiologically diagnosed adult DIPG patients. Survival analysis was conducted using Kaplan-Meier curves and univariate and multivariate Cox regression. The chi-square test/Wilcoxon rank-sum test and multivariable logistic regression were used to examine the clinical and radiological characteristics of patients with long-term survival (LTS). Interaction analyses between clinical factors were also conducted.

RESULTS The median age at symptom onset was 33.5 years, and the median duration of symptoms was 4.5 months. The frequencies of H3K27M and IDH1 mutations were 37.2% and 26.5%, respectively. All adult DIPG patients had a median overall survival (OS) of 19.5 months, with 1-, 2-, and 3-year survival rates of 67.0%, 42.8%, and 36.0%, respectively. The median OS of 40 patients who did not undergo treatment was 13.4 months. Patients with H3K27M-mutant tumors had a poorer prognosis than those with IDH-mutant tumors (p < 0.001) and H3K27M(−)/IDH–wild-type tumors (p = 0.002), with a median OS of 11.4 months. The median OSs of patients with H3K27M-mutant tumors who received treatment and those who did not were 13.8 months and 7.5 months, respectively (p = 0.016). Among patients with and without a pathological diagnosis, H3K27M mutation (p < 0.001) and contrast enhancement on MRI (p = 0.003), respectively, imparted a worse prognosis. Treatments were the predictive factor for patients with H3K27M-mutant tumors (p = 0.038), whereas contrast enhancement on MRI was the prognostic factor for the H3K27M(−) group (p = 0.038). In addition, H3K27M mutation and treatment were significant predictors for patients with symptom duration ≤ 4 months (H3K27M, p = 0.020; treatment, p = 0.014) and tumors with no contrast enhancement (H3K27M, p = 0.003; treatment, p = 0.042). Patients with LTS were less likely to have cranial nerve palsy (p = 0.002) and contrast enhancement on MRI at diagnosis (p = 0.022).

CONCLUSIONS It is recommended that all adult DIPG patients undergo genomic testing for H3K27M and IDH mutations. Despite the low prevalence, additional study is needed to better characterize the efficacy of various treatment modalities in adults with DIPG.