#### Journal of Neurosurgery

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ISSN / EISSN : 0022-3085 / 1933-0693
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Shameer Aslam, Natesan Damodaran, Ramiah Rajeshkannan, Manjit Sarma, Siby Gopinath,
Published: 1 August 2022
Journal of Neurosurgery, Volume -1, pp 1-9; https://doi.org/10.3171/2022.6.jns22717

Abstract:
OBJECTIVE: Positron emission tomography (PET) imaging has assumed an essential role in the presurgical evaluation of epileptogenic foci in drug-resistant epilepsy by identifying the hypometabolic cerebral cortex. The authors herein designed a pilot study to test a novel technique of PET asymmetry after anatomical symmetrization coregistered to MRI (PASCOM), utilizing interhemispheric metabolic asymmetry on interictal fluorine 18–labeled fluorodeoxyglucose (FDG)-PET to better localize the epileptogenic zone. METHODS: The authors analyzed interictal FDG-PET scans from 23 patients with drug-resistant epilepsy, mean (± SD) age 20.9 ± 13.1 years old, who had an Engel class I postsurgical outcome while followed up for > 12 months. T1-weighted and FLAIR MRI were used to create a patient-specific, structurally symmetrical template. The asymmetry index (AI) image was computed to detect the cerebral region of hypometabolism using different z-score threshold criteria to optimize sensitivity and specificity. The detected regions were compared with the resection cavity on postoperative MRI using predefined anatomical labels. PASCOM was compared with the visual analysis of FDG-PET by a nuclear medicine consultant blinded to other clinical data (VIS) and visual analysis during multidisciplinary team discussion (MDT). The efficacy of each technique was compared based on a performance score (S), sensitivity, specificity, and correct lateralization of epileptogenicity. RESULTS: The mean S was maximum (1.30 ± 1.23) for AI images when thresholded at z > 4 and retaining the cluster of more than 100 voxels containing the peak AI value (Z4C) with 73.03% sensitivity and 96.43% specificity. The mean S was minimum for VIS (0.27 ± 0.31). The mean sensitivity was maximum for MDT (85.04%) and minimum for Z5C (AI images thresholded at z > 5 and clustered; 59.47%), whereas the mean specificity was maximum for Z5C (97.77%) and minimum for VIS (64.60%). Z3C (AI images thresholded at z > 3 and clustered) and Z4C were able to correctly identify the side of epileptogenicity in all the patients. CONCLUSIONS: The PASCOM technique with a Z4C threshold had a maximum performance score with good sensitivity and specificity in localizing and lateralizing the epileptogenic zone. The described technique outperformed the conventional visual analysis of FDG-PET and hence warrants further prospective verification.
, Henrik Giese, Julius Höhne, Karl Michael Schebesch, Christian Henker, Andreas Strauss, Kerim Beseoglu, Niklas von Spreckelsen, Jürgen A. Hampl, Jan Walter, et al.
Published: 1 August 2022
Journal of Neurosurgery, Volume 137, pp 591-598; https://doi.org/10.3171/2021.9.jns211549

Abstract:
OBJECTIVE: Cranioplasty (CP) is a crucial procedure after decompressive craniectomy and has a significant impact on neurological improvement. Although CP is considered a standard neurosurgical procedure, inconsistent data on surgery-related complications after CP are available. To address this topic, the authors analyzed 502 patients in a prospective multicenter database (German Cranial Reconstruction Registry) with regard to early surgery-related complications. METHODS: Early complications within 30 days, medical history, mortality rates, and neurological outcome at discharge according to the modified Rankin Scale (mRS) were evaluated. The primary endpoint was death or surgical revision within the first 30 days after CP. Independent factors for the occurrence of complications with or without surgical revision were identified using a logistic regression model. RESULTS: Traumatic brain injury (TBI) and ischemic stroke were the most common underlying diagnoses that required CP. In 230 patients (45.8%), an autologous bone flap was utilized for CP; the most common engineered materials were titanium (80 patients [15.9%]), polyetheretherketone (57 [11.4%]), and polymethylmethacrylate (57 [11.4%]). Surgical revision was necessary in 45 patients (9.0%), and the overall mortality rate was 0.8% (4 patients). The cause of death was related to ischemia in 2 patients, diffuse intraparenchymal hemorrhage in 1 patient, and cardiac complications in 1 patient. The most frequent causes of surgical revision were epidural hematoma (40.0% of all revisions), new hydrocephalus (22.0%), and subdural hematoma (13.3%). Preoperatively increased mRS score (OR 1.46, 95% CI 1.08–1.97, p = 0.014) and American Society of Anesthesiologists Physical Status Classification System score (OR 2.89, 95% CI 1.42–5.89, p = 0.003) were independent predictors of surgical revision. Ischemic stroke, as the underlying diagnosis, was associated with a minor rate of revisions compared with TBI (OR 0.18, 95% CI 0.06–0.57, p = 0.004). CONCLUSIONS: The authors have presented class II evidence–based data on surgery-related complications after CP and have identified specific preexisting risk factors. These results may provide additional guidance for optimized treatment of these patients.
, Toshiki Endo, Toshitaka Seki, Tomoo Inoue, Izumi Koyanagi, Takafumi Mitsuhara, Keisuke Ito, Motoyuki Iwasaki, Hisaaki Uchikado, Daisuke Umebayashi, et al.
Published: 1 August 2022
Journal of Neurosurgery, Volume 137, pp 373-380; https://doi.org/10.3171/2021.10.jns212205

Abstract:
OBJECTIVE: Craniocervical junction (CCJ) arteriovenous fistulas (AVFs) are treated using neurosurgical or endovascular options; however, there is still no consensus on the safest and most effective treatment. The present study compared the treatment results of neurosurgical and endovascular procedures for CCJ AVFs, specifically regarding retreatment, complications, and outcomes. METHODS: This was a multicenter cohort study authorized by the Neurospinal Society of Japan. Data on consecutive patients with CCJ AVFs who underwent neurosurgical or endovascular treatment between 2009 and 2019 at 29 centers were analyzed. The primary endpoint was the retreatment rate by procedure. Secondary endpoints were the overall complication rate, the ischemic complication rate, the mortality rate, posttreatment changes in the neurological status, independent risk factors for retreatment, and poor outcomes. RESULTS: Ninety-seven patients underwent neurosurgical (78 patients) or endovascular (19 patients) treatment. Retreatment rates were 2.6% (2/78 patients) in the neurosurgery group and 63% (12/19 patients) in the endovascular group (p < 0.001). Overall complication rates were 22% and 42% in the neurosurgery and endovascular groups, respectively (p = 0.084). Ischemic complication rates were 7.7% and 26% in the neurosurgery and endovascular groups, respectively (p = 0.037). Ischemic complications included 8 spinal infarctions, 2 brainstem infarctions, and 1 cerebellar infarction, which resulted in permanent neurological deficits. Mortality rates were 2.6% and 0% in the neurosurgery and endovascular groups, respectively (p > 0.99). Two patients died of systemic complications. The percentages of patients with improved modified Rankin Scale (mRS) scores were 60% and 37% in the neurosurgery and endovascular groups, respectively, with a median follow-up of 23 months (p = 0.043). Multivariate analysis identified endovascular treatment as an independent risk factor associated with retreatment (OR 54, 95% CI 9.9–300; p < 0.001). Independent risk factors associated with poor outcomes (a postoperative mRS score of 3 or greater) were a pretreatment mRS score of 3 or greater (OR 13, 95% CI 2.7–62; p = 0.001) and complications (OR 5.8; 95% CI 1.3–26; p = 0.020). CONCLUSIONS: Neurosurgical treatment was more effective and safer than endovascular treatment for patients with CCJ AVFs because of lower retreatment and ischemic complication rates and better outcomes.
Yi Wang, Maki Sakaguchi, Hemragul Sabit, Sho Tamai, Toshiya Ichinose, Shingo Tanaka, Masashi Kinoshita, Yasuo Uchida, Sumio Ohtsuki,
Published: 1 August 2022
Journal of Neurosurgery, Volume -1, pp 1-10; https://doi.org/10.3171/2022.6.jns22319

Abstract:
OBJECTIVE: An extracellular matrix such as collagen is an essential component of the tumor microenvironment. Collagen alpha-2(I) chain (COL1A2) is a chain of type I collagen whose triple helix comprises two alpha-1 chains and one alpha-2 chain. The authors’ proteomics data showed that COL1A2 is significantly higher in the blood of patients with glioblastoma (GBM) compared with healthy controls. COL1A2 has many different functions in various types of cancers. However, the functions of COL1A2 in GBM are poorly understood. In this study, the authors analyzed the functions of COL1A2 and its signaling pathways in GBM. METHODS: Surgical specimens and GBM cell lines (T98, U87, and U251) were used. The expression level of COL1A2 was examined using GBM tissues and normal brain tissues by quantitative real-time polymerase chain reaction. The clinical significance of these levels was evaluated using Kaplan-Meier analysis. Small interfering RNA (siRNA) and small hairpin RNA of COL1A2 were transfected into GBM cell lines to investigate the function of COL1A2 in vitro and in vivo. Flow cytometry was introduced to analyze the alteration of cell cycles. Western blot and immunohistochemistry were performed to analyze the underlying mechanisms. RESULTS: The expression level of COL1A2 was upregulated in GBM compared with normal brain tissues. A higher expression of COL1A2 was correlated with poor progression-free survival and overall survival. COL1A2 inhibition significantly suppressed cell proliferation in vitro and in vivo, likely due to G1 arrest. The invasion ability was notably deteriorated by inhibiting COL1A2. Cyclin D1, cyclin-dependent kinase 1, and cyclin-dependent kinase 4, which are involved in the cell cycle, were all downregulated after blockade of COL1A2 in vitro and in vivo. Phosphoinositide 3-kinase inhibitor reduced the expression of COL1A2. Although downregulation of COL1A2 decreased the protein kinase B (Akt) phosphorylation, Akt activator can phosphorylate Akt in siRNA-treated cells. This finding suggests that Akt phosphorylation is partially dependent on COL1A2. CONCLUSIONS: COL1A2 plays an important role in driving GBM progression. COL1A2 inhibition attenuated GBM proliferation by promoting cell cycle arrest, indicating that COL1A2 could be a promising therapeutic target for GBM treatment.
Heidi McAlpine,
Published: 1 August 2022
Journal of Neurosurgery, Volume -1, pp 1-2; https://doi.org/10.3171/2022.5.jns22769

Kathleen M. Mulligan, Tarun K. Jella, Thomas B. Cwalina, Eve C. Tsai, Ann M. Parr, Sarah I. Woodrow, James M. Wright, Christina H. Wright
Published: 1 August 2022
Journal of Neurosurgery, Volume -1, pp 1-10; https://doi.org/10.3171/2022.4.jns212968

Abstract:
OBJECTIVE: Despite incremental progress in the representation and proportion of women in the field of neurosurgery, female neurosurgeons still represent an overwhelming minority of the current US physician workforce. Prior research has predicted the timeline by which the proportion of female neurosurgery residents may reach that of males, but none have used the contemporary data involving the entire US neurosurgical workforce. METHODS: The authors performed a retrospective analysis of the National Plan and Provider Enumeration System (NPPES) registry of all US neurosurgeons to determine changes in the proportions of women in neurosurgery across states, census divisions, and census regions between 2010 and 2020. A univariate linear regression was performed to assess historical growth, and then Holt-Winter forecasting was used to predict in what future year gender parity may be reached in this field. RESULTS: A majority of states, divisions, and regions have increased the proportion of female neurosurgeons from 2010. Given current growth rates, the authors found that female neurosurgeons will not reach the proportion of women in the overall medical workforce until 2177 (95% CI 2169–2186). Furthermore, they found that women in neurosurgery will not match their current proportion of the overall US population until 2267 (95% CI 2256–2279). CONCLUSIONS: Whereas many studies have focused on the overall increase of women in neurosurgery in the last decade, this one is the first to compare this growth in the context of the overall female physician workforce and the female US population. The results suggest a longer timeline for gender parity in neurosurgery than previous studies have suggested and should further catalyze the targeted recruitment of women into the field, an overhaul of current policies in place to support and develop the careers of women in neurosurgery, and increased self-reflection and behavioral change from the entire neurosurgery community.
Eric Suero Molina, Sönke J. Hellwig, Anna Walke, Astrid Jeibmann, Herbert Stepp,
Published: 1 August 2022
Journal of Neurosurgery, Volume 137, pp 582-590; https://doi.org/10.3171/2021.10.jns211911

Abstract:
OBJECTIVE: Fluorescence-guided resections performed using 5-aminolevulinic acid (5-ALA) have been studied extensively using the BLUE400 system. The authors introduce a triple–light-emitting diode (LED) headlight/loupe device for visualizing fluorescence, and compare this to the BLUE400 gold standard in order to assure similar and not more or less sensitive protoporphyrin-IX visualization. METHODS: The authors defined the spectral requirements for a triple-LED headlight/loupe device for reproducing the xenon-based BLUE400 module. The system consisted of a white LED (normal surgery), a 409-nm LED for excitation, a 450-nm LED for background illumination, and appropriate observation filters. The prototype’s excitation and emission spectra, illumination and detection intensities, and spot homogeneity were determined. The authors further performed a prospectively randomized and blinded study for fluorescence assessments of fresh, marginal, fluorescing and nonfluorescing tumor samples comparing the LED/loupe device with BLUE400 in patients with malignant glioma treated with 20 mg/kg body weight 5-ALA. Tumor samples were immediately assessed in turn, both with a Kinevo and with a novel triple-LED/loupe device by different surgeons. RESULTS: Seven triple-LED/loupe devices were analyzed. Illumination intensities in the 409- and 450-nm range were comparable to BLUE400, with high spot homogeneity. Fluorescence intensities measured distally to microscope oculars/loupes were 9.9-fold higher with the loupe device. For validation 26 patients with malignant gliomas with 240 biopsies were analyzed. With BLUE400 results as the reference, sensitivity for reproducing fluorescence findings was 100%, specificity was 95%, positive predictive value was 98%, negative predictive value was 100%, and accuracy was 95%. This study reached its primary aim, with agreement in 226 of 240 (94.2%, 95% CI 0.904–0.968). CONCLUSIONS: The authors observed only minor differences regarding spectra and illumination intensities during evaluation. Fluorescence intensities available to surgeons were 9.9-fold higher with the loupe device. Importantly, the independent perception of fluorescence achieved using the new system and BLUE400 was statistically equivalent. The authors believe the triple-LED/loupe device to be a useful and safe option for surgeons who prefer loupes to the microscope for resections in appropriate patients.
Runting Li, Fa Lin, Yu Chen, Junlin Lu, Heze Han, Debin Yan, Ruinan Li, Jun Yang, Zhipeng Li, Haibin Zhang, et al.
Published: 1 August 2022
Journal of Neurosurgery, Volume 137, pp 381-392; https://doi.org/10.3171/2021.10.jns211484

Abstract:
OBJECTIVE: More than 10 years have passed since the two best-known clinical trials of ruptured aneurysms (International Subarachnoid Aneurysm Trial [ISAT] and Barrow Ruptured Aneurysm Trial [BRAT]) indicated that endovascular coiling (EC) was superior to surgical clipping (SC). However, in recent years, the development of surgical techniques has greatly improved; thus, it is necessary to reanalyze the impact of the differences in treatment modalities on the prognosis of patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The authors retrospectively reviewed all aSAH patients admitted to their institution between January 2015 and December 2020. The functional outcomes at discharge and 90 days after discharge were assessed using the modified Rankin Scale (mRS). In-hospital complications, hospital charges, and risk factors derived from multivariate logistic regression were analyzed in the SC and EC groups after 1:1 propensity score matching (PSM). The area under the receiver operating characteristic curve was used to calculate each independent predictor’s prediction ability between treatment groups. RESULTS: A total of 844 aSAH patients were included. After PSM to control for sex, aneurysm location, Hunt and Hess grade, World Federation of Neurosurgical Societies (WFNS) grade, modified Fisher Scale grade, and current smoking and alcohol abuse status, 329 patients who underwent SC were compared with 329 patients who underwent EC. Patients who underwent SC had higher incidences of unfavorable discharge and 90-day outcomes (46.5% vs 33.1%, p < 0.001; and 19.6% vs 13.8%, p = 0.046, respectively), delayed cerebral ischemia (DCI) (31.3% vs 20.1%, p = 0.001), intracranial infection (20.1% vs 1.2%, p < 0.001), anemia (42.2% vs 17.6%, p < 0.001), hypoproteinemia (46.2% vs 21.6%, p < 0.001), and pneumonia (33.4% vs 24.9%, p = 0.016); but a lower incidence of urinary tract infection (1.2% vs 5.2%, p = 0.004) and lower median hospital charges ($12,285 [IQR$10,399–$15,569] vs$23,656 [IQR $18,816–$30,025], p < 0.001). A positive correlation between the number of in-hospital complications and total hospital charges was indicated in the SC (r = 0.498, p < 0.001) and EC (r = 0.411, p < 0.001) groups. The occurrence of pneumonia and DCI, WFNS grade IV or V, and age were common independent risk factors for unfavorable outcomes at discharge and 90 days after discharge in both treatment modalities. CONCLUSIONS: EC shows advantages in discharge and 90-day outcomes, in-hospital complications, and the number of risk factors but increases the economic cost on patients during their hospital stay. Severe in-hospital complications such as pneumonia and DCI may have a long-lasting impact on the prognosis of patients.
Ching-Jen Chen, Nisha Dabhi, M. Harrison Snyder, Natasha Ironside, Isaac Josh Abecassis, Ryan T. Kellogg, Min S. Park, Dale Ding
Published: 1 August 2022
Journal of Neurosurgery, Volume 137, pp 360-372; https://doi.org/10.3171/2021.9.jns211706

Abstract:
OBJECTIVE: The long-term safety and efficacy of intrasaccular flow disruption (IFD) for the treatment of brain aneurysms remain unclear. With accumulating experience and increasing use of IFD devices, recent studies have provided additional data regarding their outcomes. This review summarizes the long-term outcomes of IFD-treated brain aneurysms. METHODS: A systematic literature review was performed on May 23, 2021, in PubMed, Web of Science, and Ovid MEDLINE for aneurysm treatment outcomes with IFD devices. Procedural details, including use of adjunctive devices and complications, were collected. The quality of studies was assessed using the Downs and Black checklist. Angiographic outcomes were classified as complete occlusion, residual neck, and residual aneurysm. Other outcomes included need for retreatment, permanent neurological deficit, and mortality. Pooled analyses were performed. RESULTS: The final analysis comprised 1217 patients with 1249 aneurysms from 22 studies. The mean aneurysm diameter and neck width were 6.9 and 4.5 mm, respectively, and 27.6% of aneurysms were ruptured. The complete occlusion rates at 12 months and final follow-up (pooled mean duration 15.7 months) were 50.1% and 58.2%, respectively. Adjunctive devices were used in 6.4% of cases. The rates of hemorrhage, symptomatic infarction, permanent neurological deficit, and mortality were 1.2%, 2.8%, 1.0%, and 2.6%, respectively. CONCLUSIONS: IFD is a very safe treatment for appropriately selected brain aneurysms with low complication and neurological deterioration rates. However, complete occlusion is achieved in only half of IFD-treated aneurysms at 1 year with a modest increase beyond this time point. As the majority of the studies were single arm, the pooled data are subject to selection and reporting biases. Future device developments, increased operator experience, and direct comparisons with alternative endovascular strategies and surgical clipping may clarify the role of IFD in aneurysm management.
, Jason Gurewitz, Ami Kavi, Kenneth Bernstein, Joshua Silverman, Monica Mureb, Bernadine Donahue, Douglas Kondziolka
Published: 1 August 2022
Journal of Neurosurgery, Volume 137, pp 571-581; https://doi.org/10.3171/2021.9.jns21882

Abstract:
OBJECTIVE: In the era in which more patients with greater numbers of brain metastases (BMs) are being treated with stereotactic radiosurgery (SRS) alone, it is critical to understand how patient, tumor, and treatment factors affect functional status and overall survival (OS). The authors examined the survival outcomes and dosimetry to critical structures in patients treated with Gamma Knife radiosurgery (GKRS) for ≥ 25 metastases in a single session or cumulatively over the course of their disease. METHODS: A retrospective analysis was conducted at a single institution. The institution’s prospective Gamma Knife (GK) SRS registry was queried to identify patients treated with GKRS for ≥ 25 cumulative BMs between June 2013 and April 2020. Ninety-five patients were identified, and their data were used for analysis. Treatment plans for dosimetric analysis were available for 89 patients. Patient, tumor, and treatment characteristics were identified, and outcomes and OS were evaluated. RESULTS: The authors identified 1132 patients with BMs in their institutional registry. Ninety-five patients were treated for ≥ 25 cumulative metastases, resulting in a total of 3596 tumors treated during 373 separate treatment sessions. The median number of SRS sessions per patient was 3 (range 1–12 SRS sessions), with nearly all patients (n = 93, 98%) having > 1 session. On univariate analysis, factors affecting OS in a statistically significant manner included histology, tumor volume, tumor number, diagnosis-specific graded prognostic assessment (DS-GPA), brain metastasis velocity (BMV), and need for subsequent whole-brain radiation therapy (WBRT). The median of the mean WB dose was 4.07 Gy (range 1.39–10.15 Gy). In the top quartile for both the highest cumulative number and highest cumulative volume of treated metastases, the median of the mean WB dose was 6.14 Gy (range 4.02–10.15 Gy). Seventy-nine patients (83%) had all treated tumors controlled at last follow-up, reflecting the high and durable control rate. Corticosteroids for tumor- or treatment-related effects were prescribed in just over one-quarter of the patients. Of the patients with radiographically proven adverse radiation effects (AREs; 15%), 4 were symptomatic. Four patients required subsequent craniotomy for hemorrhage, progression, or AREs. CONCLUSIONS: In selected patients with a large number of cumulative BMs, multiple courses of SRS are feasible and safe. Together with new systemic therapies, the study results demonstrate that the achieved survival rates compare favorably to those of larger contemporary cohorts, while avoiding WBRT in the majority of patients. Therefore, along with the findings of other series, this study supports SRS as a standard practice in selected patients with larger numbers of BMs.