Perry, Avital

Abstract Objective Vestibular schwannoma (VS) treated with Gamma Knife stereotactic radiosurgery (SRS) was typically performed at 50% isodose line (IDL50); however, the impact of IDL variation on outcomes is poorly understood. This study aimed to compare tumor control (TC) and toxicities between treatment at 40% (IDL40) and 50% (IDL50). Methods Sporadic/unilateral VS patients treated with SRS dose 12 to 14 Gy and prescription isodose volume ≤10cm3 were included. Propensity score matching was applied to IDL40 cohort to generate an IDL50 companion cohort, adjusting for age and prescription isodose volume. After exclusion of patients with follow-up <24 months, there were 30 and 28 patients in IDL40 and IDL50 cohorts, respectively. Results Median follow-up time was 96 months (24–225 months). Actuarial and radiographic TC rates were 91.8% and clinical TC was 96.2% both at 5 and 10 years. TC was higher in IDL40 cohort but not significant (96.4 vs. 86.7%; p = 0.243). Hearing preservation (HP) rates were 71.9 and 39.2% at 5- and 10-year intervals, with significantly higher rates of HP noted in IDL40 cohort (83.3 vs. 57.1% at 5-year interval; 62.5 vs. 11.4% at 10-year interval; p = 0.017). Permanent facial neuropathy occurred in two patients, both from the IDL50 cohort (3.5%). Rates of post-SRS steroid treatment or shunt placement for hydrocephalus were slightly higher in IDL50 patients (6.9 vs. 17.9%; p = 0.208 and 3.3 vs. 7.1%; p = 0.532). Conclusion For treatment of VS with SRS, dose prescription at IDL40 or IDL50 provides excellent long-term TC and toxicity profiles. IDL40 may be associated with improved long-term HP.

Abstract BACKGROUND The lateral craniopharyngeal or Sternberg's canal (SC) originates from superior orbital fissure (SOF) and traverses the sphenoid body into the nasopharynx. A remnant of the canal, Sternberg's defect (SD), has been debated as a source of cerebrospinal fluid (CSF) leak. The canal was described in 1888, and there is limited accurate visual illustration in the literature. OBJECTIVE To provide a detailed anatomic and radiological illustration of the canal in pediatric and adult population including the mechanism undermining the incidence of the canal, and the possibility of the canal as a source of CSF leak. METHODS A total of 195 high-resolution computed tomographies (CT) of patients (50 3-yr-old, 20 5-yr-old, and 125 adults) and 43 dry adult skulls (86 sides) were analyzed for a canal matching the description of the SC. RESULTS A SC was identified in 86% of the 3-yr-old and 40% of 5-yr–old patients. The diameter and length were 2.12 mm and 12 mm, respectively. The incidence of the canal decreased with age as sinus pneumatization extended into the sphenoid sinus. Only 0.8% of the adult skull on CT had the canal. The canal was not present on the dry adult skulls examination, but SD was found in 4.65%. CONCLUSION SC exists with high incidence in the pediatric group. Sinus pneumatization obliterates the canal in the adult population, leaving a defect in 4.65% of cases, which given the location and related anatomic structures, is unlikely to be a source of CSF leak.

Abstract BACKGROUND Hypopituitarism is the most frequent complication after pituitary adenoma stereotactic radiosurgery (SRS) and is correlated with increasing radiation to the pituitary gland. Biological effective dose (BED) is a dosimetric parameter that incorporates a time component to adjust for mechanisms of deoxyribonucleic acid repair activated during treatment. OBJECTIVE To assess mean gland BED as a predictor of post-SRS hypopituitarism, as compared to mean gland dose, in a contemporary cohort study of patients undergoing single-fraction SRS for pituitary adenoma. METHODS Cohort study of 97 patients undergoing single-fraction SRS from 2007 to 2014. Eligible patients had no prior pituitary irradiation, normal pre-SRS endocrine function, and >24 mo of endocrine follow-up. Cox proportional hazards analysis was used to assess mean gland dose and BED as predictors of new post-SRS hypopituitarism. RESULTS Median post-SRS follow-up was 48 mo (interquartile range [IQR], 34-68). A total of 27 patients (28%) developed new hypopituitarism at a median 22 mo (IQR, 12-36). Actuarial rates of new endocrinopathy were 17% at 2 yr (95% CI 10%-25%) and 31% at 5 yr (95% CI 20%-42%). On univariate analysis, sex ( P = .02), gland volume ( P = .03), mean gland dose ( P < .0001), and BED significantly predicted new hypopituitarism ( P < .0001). After adjusting for sex and gland volume, BED > 45 Gy 2.47 and mean gland dose > 10 Gy were significantly associated increased risk of hypopituitarism (hazard ratio [HR] = 14.32, 95% CI = 4.26-89.0, P < .0001; HR = 11.91, 95% CI = 3.54-74.0, P < .0001). CONCLUSION BED predicted hypopituitarism more reliably than mean gland dose after pituitary adenoma SRS, but additional studies are needed to confirm these results.

Abstract Background The far-lateral approach is an effective skull base technique that provides access to the lower clivus and premedullary area. This approach is also useful for maximal visualization and resection of large posterior fossa tumors with extensive medial extension, especially when aggressive resection is ideal for a malignant tumor in a young patient, or it is technically challenging because of tumor calcification. We demonstrate a microsurgical operative video to describe technical pearls in this difficult situation. Case Presentation A 45-year-old man with history of “hoarseness” for up to two decades was presented with imbalance and mild dysphagia over 3 years. Imaging demonstrated a 55-mm left cerebellopontine angle (CPA) tumor extending medially across the midline with severe calcification (Figs. 1 and 2). His neurological examination revealed left facial numbness, complete left facial weakness, left deafness, complete left vocal paralysis, as well as severe left hemibody ataxia. The tumor was resected via a left suboccipital craniotomy with far lateral approach including drilling to the occipital condyle and C1 laminectomy. Initial manipulation of the inferior pole of the tumor resulted in asystole which was managed successfully with glycol pyrolate. Pathology demonstrated IDH-1 wild type, MGMT-methylated glioblastoma. The patient subsequently underwent adjuvant chemoradiation. Conclusion The far-lateral approach is an effective approach for maximal safe resection of a malignant brainstem, cerebellar, and CPA tumor.The link to the video can be found at: https://youtu.be/AIGebJPJEnw.

OBJECTIVE Intracranial facial nerve schwannomas (FNS) requiring treatment are frequently recommended for surgery or stereotactic radiosurgery (SRS). The objective of this study was to compare facial nerve function outcomes between these two interventions for FNS via a systematic review and meta-analysis. METHODS A search of the Ovid EMBASE, PubMed, SCOPUS, and Cochrane databases from inception to July 2019 was conducted following PRISMA guidelines. Articles were screened against prespecified criteria. Facial nerve outcomes were classified as improved, stabilized, or worsened by last follow-up. Incidence was pooled by random-effects meta-analysis of proportions. RESULTS Thirty-three articles with a pooled cohort of 519 patients with FNS satisfied all criteria. Twenty-five articles described operative outcomes in 407 (78%) patients; 10 articles reported SRS outcomes in 112 (22%). In the surgical cohort, facial nerve function improved in 23% (95% CI 15%–32%), stabilized in 41% (95% CI 32%–50%), and worsened in 30% (95% CI 21%–40%). In the SRS cohort, facial nerve function was improved in 20% (95% CI 9%–34%), stable in 66% (95% CI 54%–78%), and worsened in 9% (95% CI 3%–16%). Compared with SRS, microsurgery was associated with a significantly lower incidence of stable facial nerve function (p < 0.01) and a significantly higher incidence of worsened facial nerve function (p < 0.01). Tumor progression and complication rates were comparable. Outcome certainty assessments were very low to moderate for all parameters. CONCLUSIONS Unfavorable facial nerve function outcomes are associated with surgical treatment of intracranial FNS, whereas stable facial nerve function outcomes are associated with SRS. Therefore, SRS should be recommended to patients with FNS who require treatment, and surgery should be reserved for patients with another indication, such as decompression of the brainstem. Further study is required to definitively optimize and validate management strategies for these rare skull base tumors.

Abstract BACKGROUND Central nervous system (CNS) germ cell tumors (GCT) are rare and complex pediatric neoplasms, the optimal management of which remains an area of active investigation. OBJECTIVE To present an updated cohort study, with particular attention to novel diagnostic methods and posttreatment clinical phenotypes. METHODS A single-institution cohort study of 80 primary, neurosurgically managed, CNS GCTs was conducted at Mayo Clinic, 1988-2017. RESULTS Postchemotherapy resection (eg, second-look surgery) was frequently required (27.0%), especially after adjuvant therapies for nongerminomatous GCTs (NGGCTs; 14 of 28 cases, excluding mature teratoma) and significantly associated with pineal lesions, as compared to neurohypophyseal or bifocal lesions (43.6% vs 5.9% vs 6.7%, P = .004), a finding that retained statistical significance after adjusting for index extent of resection and histology ( P = .04). Essentially every NGGCT case underwent at least 1 craniotomy, either on presentation, as second-look surgery, or following local recurrence. Mature teratomatous tissue was highly incident in second-look specimens (84.2%), even among lesions initially diagnosed as germinomas. Pretreatment cerebrospinal fluid (CSF) cell fraction analysis demonstrated an association between single lesions and neutrophil predominance, whereas nongerminomatous GCTs were associated with increased monocyte fractions. CONCLUSION CNS GCTs are clinically heterogeneous lesions, resulting in numerous opportunities for improved understanding and clinical management via novel diagnostic and therapeutic protocols. Samples from second-look surgeries for recurrent germinomas frequently demonstrate teratomatous tissue, suggesting possible underdiagnosis of mixed GCTs—particularly among pineal lesions. GCT subtypes demonstrate differential cell fraction distributions on CSF analysis, a novel and perhaps diagnostically helpful finding that requires validation in external cohorts.

1502 Background: High-grade gliomas (HGG, WHO grades III-IV) are morphologically and genetically diverse, with survivals ranging from months to decades. Although WHO 2000 grading criteria are well established for pure astrocytomas [anaplastic astrocytoma (AA) and glioblastoma (GBM)], those for oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and oligodendroglioma (AO)] remain subjective, there being a debate regarding the existence of a grade IV variant based on the finding of necrosis, particularly with pseudopalisading (PPN). Methods: Overall survival of 916 adult (>20 yr) patients diagnosed between 1990 and 2005 with supratentorial HGG (77 AA, 481 GBM, 183 AOA, 175 AO) was analyzed by uni- (log-rank) and multivariate (Cox proportional hazards) models for significance of the following factors: microvascular proliferation, necrosis, patient age, surgery (stereotactic vs. open), location, primary vs. secondary tumor, year of diagnosis, and chromosome 1p and 19q losses by fluorescence in situ hybridization. Results: Necrosis was a statistically significant predictor of poor survival on multivariate analyses in AOA (P=0.035), but not in AO (log-rank P=0.048, Cox P=0.9), while PPN showed a trend towards significance on multivariate analysis only in AOA (P=0.096). Other independent predictors on multivariate analysis included age, grade, surgery type, and year of diagnosis for AA/GBM and age, primary tumor, and 1p/19q codeletion for both AOA and AO (P<0.05). Median survival for AOA patients whose tumors featured necrosis (20.7 mo) was significantly worse than their counterparts lacking necrosis (>104 mo); survival of the latter was more similar to that of AO (83.5 mo), whereas in the former it was better than GBM (10.5 mo) (log-rank P<0.0001). Conclusions: Stratification of oligoastrocytomas, but not of pure oligodendrogliomas, into grades III (AOA) and IV (GBM with oligodendroglial features) on the basis of necrosis is prognostically justified and is more accurate than the current approach of using a single anaplastic grade. These data provide impetus for the modification of present WHO criteria. No significant financial relationships to disclose.

Study Design. Review. Objective. To provide practicing spine surgeons a primer with key insights for reading, interpreting, and clinically integrating systematic reviews and meta-analyses. Summary of Background Data. Evidence-based medicine (EBM) refers to a family of standardized techniques for critical appraisal of clinical research. Within the contemporary spine literature, EBM is most commonly encountered in the form of systematic reviews and meta-analyses. Although these analytic techniques are potentially useful when appropriately applied to well-formulated questions with adequate primary data in the literature, the rapid and somewhat indiscriminate increase in volume of systematic reviews and meta-analyses published may be associated with an overall dilution in their quality, as well as misperceptions regarding the applicability of particular EBM studies to spine surgery in general. Methods. The collective experience of spine specialists with vested interests in advancing EBM and its utility was summarized into a primer. Results. We emphasize components that are pertinent methodologically (search strategy, study number, meta-analysis, bias, and certainty), and pertinent clinically (outcomes) to interpreting, and clinically integrating systematic reviews and meta-analyses into spine surgery practice. Conclusions. Armed with these insights into these five perspectives, we anticipate that practicing spine surgeons will be better equipped to interpret systematic reviews and meta-analyses in a fashion that will meaningfully impact their patient care. Level of Evidence: 2

Abstract BACKGROUND Stereotactic radiosurgery (SRS) is a safe and effective treatment for acromegaly. OBJECTIVE To improve understanding of clinical and dosimetric factors predicting biochemical remission. METHODS A single-institution cohort study of nonsyndromic, radiation-naïve patients with growth hormone-producing pituitary adenomas (GHA) having single-fraction SRS between 1990 and 2017. Exclusions were treatment with pituitary suppressive medications at the time of SRS, or <24 mo of follow-up. The primary outcome was biochemical remission—defined as normalization of insulin-like growth factor-1 index (IGF-1 i ) off suppression. Biochemical remission was assessed using Cox proportional hazards. Prior studies reporting IGF-1 i were assessed via systematic literature review and meta-analysis using random-effect modeling. RESULTS A total of 102 patients met study criteria. Of these, 46 patients (45%) were female. The median age was 49 yr (interquartile range [IQR] = 37-59), and the median follow-up was 63 mo (IQR = 29-100). The median pre-SRS IGF-1 i was 1.66 (IQR = 1.37-3.22). The median margin dose was 25 Gy (IQR = 21-25); the median estimated biologically effective dose (BED) was 169.49 Gy (IQR = 124.95-196.00). Biochemical remission was achieved in 58 patients (57%), whereas 22 patients (22%) had medication-controlled disease. Pre-SRS IGF-1 i ≥ 2.25 was the strongest predictor of treatment failure, with an unadjusted hazard ratio (HR) of 0.51 (95% CI = 0.26-0.91, P = .02). Number of isocenters, margin dose, and BED predicted remission on univariate analysis, but after adjusting for sex and baseline IGF-1 i , only BED remained significant—and was independently associated with outcome in continuous (HR = 1.01, 95% CI = 1.00-1.01, P = .02) and binary models (HR = 2.27, 95% CI = 1.39-5.22, P = .002). A total of 24 patients (29%) developed new post-SRS hypopituitarism. Pooled HR for biochemical remission given subthreshold IGF-1 i was 2.25 (95% CI = 1.33-3.16, P < .0001). CONCLUSION IGF-1 i is a reliable predictor of biochemical remission after SRS. BED appears to predict biochemical outcome more reliably than radiation dose, but confirmatory study is needed.

OBJECTIVE Intracranial germ cell tumors (iGCTs) often arise at the neurohypophysis, their second most common origination, following the pineal region. Neurohypophyseal iGCTs present with stereotypical symptoms, including pituitary dysfunction and visual field deficit, due to their suprasellar location. The goal of this study was to present a large, longitudinal single-institution experience with neurohypophyseal iGCTs to better understand their natural history and identify opportunities for further improvement in treatment outcomes. METHODS This is a retrospective, single-institution cohort study of neurohypophyseal iGCTs treated between 1988 and 2017, with a focus on the epidemiology, presentation, natural history, and treatment. RESULTS Thirty-five neurosurgically managed patients met inclusion criteria; the median age was 18 years (3 months to 49 years), and 74% of patients were male (n = 26). Thirty-one tumors were germinomas, and 4 were nongerminomatous iGCTs. Presenting symptoms included pituitary insufficiency in 76% (n = 25), visual deficit in 45% (n = 15), and diabetes insipidus (DI) in 61% (n = 20) of patients. Index symptoms included isolated DI in 10 (36%), isolated hormone deficiency in 14 (50%), and concomitant DI and hormone deficiency symptoms in 4 (14%). Radiographic diagnostic latency was common, occurring at a median of 363 days (range 9–2626 days) after onset of the first symptoms and was significantly associated with both DI and hormone deficiency as the index symptoms (no DI vs DI: 360 vs 1083 days, p = 0.009; no hormone deficiency vs hormone deficiency: 245 vs 953 days, p = 0.004). Biochemical abnormalities were heterogeneous; each pituitary axis was dysfunctional in at least 1 patient, with most patients demonstrating at least 2 abnormalities, and pretreatment dysfunction demonstrating a nonsignificant trend toward association with long-term posttreatment hormone supplementation. Among germinomas, whole-brain or whole-ventricle radiotherapy demonstrated significantly improved progression-free and overall survival compared with local therapy (p = 0.009 and p = 0.004, respectively). CONCLUSIONS Neurohypophyseal iGCTs are insidious tumors that may pose a diagnostic dilemma, as evidenced by the prolonged latency before radiographic confirmation. Serial imaging and close endocrine follow-up are recommended in patients with a characteristic clinical syndrome and negative imaging, due to the propensity for radiographic latency. Pretreatment biochemical abnormalities may indicate higher risk of posttreatment pituitary insufficiency, and all patients should receive careful endocrine follow-up. Local radiotherapy is prone to treatment failure, while whole-ventricle treatment is associated with improved survival in germinomas.