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Or Cohen-Inbar, Robert M. Starke, Gabriella Paisan, Hideyuki Kano, Paul P. Huang, Rafael Rodriguez-Mercado, Luis Almodovar, Inga S. Grills, David Mathieu, Danilo Silva, Mahmoud Abbassy, Symeon Missios, John Y. K. Lee, Gene H. Barnett, Douglas Kondziolka, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

The goal of stereotactic radiosurgery (SRS) for arteriovenous malformation (AVM) is complete nidus obliteration, thereby eliminating the risk of future hemorrhage. This outcome can be observed within the first 18 months, although documentation of AVM obliteration can extend to as much as 5 years after SRS is performed. A shorter time to obliteration may impact the frequency and effect of post-SRS complications and latency hemorrhage. The authors' goal in the present study was to determine predictors of early obliteration (18 months or less) following SRS for cerebral AVM.

METHODS

Eight centers participating in the International Gamma Knife Research Foundation (IGKRF) obtained institutional review board approval to supply de-identified patient data. From a cohort of 2231 patients, a total of 1398 patients had confirmed AVM obliteration. Patients were sorted into early responders (198 patients), defined as those with confirmed nidus obliteration at or prior to 18 months after SRS, and late responders (1200 patients), defined as those with confirmed nidus obliteration more than 18 months after SRS. The median clinical follow-up time was 63.7 months (range 7–324.7 months).

RESULTS

Outcome parameters including latency interval hemorrhage, mortality, and favorable outcome were not significantly different between the 2 groups. Radiologically demonstrated radiation-induced changes were noted more often in the late responder group (376 patients [31.3%] vs 39 patients [19.7%] for early responders, p = 0.005). Multivariate independent predictors of early obliteration included a margin dose > 24 Gy (p = 0.031), prior surgery (p = 0.002), no prior radiotherapy (p = 0.025), smaller AVM nidus (p = 0.002), deep venous drainage (p = 0.039), and nidus location (p < 0.0001). Basal ganglia, cerebellum, and frontal lobe nidus locations favored early obliteration (p = 0.009). The Virginia Radiosurgery AVM Scale (VRAS) score was significantly different between the 2 responder groups (p = 0.039). The VRAS score was also shown to be predictive of early obliteration on univariate analysis (p = 0.009). For early obliteration, such prognostic ability was not shown for other SRS- and AVM-related grading systems.

CONCLUSIONS

Early obliteration (≤ 18 months post-SRS) was more common in patients whose AVMs were smaller, located in the frontal lobe, basal ganglia, or cerebellum, had deep venous drainage, and had received a margin dose > 24 Gy.

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Zane Schnurman, Michael L. Smith and Douglas Kondziolka

OBJECTIVE

Off-label therapies are widely used in clinical practice by spinal surgeons. Some patients and practitioners have advocated for increased regulation of their use, and payers have increasingly questioned reimbursment for off-label therapies. In this study, the authors applied a model that quantifies publication data to analyze the developmental process from initial on-label use to off-label innovation, using as an example recombinant human bone morphogenetic protein 2 (rhBMP-2) because of its wide off-label use.

METHODS

As a case study of off-label innovation, the developmental patterns of rhBMP-2 from FDA-approved use for anterior lumbar interbody fusion to several of its off-label uses, including posterolateral lumbar fusion, anterior cervical discectomy and fusion, and posterior lumbar interbody fusion/transforaminal lumbar interbody fusion, were evaluated using the “progressive scholarly acceptance” (PSA) model. In this model, PSA is used as an end point indicating acceptance of a therapy or procedure by the relevant scientific community and is reached when the total number of peer-reviewed studies devoted to refinement or improvement of a therapy surpasses the total number assessing initial efficacy. Report characteristics, including the number of patients studied and study design, were assessed in addition to the time to and pattern of community acceptance, and results compared with previous developmental study findings. Disclosures and reported conflicts of interest for all articles were reviewed, and these data were also used in the analysis.

RESULTS

Publication data indicated that the acceptance of rhBMP-2 off-label therapies occurred more rapidly and with less evidence than previously studied on-label therapies. Additionally, the community appeared to respond more robustly (by rapidly changing publication patterns) to reports of adverse events than to new questions of efficacy.

CONCLUSIONS

The development of off-label therapies, including the influence of investigative methods, regulation, and changing perspectives, can be characterized on the basis of publication patterns. The approach and findings in this report could inform future off-label development of therapies and procedures as well as attempts to regulate off-label use.

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Seyed H. Mousavi, Berkcan Akpinar, Ajay Niranjan, Vikas Agarwal, Jonathan Cohen, John C. Flickinger, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

Contrast enhancement of the retrogasserian trigeminal nerve on MRI scans frequently develops after radiosurgical ablation for the management of medically refractory trigeminal neuralgia (TN). The authors sought to evaluate the clinical significance of this imaging finding in patients who underwent a second radiosurgical procedure for recurrent TN.

METHODS

During a 22-year period, 360 patients underwent Gamma Knife stereotactic radiosurgery (SRS) as their first surgical procedure for TN at the authors' center. The authors retrospectively analyzed the data from 59 patients (mean age 72 years, range 33–89 years) who underwent repeat SRS for recurrent pain at a median of 30 months (range 6–146 months) after the first SRS. The isocenter was 4 mm, and the median maximum doses for the first and second procedures were 80 Gy and 70 Gy, respectively. A neuroradiologist and a neurosurgeon blinded to the treated side evaluated the presence of nerve contrast enhancement on MRI series at the time of the repeat procedure. The authors correlated the presence of this imaging change with clinical outcomes. Pain outcomes and development of trigeminal sensory dysfunction were evaluated with the Barrow Neurological Institute (BNI) Pain Scale and BNI Numbness Scale, respectively. The mean length of follow-up after the second SRS was 58 months (95% CI 49–68 months).

RESULTS

At the time of the repeat SRS, contrast enhancement of the trigeminal nerve on MRI scans was observed in 31 patients (53%). Five years after the SRS, patients with this enhancement had lower actuarial rates of complete pain relief after the repeat SRS (27% [95% CI 7%–47%]) than patients without the enhancement (76% [95% CI 58%–94%]) (p < 0.001). At the 5-year follow-up, patients with the contrast enhancement also had a higher risk for trigeminal sensory loss after repeat SRS (75% [95% CI 59%–91%]) than patients without contrast enhancement (26% [95% CI 10%–42%]) (p = 0.001). Dysesthetic pain after repeat SRS was observed for 8 patients with and for 2 patients without contrast enhancement.

CONCLUSIONS

Trigeminal nerve contrast enhancement on MRI scans observed at the time of a repeat SRS for TN was associated with less satisfactory pain control and more frequently detected facial sensory loss. Residual contrast enhancement at the time of a repeat SRS may warrant consideration of dose reduction or further separation of the radiosurgical targets.

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Christopher M. Bonfield and Douglas Kondziolka

Bill Masterton is the only man to die of injuries sustained in a National Hockey League (NHL) game. He remains the last fatality in any professional team sport involving a direct in-game injury in North America. While Masterton was originally thought to have suffered a fatal brain injury while being checked on the ice, later analysis of the case revealed evidence of second-impact syndrome and the effects of prior concussions. Masterton's death sparked both an immediate debate in the NHL on whether helmets should be compulsory and the NHL's first vote on mandatory helmet use. Although the subject of mandated helmet use met with resistance in the 10 years after Masterton's death, especially from hockey owners and coaches, the NHL finally legislated helmet use by all players entering the league beginning in the 1979–1980 season.

Several awards, including one recognizing the NHL player who best exemplifies the qualities of perseverance, sportsmanship, and dedication to hockey, have been created in memory of Masterton. However, his legacy extends far beyond the awards that bear his name. His death was the seminal event bringing head safety to the forefront of a game that was both unready and unwilling to accept change. An increase in mainstream media attention in recent years has led to unprecedented public awareness of brain injury and concussion in hockey and other sports. Advances in the diagnosis and treatment of head injury in sports have occurred recently, the impetus for which started over 45 years ago, when Bill Masterton died.

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Conor Grady, Omar Tanweer, David Zagzag, Jafar J. Jafar, Paul P. Huang and Douglas Kondziolka

Stereotactic radiosurgery is widely used to treat cerebral arteriovenous malformations (AVMs), with the goal of complete angiographic obliteration. A number of case series have challenged the assumption that absence of residual AVM on follow-up angiograms is consistent with elimination of the risk of hemorrhage. The authors describe 3 cases in which patients who had angiographic evidence of AVM occlusion presented with late hemorrhage in the area of their prior lesions. They compare the radiographic, angiographic, and histological features of these patients with those previously described in the literature.

Delayed hemorrhage from the tissue of occluded AVMs has been reported as early as 4 and as late as 11 years after initial stereotactic radiosurgery. In all cases for which data are available, hemorrhage occurred in the area of persistent imaging findings despite negative findings on conventional angiography. The hemorrhagic lesions that were resected demonstrated a number of distinct histological findings.

While rare, delayed hemorrhage from the tissue of occluded AVMs may occur from a number of distinct, angiographically occult postirradiation changes. The hemorrhages in the authors' 3 cases were symptomatic and localized. The correlation of histological and imaging findings in delayed hemorrhage from occluded AVMs is an area requiring further investigation.

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Alireza Mansouri, Benjamin Cooper, Samuel M. Shin and Douglas Kondziolka

OBJECT

Randomized-controlled trials (RCTs) are advocated to provide high-level medical evidence. However, in neurosurgery, there are barriers to conducting RCTs. The authors of this study sought to analyze the quality of neurosurgical RCTs since 2000 to determine the adequacy of their design and reporting.

METHODS

A search of the MEDLINE and EMBASE databases (2000–2014) was conducted. The medical subject heading (MeSH) terms used in the search included: “neurosurgery” OR “neurosurgical procedure,” “brain neoplasms,” “infarction” and “decompression,” “carotid stenosis,” “cerebral hemorrhage,” and “spinal fusion.” These studies were limited to RCTs, in humans, and in the English language. The Consolidated Standards for Reporting of Trials (CONSORT) and Jadad scales were used to assess the quality of RCT design and reporting. The standardized median times cited (median citations divided by years since publication) were used to assess impact. A pragmatic-explanatory continuum indicator summary-based scale was used to assess the design of the studies as primarily pragmatic or explanatory.

RESULTS

Sixty-one articles were identified, and the following subspecialties were the most common: vascular (23, 37%), followed by functional neurosurgery and neurooncology (both 13, 21%). The following nations were the primary leaders in RCTs: US (25 studies, 41%), Germany (8 studies, 13%), and the United Kingdom (7 studies, 11%). Median sample size was 100 (interquartile range [IQR] 41.5–279). The majority of the studies (40, 66%) had pragmatic objectives. The median number of times cited overall was 69 (IQR 20.5–193). The combined median CONSORT score was 36 (IQR 27.5–39). Blinding was most deficiently reported. Other areas with a relatively low quality of reporting were sample size calculation (34.2% of surgical, 38.5% of drug, and 20% of device studies), allocation concealment (28.9% of surgical, 23.1% of drug, and 50% of device studies), and protocol implementation (18.4% of surgical, 23% of drug, and 20% of device studies). The quality of reporting did not correlate with the study impact. All studies had a median Jadad score ≤ 3. Thirty-three pragmatic studies (83%) and 5 explanatory studies (25%) met the design objectives. All pragmatic studies based on drug and device trials met their objectives, while 74% of pragmatic surgical trials met their objectives.

CONCLUSIONS

The prevalence of neurosurgical RCTs is low. The quality of RCT design and reporting in neurosurgery is also low. Many study designs are not compatible with stated objectives. Pragmatic studies were more likely to meet design objectives. Given the role of RCTs as one of the highest levels of evidence, it is critical to improve on their methodology and reporting.

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Zane Schnurman and Douglas Kondziolka

Understanding how the relevant medical community accepts new therapies is vital to patients, physicians, and society. Increasingly, focus is placed on how medical innovations are evaluated. But recognizing when a treatment has become accepted practice—essentially, acceptance by the scientific community—remains a challenge and a barrierto investigating treatment development. This report aims to demonstrate the theory, method, and limitations of a model for measuring a new metric that the authors term “progressive scholarly acceptance.”

A model was developed to identify when the scientific community has accepted an innovation, by observing when researchers have moved beyond the initial study of efficacy.

This model could enable further investigations into the methods and influences of treatment development.

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Zane Schnurman and Douglas Kondziolka

OBJECT

Patients, practitioners, payers, and regulators are advocating for reform in how medical advances are evaluated. Because surgery does not adhere to a standardized developmental pathway, how the medical community accepts a procedure remains unclear. The authors developed a new model, using publication data and patterns, that quantifies this process. Using this technique, the authors identified common archetypes and influences on neurosurgical progress from idea inception to acceptance.

METHODS

Seven neurosurgical procedures developed in the past 15–25 years were used as developmental case studies (endovascular coil, deep brain stimulation, vagus nerve stimulation, 1,3-bis(2-chloroethyl)-l-nitrosourea wafer, and 3 radiosurgery procedures), and the literature on each topic was evaluated. A new metric the authors termed “progressive scholarly acceptance” (PSA) was used as an end point for community acceptance. PSA was reached when the number of investigations that refine or improve a procedure eclipsed the total number of reports assessing initial efficacy. Report characteristics, including the number of patients studied, study design, and number of authoring groups from the first report to the point of PSA, were assessed.

RESULTS

Publication data implicated factors that had an outsized influence on acceptance. First, procedural accessibility to investigators was found to influence the number of reports, number of patients studied, and number of authoring groups contributing. Barriers to accessibility included target disease rarity, regulatory restrictions, and cost. Second, the ease or difficulty in applying a randomized controlled trial had an impact on study design. Based on these 2 factors, 3 developmental archetypes were characterized to generally describe the development of surgery.

CONCLUSIONS

Common surgical development archetypes can be described based on factors that impact investigative methods, data accumulation, and ultimate acceptance by society. The approach and proposed terminologies in this report could inform future procedural development as well as any attempts to regulate surgical innovation.