Richard Mannion

Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion: a meta-analysis of individual-participant data.

BACKGROUND Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used to promote fusion in spinal surgery, but its safety has been questioned. PURPOSE To evaluate the effectiveness and safety of rhBMP-2. DATA SOURCES Individual-participant data obtained from the sponsor or investigators and data extracted from study publications identified by systematic bibliographic searches through June 2012. STUDY SELECTION Randomized, controlled trials of rhBMP-2 versus iliac crest bone graft (ICBG) in spinal fusion surgery for degenerative disc disease and related conditions and observational studies in similar populations for investigation of adverse events. DATA EXTRACTION Individual-participant data from 11 eligible of 17 provided trials sponsored by Medtronic (Minneapolis, Minnesota) (n = 1302) and 1 of 2 other eligible trials (n = 106) were included. Additional aggregate adverse event data were extracted from 35 published observational studies. DATA SYNTHESIS Primary outcomes were pain (assessed with the Oswestry Disability Index [ODI] or Short Form-36), fusion, and adverse events. At 24 months, ODI scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% to 6.5%) and radiographic fusion was 12% higher (CI, 2% to 23%). At or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [CI, 1.06 to 2.95]). Cancer was more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 to 4.54]), but the small number of events precluded definite conclusions. LIMITATION The observational studies were diverse and at risk of bias. CONCLUSION At 24 months, rhBMP-2 increases fusion rates, reduces pain by a clinically insignificant amount, and increases early postsurgical pain compared with ICBG. Evidence of increased cancer incidence is inconclusive. PRIMARY FUNDING SOURCE Yale University Open Data Access Project.

Reporting of industry funded study outcome data: comparison of confidential and published data on the safety and effectiveness of rhBMP-2 for spinal fusion.

Objective To investigate whether published results of industry funded trials of recombinant human bone morphogenetic protein 2 (rhBMP-2) in spinal fusion match underlying trial data by comparing three different data sources: individual participant data, internal industry reports, and publicly available journal publications and conference abstracts. Data collection and synthesis The manufacturer of rhBMP-2 products (Medtronic; Minneapolis, MN) provided complete individual participant data and internal reports for all its studies of rhMBP-2 in spinal fusion. We identified publications and conference abstracts through comprehensive literature searches. We compared outcomes provided in the individual participant data against outcomes reported in publications. For effectiveness outcomes, we compared meta-analyses of randomised controlled trials based on each of the three data sources. For adverse events, meta-analysis of the published aggregate data was not possible and we compared the number and type of adverse events reported between data sources. Results 32 publications reported outcomes from 11 of the 17 existing manufacturer sponsored studies. For individual randomised controlled trials, 56% (9/16) to 88% (15/17) of effectiveness outcomes known to have been collected were reported in the published literature. Meta-analyses of effectiveness data were almost identical for pain outcomes and similar for fusion across the three data sources. A minority of adverse event data known to have been collected were reported in the published literature. Several journal articles reported only “serious,” “related,” or “unanticipated” adverse events, without defining these terms. Others reported a small proportion of the collected adverse event categories. Around 23% (533/2302) of the total adverse events collected in published randomised controlled trials have been reported in the literature, with randomised controlled trials evaluating the licensed preparation (Infuse) reporting around 11% (122/1108) of collected adverse events. Conclusions The published literature only partially represents the total data known to have been collected on the effects of rhBMP-2. This did not lead to substantially different results for meta-analysis of effectiveness outcomes. In contrast, reporting of adverse event data in trial publications was inadequate and inconsistent to the extent that any systematic review based solely on the publicly available data would not be able to properly evaluate the safety of rhBMP-2. Analysis of individual participant data enabled the most complete, detailed, and in-depth analysis and was not more resource intensive than extracting, collating, and analysing aggregate data from multiple trial publications and conference abstracts. Confidential internal reports presented considerably more adverse event data than publications, and in the absence of individual participant data access to these reports would support more accurate and reliable investigation, with less time and effort than relying on incomplete published data.

Safety and efficacy of intradural extramedullary spinal tumor removal using a minimally invasive approach.

BACKGROUND: Although minimally invasive surgery for intradural tumors offers the potential benefits of less postoperative pain, a quicker recovery, and the avoidance of long-term instability from multilevel laminectomy, there are concerns over whether one can safely and effectively remove intradural extramedullary tumors in a fashion comparable to open techniques and whether the advantages of minimally invasive surgery are clinically significant. OBJECTIVE: To review our early experience with minimally invasive techniques for intradural extramedullary tumors of the spine. METHODS: Thirteen intradural tumors (1 cervical, 6 thoracic, 6 lumbar) in 11 patients were operated on using a muscle-splitting, tube-assisted paramedian oblique approach with hemilaminectomy to access the spinal canal while preserving the spinous process and ligaments. Fluoroscopy and navigation were used to determine the surgical level in all thoracic and lumbar cases. RESULTS: Satisfactory tumor resection using standard microsurgical techniques was achieved in all but 1 case using a minimally invasive approach. Surgical time and intraoperative blood loss were favorable compared with our open technique cases. There was no postoperative morbidity with the minimally invasive approach, although in 2 patients with tumors in the mid- and upper thoracic spine, the surgical incision was inaccurately placed by 1 level. In 1 case, the approach was converted to open when the tumor could not be found, and postoperatively there was a cerebrospinal fluid leak with infection that required readmission. CONCLUSION: Intradural extramedullary tumors can be safely and effectively removed using minimally invasive techniques. The pros and cons of minimally invasive vs open surgery are discussed.

Improving accuracy and reducing radiation exposure in minimally invasive lumbar interbody fusion

OBJECT The authors assessed the accuracy of placement of lumbar transpedicular screws by using a computer-assisted, imaged-guided, minimally invasive technique with continuous electromyography (EMG) monitoring. METHODS This was a consecutive case series with prospective assessment of procedural accuracy. Forty-seven consecutive patients underwent minimally invasive lumbar interbody fusion and placement of pedicle screws (PSs). A computer-assisted image guidance system involving CT-based images was used to guide screw placement, while EMG continuously monitored the lumbar nerve roots at the operated levels with a 5-mA stimulus applied through the pedicle access needle. All patients underwent CT scanning to determine accuracy of PS placement. All episodes of adjusted screw trajectory based on positive EMG responses were recorded. Pedicle screw misplacement was defined as breach of the pedicle cortex by the screw of more than 2 mm. RESULTS Two hundred twelve PSs were inserted in 47 patients. The screw misplacement rate was 4.7%. One patient experienced new postoperative radiculopathy resulting from a sacral screw that was too long, with lumbosacral trunk impingement. The trajectory of the pedicle access needle was altered intraoperatively on 20 occasions (9.4% of the PSs) based on positive EMG responses, suggesting that nerve root impingement may have resulted from these screws had the EMG monitoring not been used. CONCLUSIONS The combination of computer-assisted navigation combined with continuous EMG monitoring during pedicle cannulation results in a low rate of PS misplacement, with avoidance of screw positions that might cause neural injury. Furthermore, this technique allows reduction of the radiation exposure for the surgical team without compromising the accuracy of screw placement.

A comparison of CT-based navigation techniques for minimally invasive lumbar pedicle screw placement.

Study Design A comparison of 2 surgical techniques. Objective To determine the relative accuracy of minimally invasive lumbar pedicle screw placement using 2 different CT-based image-guided techniques. Summary of Background Three-dimensional intraoperative fluoroscopy systems have recently become available that provide the ability to use CT-quality images for navigation during image-guided minimally invasive spinal surgery. However, the cost of this equipment may negate any potential benefit in navigational accuracy. We therefore assess the accuracy of pedicle screw placement using an intraoperative 3-dimensional fluoroscope for guidance compared with a technique using preoperative CT images merged to intraoperative 2-dimensional fluoroscopy. Methods Sixty-seven patients undergoing minimally invasive placement of lumbar pedicle screws (296 screws) using a navigated, image-guided technique were studied and the accuracy of pedicle screw placement assessed. Electromyography (EMG) monitoring of lumbar nerve roots was used in all. Group 1: 24 patients in whom a preoperative CT scan was merged with intraoperative 2-dimensional fluoroscopy images on the image-guidance system. Group 2: 43 patients using intraoperative 3-dimensional fluoroscopy images as the source for the image guidance system. The frequencies of pedicle breach and EMG warnings (indicating potentially unsafe screw placement) in each group were recorded. Results The rate of pedicle screw misplacement was 6.4% in group 1vs 1.6% in group 2 (P=0.03). There were no cases of neurologic injury from suboptimal placement of screws. Additionally, the incidence of EMG warnings was significantly lower in group 2 (3.7% vs. 10% (P=0.03). Conclusions The use of an intraoperative 3-dimensional fluoroscopy system with an image-guidance system results in greater accuracy of pedicle screw placement than the use of preoperative CT scans, although potentially dangerous placement of pedicle screws can be prevented by the use of EMG monitoring of lumbar nerve roots.

A role for 11C-methionine PET imaging in ACTH-dependent Cushing's syndrome

OBJECTIVE We report our experience of functional imaging with (11)C-methionine positron emission tomography-computed tomography (PET-CT) co-registered with 3D gradient echo (spoiled gradient recalled (SPGR)) magnetic resonance imaging (MRI) in the investigation of ACTH-dependent Cushings syndrome. DESIGN Twenty patients with i) de novo Cushings disease (CD, n=10), ii) residual or recurrent hypercortisolism following first pituitary surgery (±radiotherapy; n=8) or iii) ectopic Cushings syndrome (n=2) were referred to our centre for functional imaging studies between 2010 and 2015. Six of the patients with de novo CD and five of those with persistent/relapsed disease had a suspected abnormality on conventional MRI. METHODS All patients underwent (11)C-methionine PET-CT. For pituitary imaging, co-registration of PET-CT images with contemporaneous SPGR MRI (1 mm slice thickness) was performed, followed by detailed mapping of (11)C-methionine uptake across the sella in three planes (coronal, sagittal and axial). This allowed us to determine whether suspected adenomas seen on structural imaging exhibited focal tracer uptake on functional imaging. RESULTS In seven of ten patients with de novo CD, asymmetric (11)C-methionine uptake was observed within the sella, which co-localized with the suspected site of a corticotroph microadenoma visualised on SPGR MRI (and which was subsequently confirmed histologically following successful transsphenoidal surgery (TSS)). Focal (11)C-methionine uptake that correlated with a suspected abnormality on pituitary MRI was seen in five of eight patients with residual or recurrent Cushings syndrome following first TSS (and pituitary radiotherapy in two cases). Two patients elected to undergo repeat TSS with histology confirming a corticotroph tumour in each case. In two patients with the ectopic ACTH syndrome, (11)C-methionine was concentrated in sites of distant metastases, with minimal uptake in the sellar region. CONCLUSIONS (11)C-methionine PET-CT can aid the detection of ACTH-secreting tumours in Cushings syndrome and facilitate targeted therapy.

Complications from minimally invasive lumbar interbody fusion: Experience from 100 patients

Minimally invasive lumbar fusion is well described and is reported to offer significant advantages to patients in terms of blood loss, a reduction in post-operative pain and a quicker recovery. However, this technique may expose patients to a greater risk of complications when compared to open lumbar instrumented fusion that may negate these advantages. Between January 2007 and March 2001, we conducted a prospective observational study of 100 consecutive patients (48 males and 52 females, mean age of 54 years) to investigate complications occurring from minimally invasive lumbar interbody fusion surgery using an image-guided technique. All patients underwent post-operative CT scans to assess implant placement. Scanning was repeated at 6 months to assess bony fusion. We observed the following complications: 2.5% (11/435) pedicle screw misplacement, 1.7% (2/120) interbody cage misplacement; 0.8% (1/120) interbody cage migration; 0.8% (1/120) patients requiring a post-operative blood transfusion; 2% (2/100) venous thrombo-embolism and 3% (3/100) patients with complications thought to be related to the use of bone morphogenic protein. There were no occurrences of infection and no cerebrospinal fluid leaks. We concluded that the rate of complications from minimally invasive lumbar interbody fusion is low, and compares favourably with the rates of complication from open procedures. Moreover, computerised navigation systems can be used in place of real-time fluoroscopy to guide implant placement, without an increase in the rate of complications.

Anterolateral Approach for Central Thoracic Disc Prolapse—Surgical Strategies Used to Tackle Differing Operative Findings: 3-Dimensional Operative Video

Thoracic disc prolapses causing cord compression can be challenging. For compressive central disc protrusions, a posterior approach is not suitable due to an unacceptable level of cord manipulation. An anterolateral transthoracic approach provides direct access to the disc prolapse allowing for decompression without disturbing the spinal cord. In this video, we describe 2 cases of thoracic myelopathy from a compressive central thoracic disc prolapse. In both cases, informed consent was obtained. Despite similar radiological appearances of heavy calcification, intraoperatively significant differences can be encountered. We demonstrate different surgical strategies depending on the consistency of the disc and the adherence to the thecal sac. With adequate exposure and detachment from adjacent vertebral bodies, soft discs can be, in most instances, separated from the theca with minimal cord manipulation. On the other hand, largely calcified discs often present a significantly greater challenge and require thinning the disc capsule before removal. In cases with significant adherence to dura, in order to prevent cord injury or cerebrospinal fluid leak a thinned shell can be left, providing total detachment from adjacent vertebrae can be achieved. Postoperatively, the first patient, with a significantly calcified disc, developed a transient left leg weakness which recovered by 3-month follow-up. This video outlines the anatomical considerations and operative steps for a transthoracic approach to a central disc prolapse, whilst demonstrating that computed tomography appearances are not always indicative of potential operative difficulties.

Results of Transcranial Resection of Olfactory Groove Meningiomas in Relation to Imaging-Based Case Selection Criteria for the Endoscopic Approach

BACKGROUND Endoscopic endonasal surgery (EES) is increasingly used for olfactory groove meningiomas (OGMs). The role of EES for large (≥4 cm) or complex OGMs is debated. Specific imaging features have been reported to affect the degree of gross total resection (GTR) and complications following EES for OGMs. The influence of these factors on transcranial resection (TCR) is unknown. OBJECTIVE To examine the impact of specific imaging features on outcome following TCR to provide a standard for large and endoscopically less favorable OGMs against which endoscopic outcomes can be compared. METHODS Retrospective study of patients undergoing TCR for OGMs 2002 to 2016. RESULTS Fifty patients (mean age 62.1 yr, mean maximum tumor diameter 5.04 cm and average tumor volume of 48.8 cm3) were studied. Simpson grade 1 and 2 resections were achieved in 80% and 12%, respectively. A favorable functional outcome (modified Rankin Scale [mRS] 0-2) was attained in 86%. The degree of resection, mRS, mortality (4%), recurrence (6%), infection (8%), and cerebrospinal fluid leak requiring intervention (12%) were not associated with tumor calcification, absence of cortical cuff, T2 hyperintensity, tumor configuration, tumor extension beyond midpoint of superior orbital roof, or extension to posterior wall of frontal sinus. There was no difference in resection rates but a trend towards greater complications between 3 arbitrarily divided groups of large meningiomas of increasing complexity based on extensive extension or vascular adherence. CONCLUSION Favorable outcomes can be achieved with TCR for large and complex OGMs Factors that may preclude endoscopic resection do not negatively affect outcome following TCR.

Advanced Intraoperative Imaging Techniques and Navigation in Spine Surgery

It is now taken for granted that for certain cranial neurosurgical procedures, such as brain tumor surgery or cerebral abscesses, the use of navigation is the norm. Furthermore, should a complication arise during surgery where navigation was not used, and navigation may have helped to avoid such a complication, one would find this difficult to defend. Yet this was not the situation up until recently, and even in the last 10 years, a process has been underway to convince the remaining few skeptics that the extra time required during initial setup/registration, and the limitations with respect to accuracy that accompany all of the current navigation systems on the market are more than compensated by the advantages cranial navigation offers once surgery is underway.