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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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Michael L. Smith and John Y. K. Lee

✓Metastatic disease to the brain occurs in a significant percentage of patients with cancer and can limit survival and worsen quality of life. Glucocorticoids and whole-brain radiation therapy (WBRT) have been the mainstay of intracranial treatments, while craniotomy for tumor resection has been the standard local therapy. In the last few years however, stereotactic radiosurgery (SRS) has emerged as an alternative form of local therapy. Studies completed over the past decade have helped to define the role of SRS. The authors review the evolution of the techniques used and the indications for SRS use to treat brain metastases. Stereotactic radiosurgery, compared with craniotomy, is a powerful local treatment modality especially useful for small, multiple, and deep metastases, and it is usually combined with WBRT for better regional control.

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Edward S. Ahn, R. Michael Scott, Richard L. Robertson Jr. and Edward R. Smith

Object

Chorea is a movement disorder characterized by brief, irregular, involuntary contractions that appear to flow from 1 muscle to another. There are a limited number of reports in the literature that have linked moyamoya disease and chorea. The authors describe their experience in treating moyamoya disease in patients in whom chorea developed as part of the clinical presentation.

Methods

The authors conducted a retrospective review of a consecutive series of 316 children who underwent pial synangiosis revascularization for moyamoya disease at the Boston Children's Hospital.

Results

Of 316 surgically treated patients with moyamoya disease, 10 (3.2%; 6 boys and 4 girls) had chorea as a part of their presentation. The average age at surgical treatment was 9.9 years (range 3.8–17.9 years). All patients had evidence of hypertrophied lenticulostriate collateral vessels through the basal ganglia on preoperative angiography and/or MRI on affected sides. Two patients had cystic lesions in the basal ganglia. Nine patients underwent bilateral craniotomies for pial synangiosis, and 1 patient underwent a single craniotomy for unilateral disease. Follow-up was available in 9 patients (average 50.1 months). The mean duration of chorea was 1.36 years (range 2 days to 4 years), with resolution of symptoms in all patients. One patient developed chorea 3 years after surgical treatment, 4 patients had transient chorea that resolved prior to surgery, and 5 patients experienced resolution of the chorea after surgery (average 13 months).

Conclusions

The authors describe children with moyamoya disease and chorea as part of their clinical presentation. The data suggest that involvement of the basal ganglia by the hypertrophied collateral vessels contributes to the development of chorea, which can wax or wane depending on disease stage or involution of the vessels after revascularization surgery. In most patients, however, the chorea improves or disappears about 1 year after presentation.

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Jon Glass, Fred H. Hochberg, Michael L. Gruber, David N. Louis, David Smith and Barbara Rattner

✓ Malignant oligodendrogliomas have been shown to be responsive to chemotherapy. The authors administered systemic chemotherapy to seven patients with oligodendroglioma or anaplastic oligodendroglioma, and to 14 with mixed oligodendroglioma-astrocytoma. Fourteen patients underwent chemotherapy before and seven after irradiation. The PCV (procarbazine, methyl-1-(2-chloroethyl)-1-nitrosourea (CCNU), and vincristine) chemotherapy was administered every 6 weeks (42-day cycles) for two to five cycles as follows: CCNU, 110 mg/sq m on Day 1; procarbazine, 60 mg/sq m/day on Days 8 to 21; and vincristine, 1.4 mg/sq m/day on Days 8 and 29. Complete or partial (> 50% reduction in tumor mass) responses at 20 to 100+ weeks after treatment were noted in 11 (79%) of the 14 patients treated before irradiation, including two with anaplastic oligodendroglioma and nine with mixed tumors. Complete responses were seen in two patients, one with anaplastic oligodendroglioma and one with a mixed tumor. Partial responses were seen in three of seven patients treated after radiotherapy. Stabilization of tumor growth followed PCV chemotherapy in four patients (two treated before and two after radiotherapy). Tumor growth progressed in two patients during therapy despite an initial response and in two patients despite therapy. The authors conclude that mixed oligodendroglial tumors as well as anaplastic oligodendrogliomas are responsive to PCV chemotherapy.

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Robert E. Elliott, Omar Tanweer, Akwasi Boah, Michael L. Smith and Anthony Frempong-Boadu

Object

Some centers report a lower incidence of vertebral artery (VA) injury with C-2 pars screws compared with pedicle screws without sacrificing construct stability, despite biomechanical studies suggesting greater load failures with C-2 pedicle screws. The authors reviewed published series describing C-2 pars and pedicle screw implantation and atlantoaxial fusions and compared the incidence of VA injury, screw malposition, and successful atlantoaxial fusion with each screw type.

Methods

Online databases were searched for English-language articles between 1994 and April of 2011 describing the clinical and radiographic outcomes following posterior atlantoaxial fusion with C-1 lateral mass and either C-2 pars interarticularis or pedicle screws. Thirty-three studies describing 2975 C-2 pedicle screws and 11 studies describing 405 C-2 pars screws met inclusion criteria for the safety analysis. Seven studies describing 113 patients treated with C-2 pars screws and 20 studies describing 918 patients treated with C-2 pedicle screws met inclusion criteria for fusion analysis. Standard and formal meta-analysis techniques were used to compare outcomes.

Results

All studies provided Class III evidence. Ten instances of VA injury occurred with C-2 pedicle screws (0.3%) and no VA injury occurred with pars screws. The point estimate of VA injury for C-2 pedicle screws was 1.09% (95% CI 0.73%–1.63%) and was similar to that of C-2 pars screws (1.48%, 95% CI 0.62%–3.52%). Similarly, there was no statistically significant difference in the rate of clinically significant screw malpositions (1.14% [95% CI 0.77%–1.69%) vs 1.69% [95% CI 0.73%–3.84%]). Radiographically identified screw malposition occurred in a higher proportion of C-2 pedicle screws compared with C-2 pars screws (6.0% [95% CI 3.7%–9.6%] vs 4.0% [95% CI 2.0%–7.6%], p < 0.0001). Pseudarthrosis occurred in a greater proportion of patients treated with C-2 pars screws (5 [4.4%] of 113) compared with those treated with C-2 pedicle screws (2 [0.22%] of 900). Point estimates with 95% confidence intervals show a slightly higher rate of successful atlantoaxial fusion in the pedicle screw cohort (97.8% [CI 96.0%–98.8%] vs 93.5% [CI 86.6%–97.0%]; p < 0.0001). Q-testing ruled out heterogeneity between the study groups.

Conclusions

With a thorough knowledge of axis anatomy, surgeons can place both C-2 pars and C-2 pedicle screws accurately with a small risk of VA injury or clinically significant malposition. There may be subtle trade-off of safety for rigidity when using axial pedicle instead of pars screws, and the decision to use either screw type must be made only after careful review of the preoperative CT imaging and must take into account the surgeon's expertise and the particular demands of the clinical scenario in any given case.

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Shaun D. Rodgers, Bryan J. Marascalchi, Bartosz T. Grobelny, Michael L. Smith and Uzma Samadani

Recombinant human bone morphogenetic protein–2 (rhBMP-2) promotes the induction of bone growth and is widely used in spine surgery to enhance arthrodesis. Recombinant human BMP-2 has been associated with a variety of complications including ectopic bone formation, adjacent-level fusion, local bone resorption, osteolysis, and radiculitis. Some of the complications associated with rhBMP-2 may be the result of rhBMP-2 induction of the inflammatory host response. In this paper the authors report on a patient with prior transforaminal lumbar interbody fusion (TLIF) using an interbody cage packed with rhBMP-2, in which rhBMP-2 possibly contributed to vascular injury during an attempted anterior lumbar interbody fusion. This 63-year-old man presented with a 1-year history of worsening refractory low-back pain and radiculopathy caused by a Grade 1 spondylolisthesis at L4–5. He underwent an uncomplicated L4–5 TLIF using an rhBMP-2–packed interbody cage. Postoperatively, he experienced marginal improvement of his symptoms. Within the next year and a half the patient returned with unremitting low-back pain and neurogenic claudication that failed to respond to conservative measures. Radiological imaging of the patient revealed screw loosening and pseudarthrosis. He underwent an anterior retroperitoneal approach with a plan for removal of the previous cage, complete discectomy, and placement of a femoral ring. During the retroperitoneal approach the iliac vein was adhered with scarring and fibrosis to the underlying previously operated L4–5 interbody space. During mobilization the left iliac vein was torn, resulting in significant blood loss and cardiac arrest requiring chest compression, defibrillator shocks, and blood transfusion. The patient was stabilized, the operation was terminated, and he was transferred to the intensive care unit. He recovered over the next several days and was discharged at his neurological baseline. The authors propose that the rhBMP-2–induced host inflammatory response partially contributed to vessel fibrosis and scarring, resulting in the life-threatening vascular injury during the reoperation. Spine surgeons should be aware of this potential inflammatory fibrosis in addition to other reported complications related to rhBMP-2.

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Kyle A. Smith and Morgan B. Glusman

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Mark L. Rosenblum, Arden F. Reynolds Jr., Kendall A. Smith, Barry H. Rumack and Michael D. Walker

✓ Oral 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), a lipid-soluble non-ionized chemotherapeutic agent, was used in the treatment of 26 patients with malignant brain tumor, primarily glioblastoma. Most patients had first received conventional surgery, and about one half had received x-ray therapy. Over 1½ years, 113 courses of CCNU (130–150 mg/m2) were given and analyzed for clinical results and agent toxicity. A new central nervous system (CNS) disease staging system was used to measure patient impairment and therapeutic response. Thirty-seven per cent of all symptomatic patients had significant remission of clinical disease, lasting a median of 5 months. Data are presented implying that the treatment of asymptomatic patients may also be of considerable value. The most significant toxicity was delayed reversible thrombocytopenia, which was less severe than that seen with nitrosourea BCNU. Despite the cumulative toxicity observed with all three bone-marrow elements, serious complications were rare. Our initial experience indicates that CCNU is an effective agent for the treatment of malignant brain tumor and that the CNS disease staging system is useful in obtaining quantitative results.

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Amit Singla, Ning Lin, Allen L. Ho, R. Michael Scott and Edward R. Smith

Surgically created openings such as bur holes can serve as avenues for the development of collateral blood supply to the brain in patients with moyamoya disease. When such collateralization occurs through preexisting shunt catheter sites, the potential exists for perioperative stroke if these vessels are damaged during revision of a ventricular catheter for shunt malfunction. In this paper the authors report on a series of patients with a history of ventriculoperitoneal (VP) shunts who later developed moyamoya disease and were found to have spontaneous transdural collateral vessels at ventricular catheter sites readily visualized on diagnostic angiography. A consecutive surgical series of 412 patients with moyamoya disease treated at Boston Children's Hospital from 1990 to 2010 were reviewed to identify patients with concomitant moyamoya and a VP shunt. The clinical records and angiograms of these patients were reviewed to determine the extent of bur hole collaterals through the shunt site. Three patients were identified who had VP shunts placed for hydrocephalus and subsequently developed moyamoya disease. All 3 patients demonstrated spontaneous transdural collaterals at the ventricular catheter bur hole, as confirmed by angiography during the workup for moyamoya disease. No patients required subsequent revision of their ventricular catheters following the diagnosis of moyamoya. All patients have remained stroke free and clinically stable following pial synangiosis. Although the association of moyamoya and shunted hydrocephalus is rare, it may present a significant potential problem for the neurosurgeon treating a shunt malfunction in this patient population, because shunt bur holes may become entry sites for the ingrowth of significant cortical transdural collateral blood supply to the underlying brain. Shunt revision might therefore be associated with an increased risk of postoperative stroke or operative-site hemorrhage in this population if this vascularization is interrupted when shunt catheters are removed and replaced. A knowledge of the existence of shunt-related collaterals in patients with moyamoya may aid the surgeon in planning shunt revisions and considering, for example, a new entry point for a ventricular catheter, rather than replacing an existing one, to minimize the risk of jeopardizing existing collaterals.

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Alfred P. See, Alexander E. Ropper, Daniel L. Underberg, Richard L. Robertson, R. Michael Scott and Edward R. Smith

OBJECT

Moyamoya can cause cerebral ischemia and stroke in Down syndrome (DS) patients. In this study, the authors defined a surgically treated population of patients with DS and moyamoya and compared their clinical presentation, response to surgical treatment, and long-term prognosis with those of the general population of patients with moyamoya but without DS.

METHODS

This study was a retrospective review of a consecutive operative series of moyamoya patients with DS treated at Boston Children’s Hospital from 1985 through 2012.

RESULTS

Thirty-two patients, average age 9.7 years (range 1.8–29.3 years), underwent surgery for moyamoya in association with DS. The majority presented with ischemic symptoms (87% stroke, 42% transient ischemic attacks). Twenty-four patients (75%) had congenital heart disease. Nineteen patients (59%) had bilateral moyamoya on presentation, and 13 presented with unilateral disease, of which 2 progressed to surgery on the opposite side at a later date. Patients were followed for a median of 7.5 years (1–20.2 years) after surgery, with no patients lost to follow-up. Follow-up arteriography demonstrated Matsushima Grade A collaterals in 29 of 39 (74%) hemispheres, Grade B in 5 (13%), and Grade C in 5 (13%).

Complications included postoperative strokes in 2 patients, which occurred within 48 hours of surgery in both; one of these patients had arm weakness and the other confusion (both had recovered completely at follow-up). Seizures occurred in 5 patients perioperatively, including one who had a new seizure disorder related to hypocalcemia.

CONCLUSIONS

Moyamoya disease is a cause of stroke in patients with DS. Both the incidence of preoperative stroke (87% vs 67%) and the average age at diagnosis for children under age 21 (8.4 vs 6.5 years) were greater in patients with DS and moyamoya than in the general moyamoya surgical population, suggesting a possible delay in reaching a correct diagnosis of the cause of cerebral ischemia in the DS patient population. Pial synangiosis provided long-term protection from stroke in all patients treated.