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The Journal of Bone and Joint Surgery (American) 85:1626-1636 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.

Specialty Update

What's New in Spine Surgery

Jack E. Zigler, MD, Paul A. Anderson, MD, Scott D. Boden, MD, Keith H Bridwell, MD and Alexander R. Vaccaro, MD

Jack E. Zigler, MD
Texas Back Institute, 6300 West Parker Road, Plano, TX 75093

Paul A. Anderson, MD
University of Wisconsin Hospitals, 600 Highland Avenue, Suite K4-738, Madison, WI 53792

Scott D. Boden, MD
The Emory Spine Center, 2165 North Decatur Road, Decatur, GA 30033-5307

Keith H. Bridwell, MD
Department of Orthopaedic Surgery, Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, Suite 11300, West Pavilion, Campus Box 8233, St. Louis, MO 63110

Alexander R. Vaccaro, MD
Rothman Institute at Jefferson, 925 Chestnut Street, 5th Floor, Philadelphia, PA 19107-4216

The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Specialty Update has been developed in collaboration with the Council of Musculoskeletal Specialty Societies (COMSS) of the American Academy of Orthopaedic Surgeons.

Spine surgery continues to be an exciting and dynamic subspecialty of orthopaedic surgery. Biologic enhancement of fusion and disc arthroplasty are two of the "hottest" areas undergoing investigation. Both basic science and clinical research into the role of bone morphogenetic proteins (BMPs) and molecular biological applications in the spine are ongoing. BMP has been approved by the United States Food and Drug Administration (FDA) for use in the LT lumbar fusion cage (Medtronic Sofamor Danek, Memphis, Tennessee). Patient enrollment has been completed for the trial of the one-level SB Charité artificial lumbar disc (Link Spine Group, Branford, Connecticut), and clinical trials of the one and two-level ProDisc (Spine Solutions, New York, NY) will close in 2003. FDA submissions for approval may be made as early as December 2003 for the Charité device. Clinical trials of the Bryan Cervical Disc (Spinal Dynamics, Mercer Island, Washington) started in the United States this year, and investigational device studies may be launched on several more cervical and lumbar arthroplasty designs within the next six to twelve months.

What's New in the Treatment of the Cervical Spine

Natural History
Edwards et al. evaluated the accuracy of surgeon records in documenting dysphagia and dysphonia after cervical spine surgery 1 . Four surgeons at two academic centers consistently underreported both of these postoperative events when compared with the responses on patient surveys at the same time-periods, suggesting that the prevalence of these adverse outcomes may be seriously underreported in studies that rely purely on a retrospective analysis of office notes.

Specialized tracking software allowed Reitman and associates to fluoroscopically evaluate motion at segments adjacent to a cervical fusion 2 . At thirteen months after fusion, no abnormal motion was identified at the segment immediately cephalad to one, two, or even three-level fusions. This patient cohort will be followed serially to determine at what point after fusion a transition syndrome may develop.

Matsunaga et al. reported the results of a study evaluating the pathogenesis of myelopathy in patients with ossification of the posterior longitudinal ligament 3 . Of the 167 patients who were conservatively followed, 22% had an aggravation of their presenting symptoms and signs after a mean of eleven years of follow-up. Eighteen percent of 140 asymptomatic patients had myelopathy by the time of the last examination. Prognostic factors were the diameter of the space available for the cord (SAC) and the cervical range of motion. Myelopathy developed in all patients with a SAC of <6 mm and in none with a SAC of >14 mm. In the group with a SAC of 6 to 14 mm, patients with restricted range of motion had a lower prevalence of myelopathy than those who had greater motion, suggesting a dynamic component to the pathogenesis.

Disc Replacement
The Bristol Cervical Disc (Medtronic Sofamor Danek) is a two-piece metal-on-metal design. In a prospective, randomized, multicenter study, Nelson et al. evaluated thirty-six patients with primary single-level cervical disc disease who had either an anterior discectomy and fusion or a Bristol arthroplasty 4 . After one year of follow-up, the group that had received the artificial disc had greater improvement inclinical outcome measures, with no device-related complications.

Goffin et al. presented the ongoing results of a multicenter clinical trial assessing the safety and effectiveness of the Bryan Cervical Disc prosthesis in the treatment of single-level degenerative disc disease 5 . Forty-six patients showed 68% excellent or good and 19% fair results according to the criteria of Odom at one year of follow-up. Nine patients demonstrated 64% excellent or good and 25% fair results at two years of follow-up. Range of motion at the disc spaces at six and twelve months averaged 7° and 9°, respectively. Varying degrees of heterotopic ossification were reported in the longus colli muscles.

A radiostereometric analysis of the interface of the Bryan Cervical Disc showed some motion between the shells of the implant and the vertebral end plates within the first three to six months 6 . At six months, ten of eleven implants were stable at the junction with the vertebral end plate.

Laminaplasty
Ratliff and Cooper, in a meta-analysis of the English-language literature on laminaplasty, reviewed seventy-one reports involving over 2000 patients 7 . The overall clinical results were similar to those of laminectomy with posterior fusion. The reported prevalence of axial neck pain ranged from 6% to 60%, the prevalence of C5 nerve-root dysfunction ranged from 5% to 12%, and a progressive loss of range of motion was noted over time.

Shiraishi et al. described a "skip laminectomy" that involved retaining but undercutting the C5 and C7 laminae, with their musculoligamentous attachments left intact 8 . This somewhat technically demanding procedure is thought to offer an alternative to laminaplasty with less potential for neck pain, restriction of motion, and loss of cervical lordosis as the deep extensor musculature and its attachments are largely preserved.

A novel plate used to maintain the open door of a classic Hirabayashi laminaplasty was reported by Heller and Qureshi 9 . Mechanical analysis showed that either the plate or a spinous process graft on the open side was more resistant to door closure than was a suture anchor placed on the hinge side.

Craniovertebral Junction
Posterior C1-C2 intra-articular fixation with use of a cannulated 5.6 or 6.5-mm screw and bilateral Halifax clamps as fixation in a fusion construct was reported on by Tokuhashi and Matsuzaki 10 . Union was achieved in thirty (93.8%) of thirty-two patients, most of whom had rheumatoid arthritis. Biomechanical testing revealed that this construct resisted torsion better than Halifax clamps alone and that it was nearly as rigid as Magerl C1-C2 transarticular screws without the technical difficulties associated with their insertion.

Currier and associates described the relationship of the internal carotid artery to the anterior aspect of the C1 vertebra and noted its implications for C1-C2 transarticular and C1 lateral mass screw fixation 11 . In a pilot study of three human cadaveric specimens, they found that the artery was located within 1 mm of the anterior cortex of C1 and in the path of either one of these screw trajectories. Computed tomography scans of the head and neck of fifty random patients were also analyzed, and potential screw trajectories were transposed onto the scans. The proximity of the internal carotid artery to the anterior cortex of C1 posed some degree of risk in 94% of these cases and at least a moderate risk in 58%.

Tannoury et al. placed twenty-two C1-C2 transarticular screws in eleven cadavera with the aid of either conventional fluoroscopy or virtual fluoroscopy (FluoroNav; Sofamor Danek) 12 . Although fluoroscopy time was significantly decreased in the virtual fluoroscopy group (p = 0.046), accuracy was also decreased. In the standard fluoroscopy group, one of eleven screws was malpositioned. In the virtual fluoroscopy group, four of eleven screws were malpositioned, including one screw that was in contact with the vertebral artery. The authors recommended against relying on virtual fluoroscopy alone when placing C1-C2 screws.

Anterior Cervical Surgery
Kuribayashi and Matsuda reported on a cervical screw made of hydroxyapatite and beta-tricalcium phosphate 13 . The beta-tricalcium phosphate promotes osteogenesis and is eventually replaced with new bone, while the hydroxyapatite has good compressive resistance as well as osteoconductive properties. Two of these screws were placed side-by-side in the evacuated disc space. After one year of follow-up, bridging bone was observed in seventeen of twenty-four patients.

Radiostereometric analysis was used by Zoega and Lind to study twenty-four patients who were randomized to anterior cervical fusion with use of either autologous bone graft and a plate or paired BAK-C cages (Sulzer Spinetech, Minneapolis, Minnesota) with use of autologous local bone from reaming 14 . A 5° kyphotic deformation with a 1.5-mm loss of height was noted in both groups, although it was seen earlier in the BAK-C group. Relative motion was observed for as long as one year but was not observed at the time of the two-year final evaluation. The BAK-C group had less arm pain at one year.

The effects of smoking and compensation status following anterior cervical discectomy and fusion with cages were studied by Michael et al. 15 . The first analysis compared 145 smokers with 187 nonsmokers, while the second analysis compared 107 patients with work-related injuries with 225 patients whose injuries were not work-related. All patients had fusion with a BAK-C cage at one or two levels. The majority of patients (74.5%) rated the result of the procedure as good or excellent; specifically, the result was classified as good or excellent by 66% of smokers compared with 81.2% of nonsmokers and by 63.2% of patients in the compensation group compared with 79.9% of those in the noncompensation group. Tobacco use did not adversely affect the fusion rate at twenty-four months (97.1% in the compensation group compared with 96.6% in the noncompensation group); this difference was not significant.

In a multicenter retrospective study of 567 patients, Brooks et al. evaluated the efficacy of steroids in preventing airway compromise 16 . Two hundred and fifty-six patients received intravenous Decadron preoperatively, and the remaining 311 patients did not receive steroids. In the group managed with steroids, ten patients had airway complications, four of whom required emergency reintubation. Symptoms began thirty to forty-eight hours postoperatively. In the group managed without steroids, nineteen patients had airway compromise, six of whom required reintubation. Risk factors for this occurrence included excessive blood loss (>300 mL), the involvement of cephalad cervical levels (C2, C3, and C4), and a prolonged operative time (more than five hours). The authors concluded that preoperative treatment with intravenous Decadron did not appear to decrease the risk of airway complications and the need for reintubation.

Samartzis et al., in a retrospective review of ninety-nine consecutive patients undergoing anterior cervical discectomy and arthrodesis, reported a 97% rate of successful osseous fusion 17 . All three failures occurred in patients who had been managed with a plate and autograft (one of whom was a smoker), and all occurred at the C5-C6 level. The clinical outcome was not significantly affected by the success or failure of fusion, the use of plating, or the presence or absence of a work-related injury.

What's New in the Surgical Treatment of the Lumbar Spine

Surgical Management of Chronic Low-Back Pain
In a prospective, randomized study, the Swedish Lumbar Spine Study Group compared the effectiveness of lumbar fusion with that of nonoperative treatment for patients with chronic low-back pain 18 . A total of 294 patients with chronic low-back pain of at least two years' duration and radiographic evidence of lumbar degenerative disc disease were randomized to surgical treatment with one of three different fusion techniques (222 patients) or to nonoperative treatment with a physical therapy program (seventy-two patients). At two years of follow-up, the surgical treatment arm had much better results than the nonsurgical treatment arm in almost every outcome measure, including pain, disability, overall patient assessment, overall independent observer assessment, and return to work. The authors concluded that lumbar fusion has a role in providing substantial symptomatic relief in carefully selected patients with chronic low-back pain. That report represents the first large-scale, prospective, randomized, controlled study comparing operative with nonoperative care for chronic low-back pain. After demonstrating a rapid improvement at the six-month mark, the surgical treatment group demonstrated a marked increase in back pain between the twelve and twenty-four month evaluations. Despite this finding, the patients in the surgical treatment group still had less pain than those in the nonsurgical treatment group at twenty-four months.

Additional information was gleaned from that study population by comparing the 222 patients in the surgical treatment group in an effort to determine the optimal fusion technique 19 . The patients were randomized to treatment with posterolateral fusion without instrumentation (Group 1), posterolateral fusion with instrumentation (Group 2), or posterolateral fusion with instrumentation and interbody fusion through either an anterior or posterior approach (Group 3). Despite the contemporary emphasis in the United States on improving fusion rates with instrumentation and interbody devices, no difference in pain or function was demonstrated among the three groups after two years of follow-up. Both the fusion rate (72%, 87%, and 91% for Groups 1, 2, and 3, respectively) and the early complication rates (6%, 16%, and 31% for Groups 1, 2, and 3, respectively) increased with surgical complexity. Another report by the same group of investigators assessed predictors of outcome in this surgical treatment group and found that collapsed disc height (implying severe disc degeneration) and low personality neuroticism predicted good functional improvement 20 .

Intervertebral Disc Replacement
Intervertebral disc arthroplasty continues to be extensively investigated as an alternative to fusion for the treatment of the painful sequelae of degenerative disc disease. Two devices—the SB Charité III and the ProDisc—are currently undergoing FDA-approved trials in the United States. A prospective, randomized trial comparing the SB Charité III disc replacement with a stand-alone anterior interbody fusion with use of a BAK cage (Sulzer Spinetech) was initiated in the United States in March 2000. The preliminary results for the first fifty-six consecutive patients treated with disc replacement at a single American institution were reported by Hochschuler et al. 21 . After six weeks of follow-up, the mean pain scores had improved by 52.7% and the mean Oswestry disability scores had improved by 39.6% compared with the preoperative status. These improvements were generally maintained at twelve months. A comparison with the patients in the fusion arm of the study was not performed. An evaluation of osseous ingrowth onto the hydroxyapatite-coated SB Charité prosthesis (available only in Europe) in a nonhuman primate model demonstrated a mean ingrowth area of 47.9%, which compares very favorably with that typically seen in association with hip and knee prostheses 22 .

A prospective, randomized comparison of the ProDisc disc replacement with anterior-posterior 360° circumferential fusion was begun in the United States in October 2001. At the time of the six-month follow-up of the first thirty-nine patients in this study, the ProDisc group had decreased operative time, blood loss, and hospital stay as well as more rapid rehabilitation, better patient satisfaction, and improved Oswestry Disability Index scores 23 . Bertagnoli and Kumar 24 reported the results of a European prospective study in which 108 patients who had had a total of 134 arthroplasties with the ProDisc device were followed for three to twenty-four months. Using an undefined outcomes scale, the authors reported that the "overall clinical outcome" was excellent for 90.8% of the patients, good for 7.4%, fair for 1.8%, and poor for none. The authors attempted to define predictive factors for good outcome and concluded that the best candidates for this procedure had single-level disc degeneration with >4 mm of disc height, no arthritic changes in the facet joints, no adjacent-level degeneration, and intact posterior elements.

Cunningham et al. reported on another disc replacement device, the AcroFlex lumbar disc (DePuy AcroMed, Raynham, Massachusetts) in a nonhuman primate model 25 . The prosthetic device was compared with tricortical iliac crest autograft fusion in mature male baboons. The authors found excellent osseous ingrowth into the AcroFlex interfaces at twelve months postoperatively. Unfortunately, at the twelve-month evaluation, the range of motion was not significantly different between the levels treated with a prosthesis and the levels treated with fusion. This loss of motion appeared to be related to perianular calcification bridging the arthroplasty segments.

The European Spine Journal published a supplement (Volume 11, Supplement 2, October 2002) dedicated to spinal arthroplasty. This supplement covers many aspects of the history and development of motion-sparing devices for disc degeneration and discusses the clinical results associated with a number of contemporary prosthetic devices.

Minimally Invasive Techniques in the Lumbar Spine
Minimally invasive techniques have enormous potential to reduce perioperative morbidity in the lumbar spine. As interest in this area continues to grow, the journal Neurosurgery devoted an entire issue (Volume 51, Number 5, November 2002) to a comprehensive overview of topics pertaining to minimally invasive spine surgery. This technology is evolving, and the indications for its use are still being established. Guiot et al. reported on the technical feasibility of percutaneous microendoscopic posterior lumbar decompression with use of a cadaveric model 26 . They reported on the use of the METRx system (Medtronic Sofamor Danek), which allows for visualization and decompression through an 18-mm working channel that is established by passing serial dilators over a Steinmann pin. They were able to perform unilateral and bilateral laminotomies comparable with an open technique, although there was a learning curve as the later procedures took half the time (two hours) of the first procedures in the series. Khoo and Fessler performed an analysis in which twenty-five consecutive patients with lumbar spinal stenosis who underwent decompression with use of this percutaneous microendoscopic system were compared with twenty-five patients who underwent a standard open posterior lumbar laminectomy 27 . They found similar clinical outcomes in the two groups, but the blood loss, length of postoperative stay, and postoperative use of narcotics were less in the group that had been treated with the minimally invasive technique.

While minimally invasive techniques for posterior lumbar spine surgery appear to be gaining momentum, several recently published reports have questioned the effectiveness of laparoscopic techniques of anterior lumbar interbody fusion. Rodriguez et al. compared thirty-one patients undergoing laparoscopic L5-S1 fusions with fourteen patients undergoing open L5-S1 procedures 28 . They found that the laparoscopic procedure was associated with less blood loss and slightly shorter operative times but was not associated with advantages in terms of perioperative narcotic analgesia, length of hospital stay, or estimated hospital costs (which were more than $1300 higher than those for the open technique). Kaiser et al. compared forty-seven patients who underwent a laparoscopic anterior lumbar interbody fusion with fifty-one patients who were treated with use of a mini-open technique 29 . The laparoscopic procedures took longer and were associated with a higher rate of retrograde ejaculation, although the length of hospital stay was slightly shorter and the immediate postoperative complications were fewer. Liu et al. reviewed fourteen patients who underwent laparoscopic anterior lumbar fusion and reported that while the length of hospital stay postoperatively was marginally shorter than that associated with the open technique, the laparoscopic procedure took much longer (even after the initial learning curve), required conversion to an open procedure in three of fourteen cases, and provided inferior exposure than did the open technique 30 .

What's New in the Treatment of Spinal Deformity

Adolescent Idiopathic Scoliosis
Investigators at several centers are attempting to characterize the amount of back pain, quality of life, and function many years after fusion with Harrington instrumentation is performed for the treatment of adolescent idiopathic scoliosis. Investigators from Sweden and Germany reported on the outcomes of the procedure after fifteen to twenty-five years of follow-up 31,32 . The group from Sweden found that both back pain and function were approximately the same in the surgically treated group as in the general population 31 . In that study, contrary to previous studies from the same center, the authors were not able to find a significant correlation between back pain and the caudad extent of the fusion. The group from Germany found that the surgically treated group had excellent quality-of-life scores 32 . The psychological status of these patients was somewhat impaired, although the impairment did not appear to be related to curve type or the size of the deformity.

Selective fusion of thoracic curves in patients with a false double-major pattern continues to generate interest. Criteria for establishing the difference between a false double-major pattern and a true double-major pattern continue to evolve. With intermediate-term follow-up, selective fusion continues to be an appropriate treatment method. However, the ability of the lumbar curve to truly correct spontaneously is limited and somewhat unpredictable. True spontaneous correction of the lumbar curve is best measured by a decrease in the apical vertebral translation rather than a decrease in the Cobb measurement, which can be misleading.

Spondylolisthesis
Over the last several years, there has been increasing interest in providing interbody fusion (rather than simply posterolateral fusion) at the L5-S1 level for medium and low-grade isthmic spondylolisthesis. Work from Sapporo, Japan suggested that interbody fusion is especially appropriate if patients have a segmental kyphosis at L5-S1 and/or preserved disc height, implying more potential for progression and failure of posterior instrumentation alone 33 .

Postfracture Treatment
Suk and his colleagues in Korea continue to suggest that posterior eggshell decompression in patients with posttraumatic kyphosis is a very reasonable alternative to combined anterior and posterior surgery 34 . The posterior-only approach can be accomplished with less operating time and less blood loss. Particularly in the elderly patient, the morbidity associated with an anterolateral approach is substantial.

Pediatric Spinal Disorders
The crankshaft phenomenon refers to progression of the spinal deformity in spite of a solid posterior fusion due to continued anterior growth and rotation of the vertebral bodies around the posterior fusion mass. Pedicle screw fixation may prevent this phenomenon and negate the need for anterior fusion 35 . Although there are some soft data to suggest that this may be the case, it has not been definitively demonstrated.

Treatment of thoracic insufficiency syndrome in children with extensive thoracic congenital scoliosis has been a strong focus of Robert Campbell 36 . Early data based on extensive studies in a small number of patients suggest that opening-wedge expansion thoracostomy may lead to increased lung volume.

Treatment of spinal deformities in patients with cerebral palsy has always been a strong interest of the Scoliosis Research Society. Despite the difficulty of measuring outcomes in this group of patients, Lonstein et al. demonstrated that the majority of families noted functional benefits following spine surgery and 92% would agree to surgery again 37 . There is no single good outcomes instrument for this group of patients.

Etiology and Natural History
Ongoing work in Dallas, Texas, and Baltimore, Maryland, has demonstrated that idiopathic scoliosis clearly has a genetic component but that it is quite complex 38,39 . Investigators in Montreal, Canada, are studying whether melatonin plays a role 40 . Data suggest that melatonin signaling is impaired in osteoblastic cells isolated from patients with adolescent idiopathic scoliosis. It is hoped that at some point pharmacologic approaches will be used in the treatment of idiopathic scoliosis, but this work is still very preliminary.

Complications
Pedicle subtraction osteotomy represents a very valuable method for the treatment of severe sagittal deformities. This method is very technically demanding and carries the risks of substantial potential complications. There is a high prevalence of solid fusion at the segments treated with pedicle subtraction osteotomy, but it is very difficult to obtain solid fusion at all of the other instrumented segments, especially in older, osteoporotic patients 41 .

The number of short-term complications associated with spinal fusion for the treatment of thoracic adolescent idiopathic scoliosis is relatively small. Fusion is achieved fairly easily and, as expected, complications are rare in this young, very healthy patient population. In a multicenter study, there was no difference in the rate of early complications between patients managed with an anterior approach and those managed with a posterior approach 42 .

The use of thoracotomy in the treatment of thoracic idiopathic scoliosis is less popular now than it was several years ago. A study analyzing pulmonary function at a minimum of five years after surgical treatment of idiopathic scoliosis showed that open thoracotomy clearly had a negative effect on ultimate pulmonary function 43 . The long-term clinical importance of this finding is unknown at this time.

Blood Transfusion
Methods of reducing the blood loss associated with surgical treatment of spinal deformities continue to evolve. Studies from St. Louis, Missouri, and Cleveland, Ohio, have suggested that the agents Aprotonin and Amicar may be useful to reduce blood loss 44,45 .

Spinal Fusion
Interest in the use of BMP-2 and BMP-7 to facilitate fusion in the treatment of spinal deformities continues to be high. Unfortunately, to date, all human clinical studies have focused on single-level pathology. One study, in which BMP-7 (OP-1) was compared with autograft for multilevel fusion to the sacrum in sheep, demonstrated a high rate of nonunion in both groups 46 .

Adult Spinal Deformity
A long fusion to the sacrum that is accomplished without pseudarthrosis and with good coronal and sagittal balance yields a very high functional result in the majority of cases. However, pseudarthrosis remains a substantial obstacle. Ending the fusion at L5 rather than at the sacrum is not a solution as complications related to implant loosening at L5 and subsequent degeneration at L5-S1 reduce the utility of this approach 47 . Sacropelvic fixation and circumferential fusion at L5-S1 are both useful techniques but also do not eliminate the possibility of pseudarthrosis.

For major deformities, there are advantages and disadvantages to both same-day surgery and staged surgery. Medical complications are somewhat more frequent in patients having same-day surgery. Staging the procedures is reasonable as long as parenteral nutrition is utilized and the patient is mobilized between the procedures.

Outcomes
The SRS-22 (the Scoliosis Research Society instrument) continues to perform well for measuring outcomes in adolescents with idiopathic scoliosis 48 . Even though very little data exist regarding the use of the SRS-22 for the evaluation of patients with adult spinal deformity, it has been suggested that this instrument may be as useful for that purpose as it is for the evaluation of patients with adolescent idiopathic scoliosis 49 .

New Technology
Investigators at several centers are currently exploring "fusionless" surgery in young patients with idiopathic scoliosis 50,51 . The concept here is to alter growth of the spine with use of instrumentation without fusing segments. Although the early data are encouraging, longer follow-up and refinement of these techniques will be needed.

What's New in the Treatment of Spinal Cord Injury

High-Dose Methylprednisolone
High-dose methylprednisolone is the only neuroprotective agent currently used to treat spinal cord injury. The drug must be administered early following spinal cord injury and in high doses. The National Acute Spinal Cord Injury Studies (NASCIS) II and III are controlled, randomized trials and are considered Level-I evidence demonstrating efficacy. These studies have shown increased neurologic recovery in patients treated with methylprednisolone within eight hours after an injury. Controversy regarding these studies began immediately following their publication and has recently intensified.

The use of methylprednisolone has not been as well accepted outside the United States. Hugenholtz et al. questioned surgeons in Canada regarding their use of the NASCIS protocols 52 . Only 30% of the respondents followed the recommendations of NASCIS II, and 36% followed the recommendations of NASCIS III. When asked why they recommended methylprednisolone, only 17% did so because they believed that patients benefited whereas 35% did so to avoid litigation. Similar findings were observed in a poll of members of the European Cervical Spine Research Society 53 . In the United Kingdom, Molloy et al. audited 100 patients at regional centers regarding compliance with NASCIS II or III standards 54 . Only 25% had the received the correct administration of methylprednisolone. Another 10% had received the correct dose but for too short of an interval, and 6% had received steroids more than eight hours after the injury.

The lack of functional data was a major criticism of NASCIS II that was corrected in NASCIS III by the inclusion of functional independence measures. Pollard and Apple analyzed functional improvement in 412 patients with incomplete tetraplegia who were treated at a model spinal cord injury center 55 . The investigators found better recovery in younger patients and those with central cord or Brown-Sequard injuries. The administration of high-dose methylprednisolone had no significant effect on outcome.

To further argue against steroids, Pointillart et al. of Bordeaux, France reviewed 100 patients who had been randomized to pharmacologic treatment or placebo and found no benefit in association with any of the pharmacologic treatments, including high-dose methylprednisolone 56 . Matsumoto et al., in Japan, performed a randomized placebo-controlled study similar to NASCIS II 57 . No benefit was observed in association with the use of steroids. However, a significant increase in pulmonary and gastrointestinal complications was seen in the methylprednisolone group, especially in patients more than sixty years of age.

Molano et al. analyzed the rates of complications in patients who initially were treated with methylprednisolone and subsequently underwent a surgical procedure 58 . Eighteen patients received no additional methylprednisolone, and fifty-five patients received a second dose according to NASCIS II. The average delay before surgery was five days in both groups. Complications were seen twice as often in the patients who received a second dose. More importantly, the patients who received a second dose had the more serious complications of pulmonary sepsis, gastrointestinal bleeding, and thromboembolic disease, and three of those patients died.

In the most probing analysis, Hurlbert statistically analyzed the NASCIS II and III data 59 . He found no differences between the three study groups (patients who had received a placebo, patients who had received methylprednisolone for twenty-four hours, and patients who had received methylprednisolone for forty-eight hours) in terms of the primary outcome variable (neurologic recovery). Any reported significant results were a result of post hoc analysis, analysis of only left-sided data, deletion of a motor level segment, failure to account for noncompliance, and division into artificial groups. Although the complication rate was higher in the twenty-four-hour treatment group, the difference failed to reach significance. A power analysis revealed that three times as many patients would have been required to reach that conclusion. Finally, a significantly increased mortality rate was observed in the group that received methylprednisolone for forty-eight hours, but that finding had not been reported in the NASCIS studies.

Short performed a meta-analysis of the use of methylprednisolone in the treatment of spinal cord injuries 60 . On the basis of Level-I and II evidence, he concluded that methylprednisolone should be "excluded from correlation as an intervention for spinal cord injury." On the risk side, the evidence suggested that the studies "cannot reliably provide measurement of safety."

Finally, the editors of Neurosurgery presented guidelines for the care of patients with spinal cord injuries 61 . In this cogent analysis, the relevant clinical studies were assessed. The authors concluded "the available medical evidences does not support a significant clinical benefit from administration of methylprednisolone . . . for either 24 or 48 hours . . . the evidence suggesting harmful side effects is more consistent than the suggestion of clinical benefits."

Spinal Cord Regeneration
The ultimate cure for spinal cord injury will be the repair or regeneration of irreversibly damaged neural tissue. Several investigations are showing promise, but many years will be needed before results are of clinical use. Maiman et al., in a study of cats, applied pulsed magnetic fields to enhance axonal growth and direction 62 . The cats in the experimental group were treated with twelve weeks of pulsed magnetic fields following incomplete and complete thoracic cord injury. The cats in the experimental group had more axons, improved motor function, and better recovery of somatosensory evoked potential waveforms than did those in the control group.

Another strategy to treat spinal cord injury is to upregulate gene expression with use of genetic transfer techniques. Harrop and associates inserted two cell-specific promoter genes into the spinal cord of rats with use of an adeno-associated virus (AAV) vector 63 . They observed an efficient delivery of the genes into spinal astrocytes and other glial cells and found that the cells expressed the cell-type-specific proteins in a dose-dependent fashion.

Transplantation of immature or pluripotential neural cells may improve the local environment, provide cells for the growth of new neurons, and permit axonal regeneration. Antonacci et al. transplanted nonmodified human bone-marrow stem cells into rats following cord transection 64 . The cells were packaged in several different engineered carrier matrices. The investigators found permissive new neuronal growth in all cases. However, penetration into the distal segment by axons was seen only when genetically modified fibroblasts or a carrier such as collagen matrix was used.

Endogenous or transplanted neural precursor cells can proliferate and differentiate following spinal cord injury. However, the majority of cells become astrocytes rather than neuronal cells. This process of glial transformation appears to be facilitated in the presence of BMP. Setoguchi et al. demonstrated that blocking BMP expression with use of gene therapy increased transformation of precursor cells to neuronal cells away from astrocytes 65 .

Advances in Rehabilitation
Optimized patterned neural activity, that is, a set of specific exercise patterns, may be important to normal central nervous system development and to the process of spontaneous regeneration. These activities appear to promote cell migration, differentiation, selection of new circuits, and myelination. It is hypothesized that the performance of patterned neuronal activity may have a positive impact on physical conditioning and may increase neurologic recovery following spinal cord injury.

McDonald et al. reported a single case of late spontaneous recovery beginning five years after a complete spinal cord injury 66 . The patient had no documented improvement on careful neurologic examination prior to beginning an activity-based recovery program. This program consisted of training on an FES (functional electrical stimulation) bicycle for as much as one hour per day, three to four times per week. Surface electrical stimulation was applied on alternate days and aquatherapy was initiated later. Physical improvements were noted within six months. Two years later, the patient had normal bone mass (from a low Z-score of -4 standard deviations at the time of the most osteogenic measurement), had reduced rates of infection and other complications, and had an increase in almost all quality-of-life measures. Dramatically, the patient experienced return of sensation within nine months and voluntary movement of the index finger. The patient's American Spinal Injury Association (ASIA) motor score (possible range, 0 to 100) improved from 0 to 20, and his sensory score (possible range, 0 to 112) improved from 7 to 65. A comparison of electromyographic activity with the findings of a study done six years earlier demonstrated new voluntary activation of most muscle groups, including the diaphragm. At the time of the most recent follow-up, the patient remained ventilator-dependent but had received diaphragmatic pacemakers and enjoyed increased time off the ventilator. That case report is provocative and demonstrates that it is possible for neural function to return in impaired axonal tracts with proper training.

What's New in Biologic Topics for the Spine

One of the most exciting advances in the treatment of spinal disorders continues to be in the biologic area. There has been continued willingness on the part of spine researchers and clinicians to embrace the techniques of modern molecular biology and genetics. In the past year, an important milestone was reached when the Food and Drug Administration granted a Post Marketing Approval for the first recombinant osteoinductive protein for a spine fusion application—some thirty-eight years since Marshall Urist's first report in the journal Science 67 . There are two areas in which there was notable activity during the past year: bone-graft substitutes and the biology of intervertebral disc metabolism.

Bone-Graft Substitutes
Surgeons have used coralline hydroxyapatite for anterior cervical interbody arthrodesis for years, despite the paucity of clinical data. McConnell et al. compared Pro Osteon 200 (Interpore Cross, Irvine, California) with autogenous bone graft and found no difference in terms of the fusion rate or clinical outcomes but did observe a significant difference in terms of the rate of graft-settling (observed in association with 50% of the hydroxyapatite grafts compared with 11% of the autografts; p = 0.009) 68 . Moreover, fragmentation occurred in 89% of the hydroxyapatite grafts and only 11% of the autografts (p = 0.001). That study demonstrated that Pro Osteon 200 does not possess adequate structural integrity to resist axial loading and maintain disc height during cervical interbody arthrodesis.

Biophysical stimulation has been studied for years in orthopaedic surgery applications but has not realized its full potential in the area of spinal arthrodesis. Aynaci et al. reported on the effect of ultrasound on the healing of muscle-pediculated bone graft in a rabbit model of posterolateral spinal fusion 69 . They found that twenty minutes of ultrasound per day improved the fusion rate from 55% in the control group to 85% in the ultrasound group. It is somewhat concerning that a 100% rate of successful fusion could not be achieved even in the rabbit model, suggesting that this technology in its current form may not be as potent as osteoinductive factors such as the bone morphogenetic proteins (BMPs).

Important progress was made in the past year in the area of optimizing purified and recombinant BMPs for use in spinal arthrodesis. Damien et al. reported that a bovine BMP extract had 100% fusion efficacy in rabbits and rhesus monkeys, with an excellent safety profile 70 . Suh et al. performed an important study to advance the science of the carrier matrix or scaffold for delivery of BMP 71 . In that study, the investigators tested several ratios of hydroxyapatite and tricalcium phosphate as an additive to the original absorbable collagen sponge carrier. They pointed out that the plain collagen sponge was too easily compressed by paraspinal muscles and resorbed too quickly to be used for posterolateral spinal arthrodesis in primates. They determined that 15% hydroxyapatite and 85% tricalcium phosphate added to the collagen sponge formed a compression-resistant matrix that was very suitable for delivery of recombinant human BMP-2 (rhBMP-2; Medtronic Sofamor Danek).

Successful use of BMPs for posterolateral arthrodesis in humans has proven to be a greater challenge. Vaccaro et al. reported the early results associated with recombinant human Osteogenic Protein-1 (OP-1; Stryker Biotech, Hopkinton, Massachusetts), which contains rhBMP-7 72 . In a recent review article, they reported only a 75% rate of successful fusion following posterolateral arthrodesis without instrumentation in patients with grade-I or II spondylolisthesis who were evaluated with plain radiographs. The reason for the lack of a higher success rate is unclear, but it may have been related to suboptimal dosing or carrier properties. The 2002 Volvo Award for Low Back Pain Research for a Clinical Topic was awarded to a paper documenting the first highly successful clinical pilot trial of a recombinant BMP in posterolateral spinal arthrodesis 73 . In that study, all patients with single-level disc degeneration and grade-1 or less spondylolisthesis who received rhBMP-2 with a 60% hydroxyapatite/40% tricalcium phosphate granular carrier (Medtronic Sofamor Danek) achieved a successful arthrodesis as determined with thin-slice computed tomography scans that were evaluated by two independent observers. Half of these patients had a successful fusion without the use of any internal fixation. There continues to be interest in gene therapy as an alternative delivery strategy for BMPs, but this technology is still years away from clinical trials 74 .

Biologic Treatments for Disc Degeneration
The second main area with substantial progress in the past year involves an improved understanding of intervertebral disc biology and the development of animal models that will enable the testing of strategies designed to retard injury or degeneration 75 . Many of the strategies for biologic treatments of disc degeneration involve the implantation of cells or the use of various gene-therapy vectors such as adenovirus. An exciting opportunity for such therapies is related to the observation that the intervertebral disc appears to be immune-privileged 76 . This characteristic of the disc makes it an easier target for gene therapy with vectors that are often hampered by immune responses, and it also makes it possible to use allogeneic cells rather than autologous cells that usually require culture expansion, resulting in increased costs and inconvenience.

A major obstacle to progress in this area is the lack of a suitable validated model for natural (age-related) disc degeneration. Many of the existing models involve a disc injury (such as a stab wound) and result in a rapid onset of degenerative changes that may or may not mimic natural degeneration. A variety of new models are currently under development. Kroeber et al. described a rabbit model involving axial compression of the spine and reported that permanent changes resulted after fourteen to twenty-eight days 77 .

Another area of improved understanding involves the determination of the changes in gene expression that are associated with disc degeneration. Cs-Szabo et al. studied gene expression in disc tissue from thirty-four patients 78 . They found that decreased mRNA expression by the nucleus pulposus cells and declining protein content of the matrix make the nucleus more vulnerable to degeneration by upregulating biosynthetic processes. The cells of the anulus fibrosus respond to early degeneration by upregulating biosynthetic processes. However, in heavily degenerated tissues, the decline in the synthesis of aggrecan and the increase in the concentrations of small proteoglycans may be responsible for the failure of the repair processes. Boos et al. received a 2002 Volvo Award for their histologic study of age-related changes of the human lumbar intervertebral disc 79 . The investigators found that histologic disc alterations could be reliably graded and that diminished blood supply to the intervertebral disc in the first half of the second decade of life appears to initiate tissue breakdown.

Upcoming Meetings and Events Related to Spine Surgery

The next Annual Meeting of the Scoliosis Research Society (SRS) will be held on September 11, 12, and 13, 2003, in Quebec City, Canada. It will be preceded by a one-day course on spondylolysis and spondylolisthesis, to be held on September 10. Web site: www.srs.org

World Spine II will be held on August 10-13, 2003, at the Hyatt Regency Hotel, Chicago, Illinois. Web site: www.worldspine.org

The next Annual Meeting of the North American Spine Society (NASS) will be held on October 21-25, 2003, at the San Diego Convention Center, San Diego, California. Web site: www.spine.org

The next Annual Meeting of the Cervical Spine Research Society (CSRS) will be held on December 11, 12, and 13, 2003, at Fairmont Scottsdale Princess Hotel, Scottsdale, Arizona. Web site: www.csrs.org

The Federation of Spine Associations will present the spine program at Specialty Day on Saturday March 13, 2004, at the Annual Meeting of the American Academy of Orthopaedic Surgeons in San Francisco, California. Web site: www.aaos.org

The next Annual Meeting of the American Spinal Injury Association (ASIA) will be held on May 14, 15, and 16, 2004, in Denver, Colorado. Web site: www.asia-spinalinjury.org

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