The results of randomized controlled trials of several cervical
arthroplasty devices are becoming available and are the focus of much
attention. At the same time, secondary outcomes are being analyzed that may
address socioeconomic concerns about the costs and observable benefits of
arthroplasty. Since the introduction of a validated outcome tool to measure
swallowing dysfunction, researchers have more critically analyzed
postoperative dysphagia. With the continued expansion of the use of cervical
laminoplasty, methods to reduce complications continue to be explored.
Disc Arthroplasty
Disc arthroplasty is currently undergoing rigorous clinical testing, and
the outcomes of this procedure are being compared with those of fusion in
randomized controlled trials. The inclusion criteria are single level
radiculopathy or myelopathy, failure of nonoperative management, adult age,
and the absence of significant instability or severe spondylosis or facet
disease. Full reports on these trials are not yet available. However, pooled
results from several investigation sites have been presented for three
different prostheses. All studies have shown significant improvements in
outcome measures for both fusion and experimental groups. With arthroplasty,
the mean range of motion has increased by 1° to 2° and the rates of
complications related to the procedure have been low, with no differences
compared with controls. Two studies evaluating titanium polyurethane and
stainless steel metal-on-metal prostheses demonstrated that the pooled site
outcomes were significantly better for the arthroplasty group than for the
fusion group with regard to pain, disability, and overall success. Six-year
outcomes from Europe are encouraging, with patients maintaining clinical
improvement and motion. Adjacent-segment disease appears to progress in
patients with preexisting disease but not in its absence.
From outside the United States, there have been case reports of
complications, including the late development of central stenosis secondary to
osteophyte formation, fracture of a vertebral body during insertion,
spontaneous fusion, expulsion of the device, and kyphotic angulation. Despite
these cases, the results of disc arthroplasty are encouraging, but longer
follow-up is needed.
Early return to function is a hypothetical benefit of arthroplasty. In
general, arthroplasty does not require immobilization and patients are allowed
to rapidly return to full function. The median time to return to work is
significantly better following arthroplasty than it is following fusion. This
effect is even greater in patients receiving Workers' Compensation. From a
socioeconomic perspective, this may mitigate the additional cost of the
implant and the additional surgical time.
Complications
Wang et al. reported on the complications and mortality associated with
surgical treatment in patients with degenerative cervical spine disease. That
study was a retrospective analysis of the Nationwide Inpatient Sample (a
sample of hospital discharges). Over a ten-year period, 0.3% of hospital
admissions were for the treatment of cervical spine disease. Complications
based on specific disease codes were present in 3.9% of the patients, with an
overall mortality rate of 0.14%. Multivariate analysis identified risk factors
for complications, including age (more than seventy-four years), a diagnosis
of myelopathy, a posterior fusion alone, or combined anterior-posterior
fusion.
Dysphagia is an under-recognized morbidity after anterior cervical surgery.
Using an accepted outcome instrument, Lee et al. found that dysphagia was
present in >50% of patients at one month and as many as 15% at two years.
Risk factors included female gender, revision procedures, and multilevel
procedures. Ischemia of the upper esophageal sphincter mucosa resulting from
the use of soft-tissue retractors may be the cause of postoperative dysphagia.
Maintaining the endotracheal balloon pressures at <20 mm Hg, intermittent
relaxation of retractors, and cuff reinflation after the retractors are placed
are all strategies that may decrease dysphagia.
Myelopathy
Expansive laminoplasty for decompression in patients with multilevel spinal
cord stenosis and myelopathy generally has been shown to have an outcome
similar to that of anterior decompression and fusion. Laminoplasty avoids
problems with fusion but has been associated with kyphotic deformity and
chronic neck pain. A number of strategies have been described to decrease this
tendency. Liu et al. preserved the spinous process-ligament-muscle complex
with use of an osteotomy at the base of the spinous process reconstructed with
wire fixation. Thirty patients had a mean increase of 9° of lordosis, and
no patient had increased kyphosis. Other approaches to minimize neck pain
include avoiding C7 laminoplasty altogether and performing a laminectomy
rather that a laminoplasty at C3; this affords greater retention of the
musculature attachments to C2. These techniques have been associated with
diminished axial pain in case series. Their acceptance will require
better-designed studies to prove their safety and efficacy.
In the study by Miyata, forty patients who had postoperative ossification
of the posterior longitudinal ligament following a French-door type of
laminoplasty were evaluated with dynamic magnetic resonance imaging. The
author found that the cord had shifted posteriorly and was adequately
decompressed. This study again validates that posterior decompression allows
posterior cord translation away from the ventral pathology.
Despite surgical treatment, ossification of the posterior longitudinal
ligament appears to progress in the majority of patients and can lead to
recurrent symptoms. No means to decrease this tendency have been developed.
Furthermore, it is not known if fusion will likely increase or decrease this
phenomenon.
An important controversy is how to treat and counsel patients who have
cervical stenosis but are asymptomatic. Recent reports from the Cervical Spine
Research Society have shown that 30% of patients with stenosis experienced
minor trauma and that half of those will deteriorate neurologically. Future
studies should determine if a much more aggressive surgical approach can
prevent neural damage.
Spinal Cord Monitoring
Intraoperative neurophysiologic monitoring during cervical spine surgery
has not been shown to increase patient safety or to have a positive cost
benefit. Smith et al. reviewed 1039 cases of decompression for non-myelopathy
monitored with somatosensory evoked potentials and found a 1% incidence of any
changes. All changes in somatosensory evoked potentials were corrected by
normalizing blood pressure. There was one non-detected cord deficit, and no
differences were identified between patients who were monitored and those who
were not. In patients with myelopathy, transcranial motor evoked potentials
appear to identify C5 nerve root lesions in a majority of cases, although they
have not been shown to be useful in preventing injury to this nerve root.
Biologic tools for reconstruction and regeneration continue to be an
important focus of research related to the spine today. There are continued
efforts to enhance the process of achieving spine fusion and to eliminate the
need for autogenous iliac crest bone graft harvest. Since the United States
Food and Drug Administration's (FDA) post-marketing approval of recombinant
human bone morphogenetic protein-2 (rhBMP-2) in 2002 and the creation of a
Humanitarian Device Exemption for rhBMP-7 late in 2004, the era of recombinant
bone morphogenetic proteins for use in spine fusion has continued to blossom.
Given the limited access (with only two companies producing approved BMPs) as
well as their relatively high cost, there has been renewed interest in
promoting less expensive and potentially unvalidated alternative bone-graft
substitutes. Finally, while an increasing amount of research continues to be
focused on understanding the biology of the intervertebral disc and on
developing biologic strategies to retard or reverse degeneration, these
treatments still seem to be quite far from clinical practice.
Recombinant Osteoinductive Proteins
The initial clinical studies on the use of rhBMP-7 (OP-1; Stryker Biotech,
Hopkinton, Massachusetts) for posterolateral spine fusion yielded fusion
success rates of 50% to 70% on radiographs, and these modest fusion rates were
attributed to the use of a "more challenging" noninstrumented
spine fusion model. In 2006, nineteen patients with degenerative
spondylolisthesis were entered into a prospective, randomized, controlled
study of instrumented fusion. Patients were randomized to receive OP-1 putty
alone (3.5 mg of OP-1 per side) or local autograft with
hydroxyapatite-tricalcium phosphate granules. The fusions were evaluated with
plain radiographs and computed tomographic scans. Sixteen patients who showed
radiographic evidence of fusion underwent instrumentation removal and surgical
exploration of the fusion site. Although seven of the nine patients managed
with OP-1 were thought to have fusion on the radiographs, only four of the
seven actually had fusion at the time of exploration, for an overall OP-1
fusion rate of four of nine. In contrast, nine of the ten control patients who
were managed with local bone graft were thought to have fusion on radiographs
and seven of the nine actually had fusion at the time of exploration, for an
overall autograft fusion rate of seven of ten. Although this difference was
not significant because the study was underpowered, the fusion rate of
approximately 50% associated with the use of OP-1 in patients managed with an
instrumented fusion is consistent with the numbers reported in studies of
uninstrumented fusion and is still not at a level equal or superior to that of
autograft. It is believed that the data from the OP-1 posterolateral United
States clinical trial will remain under review by the FDA for consideration
for post-marketing approval.
Although rhBMP-2 (INFUSE; Medtronic Sofamor Danek, Memphis, Tennessee) has
been approved by the FDA for anterior lumbar interbody fusion, much
physician-directed use has occurred in the posterolateral spine. A subset of
data from an investigational device exemption study involving the use of a
higher concentration of rhBMP-2 (20 mg BMP-2 per side) on a
compression-resistant matrix (AMPLIFY; Medtronic) has been published. The
report included ninety-eight patients from a prospective, randomized study in
which AMPLIFY was compared with iliac crest bone graft in patients undergoing
a single level instrumented posterolateral lumbar fusion. In this subset of
patients, the radiographic fusion rate was 88% for the AMPLIFY group and 73%
for the iliac crest bone graft group (p = 0.05). This was the first time that
a recombinant BMP demonstrated superiority over autogenous bone graft. With
the outcome measures used, no substantial clinical benefit was detected in
association with the avoidance of harvesting an iliac crest bone graft.
Readers should note that the BMP formulation comprising AMPLIFY is different
(with respect to dose and carrier) than the currently available INFUSE
formulation. In another study, the approved INFUSE kit was used in addition to
iliac crest cancellous bone graft for instrumented posterolateral fusion. The
use of INFUSE in combination with iliac crest bone improved the fusion success
rate (as determined with thin-slice computed tomography scans) from 77% with
iliac crest graft alone to 97% with iliac crest graft plus one large InFuse
kit (6 mg BMP-2 per side) wrapped around local bone as a bulking agent. This
finding suggests that the current kit, while likely not sufficient as a
stand-alone graft substitute for the posterolateral spine, can provide a
significant enhancer effect, improving the success of autogenous bone
graft.
A primary concern with off-label use of recombinant BMPs relates to local
adverse events. The three most commonly reported local side effects have been
heterotopic bone formation in the surgical approach track, transient bone
resorption when used near exposed cancellous bone, and sterile seroma fluid
collections and/or local edema. Most of these local side effects are believed
to be related to the surgeon's use of too much BMP either by increasing the
concentration of the growth factor or by overstuffing the defect, which can
result in a higher concentration or leakage of BMP into the surrounding
tissues. Two reports have described perioperative swelling in the cervical
spine, again most often in association with excessive BMP doses and with the
implant being placed outside the structural cage or ring. Surgeons who are
encountering these local side effects with any regularity should carefully
examine their technique to limit the exposure of BMP directly to cancellous
bone (e.g., through less aggressive end plate decortication) and should avoid
the use of excessive amounts of BMPs in small spaces or overpacking of the BMP
implants.
Other Bone-Graft Substitutes
Although much focus remains on recombinant osteoinductive proteins, their
relatively high cost has continued to encourage research involving other
bone-grafting solutions. A recently published study demonstrated the failure
of platelet concentrates to improve spine fusion healing. This study adds to a
growing body of literature suggesting that platelet gels either inhibit or
have no effect on spine fusion healing. In addition, an animal study confirmed
that platelet-derived growth factor, transforming growth factor-beta, and
platelet gel inhibited the BMP activity in demineralized bone when implanted
together in animals. While platelet gels may serve a purpose for impaired
wound-healing, their role in promoting bone formation remains in question.
A recently published animal study investigated the role of simvastatin in
achieving posterolateral spine fusion in rabbits. Statins have been shown to
increase the expression of BMPs and may enhance bone formation in certain
situations. In this study, the systemic administration of simvastatin did not
positively or negatively affect spine fusion. It is possible that local
administration of statins may have more profound effects.
Interest in mesenchymal stem cells has increased with the introduction of
two mineralized allograft products that are claimed to have cryopreserved stem
cells. These products are claimed to immunodeplete the non-stem cells from
allograft and to provide a mineralized scaffold with allogeneic stem cells.
Since these products are regulated as "minimally manipulated
tissues," little outcome data are available. The studies that are under
way may not include the proper controls to assess whether the stem cells are
providing any increased healing in comparison with the allograft alone. These,
as well as other, minimally manipulated products that are claimed to have
bone-healing potential must be carefully evaluated by surgeons because the FDA
does not require definitive proof of bone-enhancing capability. In general,
the number of stem cells present in bone marrow is relatively small, and
without specific signals (e.g., BMP) it is not clear whether sufficient
numbers of cells are present to initiate bone formation de novo.
Biologic Treatments for Disc Degeneration
Progress toward biologic treatments to prevent or retard disc degeneration
continued at a slow pace. Continued evidence of beneficial effects of
recombinant BMPs (BMP-7, BMP-2, growth differentiation factor-5) on disc
metabolism in animals has prompted the planning of a clinical trial to
investigate the response in humans. A majority of this preclinical work has
been performed with OP-1, which can prevent disc height loss after needle
puncture injury and can restore disc height that has been already lost after
anular puncture in rabbits. Although this technology is a long way from
clinical use, it is worth monitoring developments in this area, which could
ultimately provide a groundbreaking technology for the treatment and
prevention of many degenerative spine disorders.
Over the past year, many articles and presentations addressed the etiology
of adolescent idiopathic scoliosis and the treatment of early-onset scoliosis
as well as congenital spinal deformity, particularly thoracic insufficiency
syndrome. There also have been advances in the treatment of kyphosis,
neuromuscular scoliosis, and spondylolisthesis. The Scoliosis Research Society
(SRS) continues to be very interested in investigating complications of
surgical treatment.
Etiology of Adolescent Idiopathic Scoliosis
Investigators from two centers presented papers at the recent SRS meeting
that further emphasized the potential genetic markers and familial
characteristics of idiopathic scoliosis. Identification of the etiology of
idiopathic scoliosis remains the number-one research goal of the SRS.
Early-Onset Scoliosis
Several new methods are evolving to allow for continued growth with
intermittent surgical lengthening of the spine for patients with infantile and
juvenile scoliosis. Such techniques utilize bilateral instrumentation,
intermittent distraction, and multiple fixation points at the top and bottom
and potentially at the apex of the deformity.
Congenital Spinal Deformity
The "titanium rib" technique with expansion thoracostomy has
continued to gain popularity and momentum. Early data continue to suggest that
distraction techniques associated with chest wall surgery can slowly lengthen
the spine without creating a major neurologic deficit and with modest
improvement in chest volumes. Documentation of changes in pulmonary function
in these patients is not straightforward, however. One study, conducted at The
Children's Hospital of Philadelphia, did not demonstrate a significant
improvement in lung function after expansion thoracostomy surgery. According
to one multicenter study presented at the SRS meeting, patients with thoracic
insufficiency syndrome clearly had marked reduction in their quality of life
when compared with other children on the basis of the Child Health
Questionnaire.
Kyphosis
One excellent paper that was presented at the SRS annual meeting emphasized
the risk of increased kyphosis and pain following implant removal because of
idiopathic scoliosis. Previous presentations have emphasized the problems
associated with implant removal in the adult population. It appears that this
is a substantial concern in the teenage population as well. The extent to
which changes in the deformity reflected bending of the fusion mass as opposed
to motion at undetected pseudarthroses was not entirely clear.
Neuromuscular Scoliosis
Assessment of the benefits of surgical treatment for patients with cerebral
palsy and spinal deformity is quite complex. Most previous studies have only
assessed radiographic parameters as opposed to a patient/parent evaluation.
One paper that was presented at the SRS meeting focused on eighty-one children
with cerebral palsy (and their families) who were undergoing spinal fusion.
The postoperative complication rate was high (33%). However, the family
satisfaction rate was quite high (92%). Eighty-seven percent reported
improvement in sitting balance, and 66% believed that quality of life had
improved. Unfortunately, at this time, health-related quality-of-life measures
for this population of patients are not standardized and validated.
Spondylolisthesis
Classification of spondylolisthesis has remained elusive. Authors from
Boston, Montreal, and France, as part of a multicenter study, have identified
two distinct groups regarding the sagittal alignment of patients with
high-grade spondylolisthesis. Critical factors appear to be the orientation of
the pelvis and the sacrum, the obliquity of the L5-S1 disc, and the degree of
dysplasia of the L5 element.
Adolescent Spinal Deformity
There continues to be a substantial effort to investigate the results
associated with the use of pedicle screw implants, particularly in the
thoracic spine, for the treatment of adolescent idiopathic scoliosis. Most
data suggest that correction is somewhat better in association with this
technique than in association with techniques involving the use of either
hooks or wires or a combination of hooks, wires, and screws. It appears that
Cobb angle correction, translational correction, and rotational correction are
all slightly better with pedicle screws than with other implants. Furthermore,
for curves of between 70° and 100°, it appears that anterior and
thoracoscopic releases frequently are not required if pedicle screw implants
are used to achieve fixation at all levels. In terms of cost analysis, pedicle
screw implants are expensive, but if they obviate the need for open or
thoracoscopic anterior releases, this is offset by the shorter operating time,
decreased surgical morbidity, and fewer days spent in the hospital and the
intensive care unit than is the case with a combined approach. One potential
disadvantage of the pedicle screw technique is that the hypokyphotic thoracic
spine remains hypokyphotic postoperatively as most of the pedicle screw
derotational techniques being employed now push anteriorly on the posterior
convex spine. Furthermore, there is no clear evidence that the increased
correction achieved with pedicle screw implants translates to higher Health
Related Quality of Life scores on SRS surveys.
Adult Spinal Deformity
An SRS classification system for adult spinal deformity continues to
evolve. This work is being accomplished by the Adult Spinal Deformity
Committee of the SRS, led by Thomas Lowe, MD. The aspects of the
classification include curve type, sagittl modifiers, distal lumbar
degenerative modifiers, and global balance parameters. In addition, Frank
Schwab, MD, has a very similar classification scheme, which is reflective of
the likelihood of surgical intervention. Factors that predict the need for
surgical treatment of adult scoliosis include sagittal and coronal plane
decompensation, substantial rotatory subluxations, spinal stenosis symptoms,
and deformity progression. The coronal Cobb angle itself is not a primary
determinant for surgical intervention. It does appear the SRS Health Related
Quality of Life instrument is far more responsive to change following the
surgical treatment of adult spinal deformity than it is following the surgical
treatment of adolescent deformity. With adolescent deformity, it appears that
the only domain that substantially changes after surgery is the self-image
domain, whereas with adult spinal deformity, changes typically are identified
in all domains.
Complications after surgery for the correction of spinal deformity are more
common in adults than in adolescents. These complications include
pseudarthrosis, proximal and distal junctional kyphosis, and an extended
recovery. RhBMP is being considered as an alternative or adjunct to reduce the
pseudarthrosis rate in adults with spinal deformity. However, use of these
products for posterior surgery constitutes an offlabel use and is
prohibitively expensive for many centers.
Complications
The Morbidity and Mortality Committee report to the membership at the
annual SRS meeting was an exhaustive study of the complications of spinal
fusion for the treatment of adult scoliosis. Adult patients who had idiopathic
scoliosis were compared with those who had scoliosis of a purely degenerative
origin. From 2003 to 2005, 2852 patients underwent spinal fusion for the
treatment of adult scoliosis. The complication rate was significantly higher
in the degenerative group than in the idiopathic group (15.6% compared with
12.3%; p < 0.01). The death rate was the same in both groups. The
neurologic complication rate was 1.3% overall, with six documented spinal cord
deficits (0.21%), but only one deficit was complete (0.04%).
Research in the area of spinal cord injury is making strides in
understanding the mechanisms of secondary injury and the factors inhibiting
axonal regeneration. Cell death not only occurs at the time of injury but also
is due to a cascade of secondary events that result in further neurologic
dysfunction. Multiple biochemical processes, including the production of
reactive oxygen species, excitotoxicity from neurotransmitter release, and
imbalances in ion concentrations at a cellular level, culminate in the death
of neurons and supporting glial cells.
Spinal cord injury is followed by changes that inhibit the regrowth of
axons and the reestablishment of neural connections. It was once thought that
axonal regeneration could not occur within the central nervous system, but it
is now understood that central nervous system axons can regenerate in the
proper environment. Formation of a glial scar and production of inhibitory
compounds in the extracellular matrix impede the regrowth of axons across the
site of injury.
As a result of a better understanding of the multiple biochemical processes
that result in secondary cell injury and the inhibition of axonal
regeneration, many new therapies are being studied. In addition, new
strategies are being investigated to bridge the gap across a damaged spinal
cord segment.
Therapies to Reduce Secondary Injury
Historically, the investigation of spinal cord injury therapies has focused
on the inhibition of lipid peroxidation and the use of anti-inflammatory
drugs, but through a better understanding of the mechanisms leading to
secondary injury, new investigational agents have targeted multiple areas of
the biochemical cascades that lead to cell death. Calpain and caspase
proteases are both upregulated and associated with secondary injury cascades
in spinal cord injury. Recent studies on 6-shogaol, an apoptotic inhibitor,
have shown significant improvements in hind-limb function in rodent models.
Erythropoietin (EPO) and derivatives of this compound exert an anti-apoptotic
effect in the setting of hypoxia and have been shown to improve cell survival
after ischemic brain injury and spinal cord injury in rodent models.
Polyethylene glycol (PEG), which is thought to interact with and stabilize
injured cell membranes, has been shown to have neuroprotective properties in
spinal cord injury models. Minocycline has been shown to have potent
anti-inflammatory and neuroprotective properties after spinal cord injury and
is currently being investigated in a preliminary clinical trial in Canada.
Growth factors also have been studied extensively as a means to reduce
secondary injury and also to improve nerve regeneration. Growth factors
administered directly at the site of experimental spinal cord injury or via
gene therapies have been shown to reduce cell death and to improve axonal
regeneration.
Therapies to Promote Axonal Regeneration
Two therapies to promote axonal regeneration have been evaluated in
clinical trials over the last three years, and a number of other potential
therapies are being evaluated in laboratory studies. Rho, a small signaling
protein, has been shown to result in the inhibition of axonal regeneration
after experimental spinal cord injury. C3 transferase (C3), an inhibitor of
Rho, was shown to have neuroprotective and regenerative properties in animal
models. Cethrin (Bio-Axone Therapeutic, Saint-Laurent, Quebec), a combination
of C3 with a transport sequence that helps the protein to cross cell
membranes, showed encouraging results in a recent Phase-I/IIa multicenter
clinical trial. The application of Cethrin in the epidural space at the time
of decompressive or stabilization surgery in thirty-seven patients with
American Spinal Injury Association (ASIA) type-A injuries resulted in
improvement of at least one ASIA grade in 30% of the patients within six
weeks. Historically, <5% of patients with an ASIA type-A lesion will have
any improvement. Obviously, that study was small, but it warrants further
clinical studies.
Although much research has been focused on reducing the immune response to
spinal cord injury, other approaches have involved the utilization of immune
cells (macrophages) to facilitate axonal regeneration. Animal testing with
genetically modified autologous macrophages showed encouraging results in
rodent models and prompted human clinical studies. ProCord (Proneuron
Biotechnologies, Los Angeles, California) therapy, involving the injection of
"activated" autologous macrophages into the contused area of a
spinal cord injury, was begun as a Phase-II clinical study in the United
States and Israel. The trial, which enrolled twenty-four patients, was
suspended from further patient recruitment because of funding issues, but the
patients who were managed are still being followed.
Other investigations have targeted neurite growth inhibitory protein,
Nogo-A, which is a cell surface protein, expressed after spinal cord injury,
that inhibits neurite growth. Antibodies to Nogo-A have been administered
intrathecally in rodent spinal cord injury models, with increasing axonal
regeneration and improved neurologic recovery being noted. Rolipram, a
specific inhibitor of phosphodiesterase 4, has also been shown to improve
axonal regeneration after spinal cord injury in rodent models.
Cell-based therapies involving Schwann cells, olfactory ensheathing cells,
and stem cells as well as other forms of implantable scaffolding have been
shown to facilitate axonal regeneration and remyelination after spinal cord
injury in animal models. Lima et al. recently reported on the implantation of
olfactory mucosa at the site of injury in seven patients with an acute
complete spinal cord injury and noted an improvement in the ASIA grade in all
patients, with two patients having two grades of improvement. Implantation of
stem cells has received substantial attention in the media as a potential cure
for spinal cord injury. However, as encouraging as the results in animal
studies have been, human clinical trials have not proven that these therapies
are currently effective.
Novel treatments and advances in the treatment of lumbar degenerative
disorders continue to be of high interest to clinicians and researchers as
these pathologies represent some of the more common musculoskeletal disorders.
The development of novel technologies is very exciting, but we certainly need
appropriate evidence of their efficacy.
Motion Preservation/Lumbar Disc Arthroplasty
The area of motion preservation of the lumbar spine—specifically,
disc arthroplasty—continues to be a topic of high interest, and several
studies have evaluated the efficacy of the treatments. Zigler et al., in a
presentation of the slightly longer-term follow-up of their prospective
randomized study of one prosthesis, compared the results of arthroplasty with
those of fusion. The minimum duration of follow-up was two years, with some
patients being followed for as long as three years. These early results showed
that disc arthroplasty was as good as fusion, with some early differences
favoring disc arthroplasty in terms of the pain score and patient satisfaction
disappearing by the third year.
One group of investigators presented a systematic literature review on the
efficacy and safety of intervertebral disc prostheses for the lumbar spine.
This meta-analysis primarily examined two of the FDA-approved disc devices in
comparison with fusion. The conclusions were that the scientific evidence
presently available for these devices was not sufficient to recommend the use
of either one for the treatment of lumbar disc pain in routine clinical
practice. The authors recommended additional studies with larger numbers of
patients.
Adjacent Segment Degeneration
Theoretically, the greatest benefit of motion preservation over fusion
would be a decrease in or the avoidance of adjacent-segment disease. However,
the delineation of the prevalence of adjacent-segment disease is critically
important. In one prospective study of eighty patients undergoing an anterior
interbody fusion at L5-S1, the two proximal adjacent levels were monitored for
an average duration of follow-up of five years. The rate of advanced
degeneration at either of these levels was not significantly changed from the
initial preoperative rate. The authors concluded that adjacent-segment disease
after anterior interbody fusion is not a clinical problem.
Two studies have examined the fate of the L5-S1 level following spine
fusion to L5. One study evaluated nineteen patients with fusion to L5 and
showed that 32% of the patients required revision of the fusion to the sacrum
at the time of the five-year follow-up, and the investigators predicted a 60%
survival rate at ten years of follow-up. Another center presented a study of
thirty patients after five years of follow-up. The investigators noted a high
rate (68%) of progressive degeneration at the L5-S1 level and noted a 20% rate
of revision to the sacrum.
Biological Promoters of Fusion
In addition to the review of biologics earlier in this update, three
studies are particularly pertinent to the lumbar spine and will be discussed
here. Dimar et al. reported the results of a prospective randomized study of
463 patients in which the use of rhBMP-2 was compared with autogenous bone
graft for posterolateral lumbar fusion. The authors reported significant
differences between the groups in terms of operative time and blood loss but
not in terms of the length of hospital stay. The fusion rates were similar in
the two groups, but the rate of nonunion failure was higher in the autograft
group than in the rhBMP-2 group.
Vaccaro et al. presented their results after the use of rhBMP-7 for
uninstrumented posterolateral spinal fusion. Twenty-six patients were followed
to the five-year time-point, and the five-year results were compared with the
earlier (two-year) results presented for a larger group. The authors reported
that the fusion rates and clinical outcomes were maintained at the longer-term
follow-up.
Angevine et al. studied the cost-effectiveness of the use of rhBMP-2 for
the primary surgical treatment of adult scoliosis. This retrospective cohort
cost-offset analysis examined the charges for each hospitalization at one
institution for all adults undergoing this procedure. The investigators found
that the use of rhBMP-2 increased the cost of the index procedure for adult
idiopathic scoliosis, but was cost-neutral when controlling for the type of
surgery, the number of levels, and the number of pedicle screws used.
Furthermore, when taking into account the differential rate of pseudarthrosis
and the associated costs, the use of rhBMP-2 was more cost-effective.
Nonoperative Care
Perhaps the most interesting and promising developments were related to the
nonoperative treatment of lumbar spine abnormalities. One group of
investigators presented the results of a prospective, randomized study of
seventy-four patients with lumbosacral radiculopathy who were managed with
oral administration of tumor necrosis factor-alpha (TNF-alpha) antagonists or
placebo. Compared with placebo, the TNF-alpha antagonist showed a reduction in
maximum daily leg pain over the first two weeks, but by three weeks there were
no differences. Additional, longer-term study is needed to fully delineate the
benefits of this approach.
One group reported on a prospective series of 346 patients receiving nerve
root injections for the treatment of a variety of degenerative lumbar
disorders. The investigators demonstrated efficacy and the avoidance of
surgery in a large percentage of patients (in increasing order of efficacy)
who had moderate disc herniations, degenerative spondylolisthesis, spinal
stenosis, isthmic spondylolisthesis, foraminal stenosis, degenerative
scoliosis, and failed back syndrome. Poor outcomes were found in association
with stenosis, extraforaminal disc herniations, recurrent disc herniations,
and failed back surgery when combined with instability.
Complications
Wound complications are always of concern. The identification of possible
risk factors for prevention was the topic of one study of 18,352 patients,
which examined risk factors for wound dehiscence and deep and superficial
infections. Significant risk factors for wound complications, in order of
increasing risk, included smoking, non-insulin-dependent diabetes mellitus,
and insulin-dependent diabetes. The combination of smoking and diabetic status
further increased the risk, and great care should be exercised when treating
these patients.
The editorial staff of The Journal reviewed a large number of
recently published research studies related to the musculoskeletal system that
received a Level of Evidence grade of I. Over 100 medical journals were
reviewed to identify these articles, which all have high-quality study design.
In addition to articles published previously in this journal or cited already
in this Update, sixteen level-I articles were identified that were relevant to
spine surgery. A list of those titles is appended to this review after the
standard bibliography. We have provided a brief commentary about each of the
articles to help guide your further reading, in an evidence-based fashion, in
this subspecialty area.
The forty-second annual meeting of the Scoliosis Research Society (SRS)
will be held on September 5 through 8, 2007, at the Edinburgh International
Conference Center, Edinburgh, Scotland. It will be preceded by a one-day
course entitled "Update on Congenital Spinal Deformity," to be
held on September 4, 2007. Web site:
The twenty-second annual meeting of the North American Spine Society (NASS)
will be held on October 23 through 27, 2007, at the Austin Convention Center
in Austin, Texas. It will be preceded by several precourses and two half-day
meetings of the Biologics Research Section and the Motion Preservation
Section, which are being developed by the society. Web site:
The thirty-fifth annual meeting of the Cervical Spine Research Society
(CSRS) will be held on November 29 through December 1, 2007, at the Palace
Hotel in San Francisco, California. It will be preceded by an Instructional
Course sponsored by the Society on November 28, 2007. Web site:
The Federation of Spine Associations will present the spine program at
Specialty Day at the annual meeting of the American Academy of Orthopaedic
Surgeons (AAOS), to be held on Saturday, March 8, 2008, in San Francisco,
California. Web site:
The annual meeting of the International Society for the Study of the Lumbar
Spine (ISSLS) will be held May 25 though 31, 2008, in Geneva, Switzerland. Web
site:
The thirty-fourth annual meeting of the American Spinal Injury Association
(ASIA) will be held on June 19 through 22, 2008, at Loews Coronado Bay Resort
in San Diego, California. Web site:
The fifteenth annual International Meeting on Advanced Spinal Techniques
(IMAST) will be held on July 8 through 11, 2008, at the Hong Kong Convention
Center in Hong Kong, China. Web site:
Brox JI, Reikerås O, Nygaard Ø, Sørensen R, Indahl
A, Holm I, Keller A, Ingebrigtsen T, Grundnes O, Lange JE, Friis A. Lumbar
instrumented fusion compared with cognitive intervention and exercises in
patients with chronic back pain after previous surgery for disc herniation: a
prospective randomized controlled study. Pain. 2006;122:145-55.
In this study from Norway, spinal fusion was compared with a cognitive
intervention and exercise program following the "failure" of a
previous disc herniation operation to relieve back pain. There was a 50%
success rate in the fusion group and a 48% success rate in the cognitive
intervention/exercise group. Depending on one's perspective, either both
modalities were equally effective or equally ineffective in this very
difficult group of patients. This study suggests there is no "one
answer" to the patient who has continued chronic low-back pain after
previous surgery for the treatment of a disc herniation.
Clarke J, van Tulder M, Blomberg S, de Vet H, van der Heijden G,
Bronfort G. Traction for low back pain with or without sciatica: an
updated systematic review within the framework of the Cochrane collaboration.
Spine. 2006; 31:1591-9.
This study was a review of the literature on traction. There was not
sufficient evidence to recommend traction for patients with low-back pain or
sciatica. Because most studies were underpowered, the literature does not
allow a negative conclusion that traction is not effective.
Clarke JA, van Tulder MW, Blomberg SE, de Vet HC, van der Heijden GJ,
Bronfort G. Traction for low-back pain with or without sciatica.
Cochrane Database Syst Rev. 2005;(4):CD003010.
This paper identified twenty-four randomized clinical trials involving
>2000 patients. Five of the trials were considered "high
quality." The authors concluded that there was conflicting evidence
regarding the short-term effectiveness of either continuous or intermittent
traction as compared with placebo, sham treatment, or other treatments when
managing patients who have either chronic low-back pain or a mixture of
low-back pain and sciatica. This finding suggests that there is nothing
"magical" about employing traction when physical therapy is being
used to treat low-back pain.
de Graaf I, Prak A, Bierma-Zeinstra S, Thomas S, Peul W, Koes B.
Diagnosis of lumbar spinal stenosis: a systematic review of the accuracy of
diagnostic tests. Spine. 2006;31:1168-76.
This was a review of the literature for published articles examining
diagnostic studies for spinal stenosis. The authors found twenty-four articles
(fifteen on imaging tests, seven on clinical tests, and two on other
diagnostic studies). The authors found that the published studies were of poor
quality and were not directly comparable, and they concluded that no firm
conclusions could be made regarding the different tests. The results of this
study are not surprising as spinal stenosis is a clinical syndrome with a
large number of varying symptoms that may all not be present in any particular
patient. The diagnosis of spinal stenosis is determined by the clinician on
the basis of a combination of the test results, the clinical information and
history, and the imaging studies.
Finckh A, Zufferey P, Schurch MA, Balagué F, Waldburger M, So
AK. Shortterm efficacy of intravenous pulse glucocorticoids in acute
discogenic sciatica. A randomized controlled trial. Spine.
2006;31:377-81.
The authors performed a randomized controlled trial evaluating the use of a
single intravenous bolus of methylprednisolone (500 mg) for the treatment of
acute sciatica (duration of symptoms, less than six weeks). The authors noted
a significant decrease in sciatic pain in association with the intravenous
administration of methylprednisolone over the first twenty-four hours but
noted that the effects were transient and of small magnitude. This study
demonstrates that a high-dose intravenous bolus of steroids may provide some
short-term pain relief and, thus, may allow patients to better participate in
physical therapy and other conservative modalities to relieve the symptoms of
sciatica.
Freeman BJ, Fraser RD, Cain CM, Hall DJ, Chapple DC. A randomized,
double-blind, controlled trial: intradiscal electrothermal therapy versus
placebo for the treatment of chronic discogenic low back pain. Spine.
2005;30:2369-78.
This was a randomized controlled study comparing intradiscal electrothermal
therapy (IDET) with sham treatment for patients with chronic low back pain.
Thirty-eight patients were randomized to IDET, and nineteen were randomized to
sham treatment. All patients had one or two-level degenerative low-back pain
confirmed with magnetic resonance imaging and discography. At six months, no
improvement from baseline was observed in either group, and no differences
were present between the IDET and sham groups. This was a well-done study that
contradicted a previous randomized controlled study that had demonstrated a
slight to moderate effect of IDET as compared with sham treatment. Taking
these studies together, IDET appears to have little clinical efficacy.
Gibson JN, Waddell G. Surgery for degenerative lumbar spondylosis:
updated Cochrane Review. Spine. 2005;30:2312-20.
The authors performed an extensive review of the literature on the surgical
treatment of degenerative lumbar spondylosis and concluded that there is a
paucity of good studies on this topic. There is limited evidence to support
some aspects of surgical practice. The authors underscored the importance of
critical appraisal of the literature when formulating individual practice
behaviors.
Kääpä EH, Frantsi K, Sarna S, Malmivaara A.
Multidisciplinary group rehabilitation versus individual physiotherapy for
chronic nonspecific low back pain: a randomized trial. Spine.
2006;31:371-6.
This was a prospective randomized trial, from two different centers, that
included 120 women who were employed as health-care and social-care
professionals and had low-back pain. The women were randomized to either a
multidisciplinary group rehabilitation program for seventy hours or individual
therapy for ten hours. The authors found no differences between the two groups
at the time of the two-year follow-up, with both groups demonstrating
favorable effects from the therapy that held up at the time of the final
followup. The study shows that group therapy that is comprehensive is as
effective as individual therapy and that both demonstrate positive effects at
the time of two-year follow-up.
Khadilkar A, Milne S, Brosseau L, Wells G, Tugwell P, Robinson V, Shea
B, Saginur M. Transcutaneous electrical nerve stimulation for the
treatment of chronic low back pain: a systematic review. Spine.
2005;30:2657-66.
The authors set out to perform a meta-analysis of the literature on
transcutaneous electrical nerve stimulation (TENS) for the treatment of
low-back pain but only found two studies that met criteria to include in this
analysis. They concluded that evidence to support the use of TENS treatment
for low-back pain is limited.
Korhonen T, Karppinen J, Paimela L, Malmivaara A, Lindgren KA,
Järvinen S, Niinimäki J, Veeger N, Seitsalo S, Hurri H. The
treatment of disc herniation-induced sciatica with Infliximab: results of a
randomized, controlled, 3-month follow-up study. Spine.
2005;30:2724-8.
This was a prospective randomized controlled study of forty patients with
sciatica due to a lumbar disc herniation. Patients were managed with either a
single infusion of the medication (antibody against TNF-alpha) or placebo.
Both groups showed a significant reduction in leg pain, without any
significant differences between the two groups. The authors concluded that
there was no support for the use of this medication for lumbar disc
herniation-induced sciatica. With the recent interest in TNF-alpha blockers
for the treatment of sciatic pain, this study demonstrates that there was no
difference between the medication and the placebo, which may reflect the
positive natural history of the disorder itself.
Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ,
Mohiuddin M, Young B. Direct decompressive surgical resection in the
treatment of spinal cord compression caused by metastatic cancer: a randomised
trial. Lancet. 2005;366:643-8.
Patients with isolated epidural spinal metastases were randomized to
radiation therapy or surgical decompression followed by postoperative
irradiation. The primary end point was the ability to walk. The study was
discontinued before full enrollment because the surgical group had
significantly better results, including the percentage of patients who
remained able to walk, the duration of walking, the number of patients who
regained the ability to walk, and a decreased need for corticosteroids and
opioids.
This convincing study demonstrates that for patients with isolated epidural
spinal cord compression, surgery followed by radiation therapy is associated
with a better outcome than radiation alone. This was true for patients with
significant neurologic deficits and for those who were neurologically
intact.
Rosenfeld M, Seferiadis A, Gunnarsson R. Active involvement and
intervention in patients exposed to whiplash trauma in automobile crashes
reduces costs: a randomized, controlled clinical trial and health economic
evaluation. Spine. 2006;31:1799-1804.
This randomized study demonstrated that for patients exposed to whiplash
trauma in a motor-vehicle collision, active involvement and intervention were
both less costly and more effective than a standard intervention. There was
reduced pain and less sick leave in the active involvement group.
Sherman KJ, Cherkin DC, Erro J, Miglioretti DL, Deyo RA. Comparing
yoga, exercise, and a self-care book for chronic low back pain: a randomized,
controlled trial. Ann Intern Med. 2005;143:849-56.
In this randomized controlled study of patients with prior episodic
low-back pain, Viniyoga was compared with group exercise taught by a physical
therapist or through an instructional booklet. Viniyoga is a safe technique
that emphasizes breathing and posture for the treatment of low-back pain
symptoms. At twenty-six weeks of follow-up, there was significant improvement
in both the exercise and yoga groups. The yoga group had superior outcomes,
but the differences were not significant compared with the exercise group.
Both therapeutic groups had significantly better results than did the subjects
who used the booklet. The conclusions of the study are limited in that the
results cannot be generalized because the treatment population was poorly
defined. Furthermore, instructions were given in each group by one
practitioner who may have biased the outcome. The duration of follow-up was
short, and it is unknown if the observed effect will be lasting. Finally,
compliance with the program was not reported.
Singh K, Samartzis D, Strom J, Manning D, Campbell-Hupp M, Wetzel FT,
Gupta P, Phillips FM. A prospective, randomized, double-blind study
evaluating the efficacy of postoperative continuous local anesthetic infusion
at the iliac crest bone graft site after spinal arthrodesis. Spine.
2005;30:2477-83.
Continuous infusion of local anesthetic has been developed to decrease
postoperative pain and is used in many surgical disciplines. This study tested
its efficacy in patients undergoing spinal fusion with use of iliac crest bone
grafts. Thirty-seven patients were randomized to placebo (saline solution
infusion) or Marcaine (90 mL of 0.5%) with use of a continuous infusion
technique. Significantly lower pain scores and less opioid consumption was
present in the anesthetic group. No complications occurred in either group.
The pump and anesthetics were cost-neutral. This was a well-done study showing
the efficacy of an inexpensive (cost-neutral) method in decreasing
postoperative pain. The use of this anesthetic technique should be considered
in other musculoskeletal surgical areas.
Steele EJ, Dawson AP, Hiller JE. School-based interventions for
spinal pain: a systematic review. Spine. 2006;31:226-33.
This was a systematic literature review of twelve papers. All twelve papers
received a "weak quality rating"; therefore, no conclusions could
be made regarding the effectiveness of a school-based spinal health
intervention program. This paper strongly suggests there is no clear evidence
that schools and health-promotion programs help with the treatment of spinal
pain. There is simply not a clear answer in the current peer-review
literature.
Yukawa Y, Kato F, Ito K, Terashima T, Horie Y. A prospective
randomized study of preemptive analgesia for postoperative pain in the
patients undergoing posterior lumbar interbody fusion: continuous subcutaneous
morphine, continuous epidural morphine, and diclofenac sodium. Spine.
2005;30:2357-61.
The authors studied the use of preoperative and postoperative continuous
subcutaneous morphine, continuous epidural morphine, and diclofenac sodium in
a prospective randomized fashion. The diclofenac treatment group had the
lowest initial visual analog scale pain scores immediately after surgery (p =
0.059) but required more supplemental analgesic medications in the first
seventy-two hours after surgery (p = 0.013). The epidural group had more side
effects, most commonly nausea and vomiting, than the other groups (p = 0.015).
This study is very relevant to the practice of spine surgery as effective
postoperative analgesia improves patient outcomes, reduces secondary
complications by allowing for early mobilization, and shortens hospital stay.
On the basis of the results of this study, it appears that the administration
of continuous subcutaneous morphine might be a safe and useful approach for
the treatment of postoperative pain after spinal surgery and warrants further
study.
Note: The authors thank Drs. Jim Harrop, Alan Hilibrand, Steve
Mardjetko, Dan Riew, and Harvinder Sandhu for peer reviewing the sections of
this manuscript.
Suggested Reading List
Dimar JR, Glassman SD, Burkus KJ,
Carreon LY. Clinical outcomes and fusion success at 2 years of single-level
instrumented posterolateral fusions with recombinant human bone morphogenetic
protein-2/compression resistant matrix versus iliac crest bone graft.
Spine.2006;31;
2534-40.312534
2006
[PubMed][CrossRef]
Hu SS, Berven SH. Preparing the adult
deformity patient for spinal surgery. Spine2006;31(19 Suppl):
S126-31.31S126
2006
[PubMed][CrossRef]
Kanayama M, Hashimoto T, Shigenobu K,
Yamane S, Bauer TW, Togawa D. A prospective randomized study of posterolateral
lumbar fusion using osteogenic protein-1 (OP-1) versus local autograft with
ceramic bone substitute: emphasis of surgical exploration and histologic
assessment. Spine.2006;31:
1067-74.311067
2006
[PubMed][CrossRef]
Kyung KS, Gon JH, Geun KY, Sup JJ, Suk
WJ, Ho KJ. 6-Shogaol, a natural product, reduces cell death and restores motor
function in rat spinal cord injury. Eur J Neurosci.2006;24:
1042-52.241042
2006
[PubMed][CrossRef]
Lee MJ, Bazaz R, Furey CG, Yoo J. Risk
factors for dysphagia after anterior cervical spine surgery: a two-year
prospective cohort study. Spine J.2007;7:
141-7.7141
2007
[PubMed][CrossRef]
Lima C, Pratas-Vital J, Escada P,
Hasse-Ferreira A, Capucho C, Peduzzi JD. Olfactory mucosa autografts in human
spinal cord injury: a pilot clinical study. J Spinal Cord Med.2006;29:
191-206.29191
2006
[PubMed]
Liu J, Ebraheim NA, Sanford CG Jr, Patil
V, Haman SP, Ren L, Yang H. Preservation of the spinous
process-ligament-muscle complex to prevent kyphotic deformity following
laminoplasty. Spine J.2007;7:
159-64.7159
2007
[PubMed][CrossRef]
Lowe T, Berven SH, Schwab FJ, Bridwell
KH. The SRS classification for adult spinal deformity: building on the
King/Moe and Lenke classification systems. Spine.2006;31(19 Suppl):
S119-25.31S119
2006
[PubMed][CrossRef]
McCarthy MJ, Aylott CE, Grevitt MP,
Hegarty J. Cauda equina syndrome: factors affecting long-term functional and
sphincteric outcome. Spine.2007;32:
207-16.32207
2007
[PubMed][CrossRef]
McClellan JW, Mulconrey DS, Forbes RJ,
Fullmer N. Vertebral bone resorption after transforaminal lumbar interbody
fusion with bone morphogenetic protein (rhBMP-2). J Spinal Disord
Tech.2006;19:
483-6.19483
2006
[CrossRef]
Malmivaara A, Slatis P, Heliovaara M,
Sainio P, Kinnunen H, Kankare J, Dalin-Hirvonen N, Seitsalo S, Herno A,
Kortekangas P, Niinimaki T, Ronty H, Tallroth K, Turunen V, Knekt P, Harkanen
T, Hurri H; Finnish Lumbar Spinal Research Group. Surgical or nonoperative
treatment for lumbar spinal stenosis? A randomized controlled trial.
Spine.2007;32:
1-8.321
2007
[PubMed][CrossRef]
Martin BI, Mirza SK, Comstock BA, Gray
DT, Kreuter W, Deyo RA. Reoperation rates following lumbar spine surgery and
the influence of spinal fusion procedures. Spine.2007;32:
382-7.32382
2007
[PubMed][CrossRef]
Masuda K, Imai Y, Okuma M, Muehleman C,
Nakagawa K, Akeda K, Thonar E, Andersson G, An HS. Osteogenic protein-1
injection into a degenerated disc induces the restoration of disc height and
structural changes in the rabbit anular puncture model. Spine.2006;31;
742-54.31742
2006
[PubMed][CrossRef]
Ploumis A, Transfeldt EE, Gilbert TJ Jr,
Mehbod AA, Dykes DC, Perra JE. Degenerative lumbar scoliosis: radiographic
correlation of lateral rotatory olisthesis with neural canal dimensions.
Spine.2006;31:
2353-8.312353
2006
[PubMed][CrossRef]
Ronnberg K, Lind B, Zoega B, Halldin K,
Gellerstedt M, Brisby H. Patients' satisfaction with provided care/information
and expectations on clinical outcome after lumbar disc herniation surgery.
Spine.2007;32:
256-61.32256
2007
[PubMed][CrossRef]
Sanders JO, Browne RH, Cooney TE,
Finegold DN, McConnell SJ, Margraf SA. Correlates of the peak height velocity
in girls with idiopathic scoliosis. Spine.2006;31:
2289-95.312289
2006
[PubMed][CrossRef]
Shields LB, Raque GH, Glassman SD,
Campbell M, Vitaz T, Harpring J, Shields CB. Adverse effects associated with
high-dose recombinant human bone morphogenetic protein-2 use in anterior
cervical spine fusion. Spine.2006;31:
542-7.31542
2006
[PubMed][CrossRef]
Singh K, Smucker JD, Boden SD. Use of
recombinant human bone morphogenetic protein-2 as an adjunct in posterolateral
lumbar spine fusion: a prospective CT-scan analysis at one and two years.
J Spinal Disord Tech.2006;19:
416-23.19416
2006
[PubMed][CrossRef]
Smith PN, Balzer JR, Khan MH, Davis RA,
Crammond D, Welch WC, Gerszten P, Sclabassi RJ, Kang JD, Donaldson WF.
Intraoperative somatosensory evoked potential monitoring during anterior
cervical discectomy and fusion in nonmyelopathic patients—a review of
1,039 cases. Spine J.2007;7:
83-7.783
2007
[PubMed][CrossRef]
Smucker JD, Rhee JM, Singh K, Yoon ST,
Heller JG. Increased swelling complications associated with off-label usage of
rhBMP-2 in the anterior cervical spine. Spine.2006;31:
2813-9.312813
2006
[PubMed][CrossRef]
Wang MC, Chan L, Maiman DJ, Kreuter W,
Deyo RA. Complications and mortality associated with cervical spine surgery
for degenerative disease in the United States. Spine.2007;32:
342-7.32342
2007
[PubMed][CrossRef]
Weinmann O, Schnell L, Ghosh A, Montani
L, Wiessner C, Wannier T, Rouiller E, Mir A, Schwab ME. Intrathecally infused
antibodies against Nogo-A penetrate the CNS and downregulate the endogenous
neurite growth inhibitor Nogo-A. Mol Cell Neurosci.2006;32:
161-73.32161
2006
[PubMed][CrossRef]