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Fa l l 2010
Spinal Column
c e n t e r f o r s p i n e h e a lt h
|
I n n o v at i o n
Improving Spine Care with Advances in the Research
Laboratory and Operating Room
A Message from Gordon R. Bell, MD
Director, Center for Spine Health
The discipline of spinal surgery is a rapidly evolving field in which new techniques and agents are
continually emerging and becoming available to patients with various spine conditions. In this issue
Gordon R. Bell, MD
Dr. Bell can be contacted
at 216.444.8126 or
[email protected].
In This Iss ue:
Marrow Cells from
the Vertebral Body
p. 2
Surgical Benefits
of the O-arm
p. 4
Spinal Cord Stimulation
p. 6
Total Disc Replacement
p. 8
Spinal Cord
Injury Research
p. 10
of Spinal Column, we highlight some of these newer strategies.
Two articles deal with different aspects of spinal
fusion. The first, by Dr. Robert McLain, discusses a
new technique to harvest bone marrow cells from the
vertebral body in order to augment the bone-healing
potential of spinal fusion. Dr. McLain describes the
science behind this technique and outlines several
advantages.
Dr. Andre Machado discusses the salvage strategy
of spinal cord stimulation, which can be useful when
spine surgery fails to relieve patients’ preoperative
pain and further surgery is not indicated. This
technique for managing chronic back pain can be an
attractive alternative to other treatments such as
long-term opiate use.
An article by Dr. Douglas Orr reviews a new intraoperative imaging technique that facilitates the accurate
insertion of spinal instrumentation. Known as the
O-arm®, this technique involves real-time computed
tomography imaging, which is particularly useful in
patients with spinal deformity who are undergoing
fusion with spinal instrumentation. The O-arm also
is helpful for instrumenting the thoracic spine, where
accuracy of screw placement is of paramount importance in avoiding cord injury.
Finally, Dr. Michael Steinmetz recounts some exciting
new pharmacological developments in the field of
spinal cord injury. These agents are designed to limit
the secondary damage occurring from the inflammatory response that follows the initial mechanical
insult of the injury. These and other medications offer
the 11,000 patients with these devastating injuries the
potential for functional improvement.
A second piece by Dr. McLain examines disc
arthroplasty as an alternative to fusion in selected
patients with axial back pain. He briefly reviews the
history of the artificial disc, the rationale behind
its development and indications for its use, as well as
summarizing the Cleveland Clinic experience with
this new device.
We hope that our readers will find these topics
enjoyable and stimulating. As always, we welcome
your comments and suggestions for future topics in
Spinal Column.
For More Information
To learn more about the Center for Spine Health, please
contact Dr. Bell at 216.444.8126 or our administrator,
Susan Rossi, at 216.444.6890. To refer patients, call
216.636.5860 or toll-free, 866.588.2264.
cl e v e la n d cli n ic .or g / s p i n e
1
Successful spinal fusion surgery often depends on creating a solid and substantial bony fusion in
the affected area. Autograft bone, the most commonly used fusion material, has traditionally been
aspirated from the iliac crest, a rich source of autologous connective tissue progenitor cells (CTPs) –
osteogenic stem cell precursors. The iliac crest is considered the gold standard for harvested graft
material. However, iliac crest autograft harvesting is associated with considerable morbidity and
chronic pain in many patients.
Robert F. McLain, MD
Dr. McLain can be contacted
at 216.444.2744.
Within the past five years, Cleveland Clinic Center for
Spine Health surgeons have pioneered an alternative
source of CTPs, the vertebral body cancellous reservoir, and have found it to be an even richer source,
with significant advantages over the iliac crest.
Iliac Crest Poses Challenges
Iliac crest harvesting has a number of limitations:
This site is not easy to access, it may have been
harvested previously and it may have relatively small
cancellous volume for marrow aspiration. Moreover,
iliac crest bone volume may be inadequate to complete the fusion when patients require long, extensive
fusions or revision surgery after a previous graft harvest; have paralytic deformities that require fixation
into the pelvic wings; or have undergone pelvic radiation. Even when autograft material is sufficient, iliac
crest harvesting involves stripping the outer cover
of connective tissue to get to the bone, which can be
painful and debilitating and can predispose patients
to serious complications. Consequently, patients are
often reluctant to have bone taken from the hip.
Vertebral marrow harvesting is accessible to surgeons
only during specific surgical procedures, such as
instrumented spinal fusions, that depend on fusion
for clinical success. The cells can be harvested from
the pedicle screw site, which prevents other tissue
from exposure to added trauma. Removal of the
marrow progenitor cells does not compromise the
mechanical integrity of the vertebral body and can
be accomplished without incrementally increasing
surgical risk. Because entry into the vertebral pedicle
can be achieved without disrupting the facet joint
or the articular tissues, it is feasible to use this point
of access to harvest marrow cells for uninstrumented
fusions as well.
2
S p i n al C olu m n | fall 2010
Bone morphogenetic proteins (BMPs) present yet
another option. These synthetic autograft materials
do not require harvesting and are easy to use but
quite costly, with a higher risk than a patient’s own
cells of absorption. Vertebral marrow represents
an effective compromise: It is less costly than BMPs
and less painful and difficult to harvest than the
iliac crest.
Studies Support Technique
The Center for Spine Health was first to use a validated technique to apply vertebral body-aspirated
cells in a spinal fusion. In a 2005 study conducted
at Cleveland Clinic Department of Orthopaedic
Surgery,1 aspirates from the vertebral body and
the iliac crest were compared. Twenty-one adults
undergoing posterior lumbar arthrodesis and pedicle
screw instrumentation underwent transpedicular
aspiration of CTPs. Aspirates were obtained from
two depths within the vertebral body and quantified
relative to matched, bilateral iliac crest aspirates
obtained from the same patient at the same time.
Cell count, progenitor cell concentration (cells/cc
marrow) and progenitor cell prevalence (cells/million
cells) were calculated.
Aspirates of vertebral marrow demonstrated comparable or greater concentrations of progenitor cells
than the iliac crest yielded. The concentration of
osteogenic progenitor cells was, on average, 71 percent higher in the vertebral aspirates compared with
the paired iliac crest samples.
In a second study,2 we determined the concentration
of connective tissue osteoprogenitor cells available in
sequential aspirates taken from the human vertebral
body by a transpedicular route. In 13 patients undergoing lumbar surgery for degenerative disc disease
or lumbar instability, with pedicle screw instrumentation as part of the procedure, eight discrete 2.0 cc
aspirations were harvested from each vertebral level
using a coaxial, transpedicular technique.
C l e v e la n d C L i n ic c e n t e r for s p i n e h e alt h Additional studies at Cleveland Clinic have demonstrated that these cell aspiration techniques do work;
when they were applied in spine fusion surgeries, the
fusion was reliably obtained and robust. Patients
did not have to undergo a formal iliac crest graft to
achieve good results.
40.00
Cells/CC (Millions)
By Robert F. McLain, MD
Pedicle Bone Marrow Study
Depth 2
30.00
Depth 3
Depth 4
20.00
10.00
All Sites
Figure 1: Total nucleated cells per cc of aspirated marrow (millions).
Pedicle Bone Marrow Study
Standard Procedure
3000.00
Vertebral body harvesting has become easier with the
development of an aspiration tool designed specifically for this purpose, which is safer and easier to use
than a biopsy needle. With this tool, we can provide
the best care with the least trauma to the patient.
2500.00
Our research and experience show that autograft
bone from the vertebral body works well in stimulating fusion for both routine lumbar surgery and
difficult fractures of the long bone. Vertebral marrow
harvesting has become standard procedure for
augmenting fusion mass for spinal reconstruction
at the Center for Spine Health. It takes a single-step
routine and uses it for two purposes. We have not
harvested the iliac crest for routine care in several
years. Patients have been pleased with the results,
especially given that graft site pain has been eliminated altogether.
Depth 1
0.0
Total Ctps/Cc Marrow
The Vertebral Body: a Superior Site for Harvesting Marrow Cells
The results showed a viable population of CTPs
within the portion of the vertebral body routinely
instrumented during pedicle screw placement. Initial
aspiration does not deplete the marrow reservoir
along the axis of the pedicle and vertebral body
traversed during pedicle screw placement. CTP concentrations are at least comparable to iliac crest levels
and remain high enough during sequential aspirations to allow at least four aliquots to be harvested
before concentrations decrease.
Depth 1
2000.00
Depth 2
Depth 3
1500.00
Depth 4
1000.00
500.00
0.0
All Sites
Figure 2: Mean connective tissue progenitor cell concentration (with standard
error bars) for each aspiration depth from 52 pedicles. Depth 1 is significantly
greater than the other aspiration depths.
Robert F. McLain, MD, is a spine surgeon in Cleveland
Clinic’s Center for Spine Health. His specialty interests
include back and neck surgery, minimally invasive disc
and fusion surgery, and cervical and lumbar artificial
disc replacement. He can be contacted at 216.444.2744
or [email protected].
References
1. McLain RF, Fleming JE, Boehm CA, Muschler GF. Aspiration of
osteoprogenitor cells for augmenting spinal fusion: comparison
of progenitor cell concentrations from the vertebral body and iliac
crest. J Bone Joint Surg. 2005 Dec;87(12):2655-2661.
2. McLain RF, Boehm CA, Rufo-Smith C, Muschler GF. Transpedicular aspiration of osteoprogenitor cells from the vertebral body:
Figure 3: Schematic illustration of aspiration technique. The aspiration
probe is placed exactly as the usual pedicle “gear-shift” is oriented during
pilot hole preparation. Under fluoroscopic control, the tip is advanced to the
30 mm mark and the initial aspiration is performed. Probe is then advanced
5 mm and rotated 180 degrees to aspirate a fresh marrow volume. Probe is
sequentially rotated until the final aspiration is completed at 45 mm.
progenitor cell concentrations affected by serial aspiration. Spine J.
2009 Dec;9(12):995-1002.
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3
The O-arm: Seamless Integration in Spinal Surgery
By R. Douglas Orr, MD
In complex spinal surgery and in newer, minimally invasive procedures, surgeons have extensively
used intraoperative X-rays and fluoroscopy for guidance. In these cases, we are using anteroposterior
(AP) and lateral images of the spine to estimate where structures are. Optimally, surgeons would like
to visualize the axial plane as seen on a computed tomography (CT) scan.
Image-guided navigation systems have been in use for 15 years, but are limited by the requirement
that the patient have the CT performed before the procedure and that the preoperative CT then be
R. Douglas Orr, MD
Dr. Orr can be contacted at
216.363.2410.
matched with the patient in the operating room. This process leads to two problems: The first is that
the orientation of spinal structures may change between the time the preoperative CT is performed
and when the surgery is done. In addition, the preoperative CT is performed in a supine position, while
the surgery is done in the prone position. The second problem is the time-consuming process needed
to “register” the spine with the CT. The ability to seamlessly integrate the CT and the image guidance
system in real time in the OR represents a major advance in spinal surgery.
Less Radiation Exposure in
Minimally Invasive Procedures
One such advance is the O-arm , which is essentially
a portable CT unit that can be brought into the OR to
acquire images at different points during a procedure.
The O-arm can then be linked with any of a number
of image guidance systems. In this manner, surgeons
can obtain accurate scans and link them immediately
with the navigation system. If spinal alignment is
changed, a new scan can easily be obtained.
Another benefit of the O-arm is that minimally
invasive spine procedures can be performed without
the use of intraoperative fluoroscopy, thus lessening
radiation exposure for both the surgical team and the
patient. Radiation exposure to surgeons doing spinal
instrumentation is higher than with most other uses
of fluoroscopy, and annual safe radiation exposure
levels can be reached in as few as 100 surgeries.1 With
the O-arm, a scan is acquired with the surgical team
out of the field and the procedure is then performed
with no further radiation exposure, which eliminates
the need for the OR staff to wear lead gowns. Wearing
lead throughout a long procedure can increase fatigue
and also exacerbates back pain for many people.
S p i n al C olu m n | fall 2010
Figure 2: Image after screw insertion and vertebral body
resection. Scan was done to ensure complete resection of
the vertebra prior to closure of the osteotomy.
Reduced Risk in Complex Procedures
®
4
Figure 1: Intraoperative O-arm image showing kyphosis due to
congenital anomaly of the T8 vertebra. Patient had early
myelopathy due to cord compression at this level.
In complex procedures such as spinal osteotomies,
the O-arm can be used to assess the progress of
surgery at multiple points. Figure 1 shows an intraoperative image of a young man who had myelopathy
due to cord compression across a congenital kyphosis.
Resection of this type of anomaly carries a relatively
high risk of spinal cord injury. Using the O-arm, surgeons were able to safely insert the hardware, and the
image navigation system was then used to guide the
vertebral resection.
Figure 2 shows a scan of the same patient, obtained to
ensure that the vertebra had been completely resected
prior to closing of the osteotomy. With this precaution, it was verified that no remaining fragments
could compress the spinal cord. Figure 3 shows a scan
after closure of the osteotomy to ensure alignment
and adequate closure. Without the ability to acquire
images such as these in the OR, this procedure would
have been more difficult, more time consuming and
higher risk.
R. Douglas Orr, MD, is a spine surgeon in Cleveland
Clinic’s Center for Spine Health. His specialty interests
include spine surgery, spinal deformity, spinal tumors,
spinal biomechanics and materials, and minimally
invasive spine surgery. He can be contacted at
216.363.2410 or [email protected].
Reference
1. Rampersaud YR, Foley KT, Shen AC, Williams S, Solomito M.
Radiation exposure to the spine surgeon during fluoroscopically
assisted pedicle screw insertion. Spine. 2000 Oct 15;25(20):2637-2645.
Figure 3: Scan after closure of the osteotomy. Scan was
performed to ensure closure and good bone contact for
healing.
Not every spine surgery needs this technology, but it
makes many procedures easier and safer.
C l e v e la n d C L i n ic c e n t e r for s p i n e h e alt h cl e v e la n d cli n ic .or g / s p i n e
5
Spinal Cord Stimulation for Failed Back Surgery Syndrome
By Andre Machado, MD, PhD
Failed back surgery syndrome (FBSS) is defined as persistent or recurrent pain after spinal surgery.
Patients with this condition not only suffer from low back pain and/or leg pain; they also have failed
medical and surgical treatment. In the United States, FBSS is one of the most common indications for
spinal cord stimulation (SCS), which is FDA-approved for the management of chronic pain syndromes.
Recent controlled studies have demonstrated that SCS can be superior to reoperation of the lumbar spine
for FBSS in selected patients1 and that SCS is cost-effective in this patient population.2 A prospective,
randomized, international, multicenter study with 100 FBSS patients found that SCS provided significantly
Andre Machado, MD, PhD
greater improvements in quality of life compared with conventional medical management.3
Dr. Machado can be
contacted at 216.444.4270.
Diagnosis
The differential diagnosis of patients with failed back
surgery syndrome is often complex. Patients may still
suffer from the original pain syndrome that triggered
the medical and surgical interventions that failed to
help. In addition, new factors such as complications
from previous procedures may have modified the
initial pain syndrome.
The most important advantage of implantation
with percutaneous technique is that it is minimally
invasive. The procedure is routinely performed under
sedation or local anesthesia, frequently on an outpatient basis. Limitations to percutaneous implants
include migration of the leads and inconsistent
stimulation. Patients often report that the effects
are positional, varying with decubitus, posture and
activity.
The decision on implantation with paddle or percutaneous leads depends on the patient’s characteristics
and preferences, lifestyle and surgical considerations.
Some patients prefer to have a paddle lead implanted,
with the goal of achieving more stable results. Patients
who undergo implantation with percutaneous leads
may also benefit significantly from SCS without
need for revisions. Conversion of the SCS system to
a paddle lead is often considered if complications or
inadequate stimulation are attributed to the limitations of the cylindrical lead design.
Andre Machado, MD, PhD, is Director of Cleveland Clinic’s
Center for Neurological Restoration. He specializes in deep
brain stimulation for Parkinson’s disease, tremor, dystonia,
obsessive-compulsive disorder and emerging applications,
as well as in surgical treatment of medically refractory
pain and spasticity. He can be contacted at 216.444.4270.
References
Further, the more chronic the pain, the harder it is
to manage. Complications from long-term narcotic
usage and psychological comorbidities usually
add complexity to the evaluation of these patients.
Secondary gain is also a frequent concern. Formal
evaluation by an experienced psychologist can
provide helpful insight in the assessment of these
patients and can contribute to the decision-making
process and patient selection.
Options for Implantation
There are several technical alternatives and device
options for spinal cord stimulation. The implantable devices have two major components: the lead(s)
and the pulse generator (“pacemaker”). Leads can be
divided in two main categories: cylindrical leads that
can be implanted with percutaneous technique and
paddle leads that are usually implanted via a small
laminectomy or laminotomy.
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S p i n al C olu m n | fall 2010
Implantation with paddle leads tends to provide more
consistent stimulation effects, and lead migration
is uncommon. The long-term effects of stimulation
with paddle leads are likely more consistent than with
percutaneous (cylindrical) leads and the efficiency of
the electrical stimulation has been shown to be superior. However, implantation is performed via an open
– even if minimally invasive – surgical procedure, with
inpatient observation. The recovery time is greater
than with percutaneous implants and incisional pain
requires more management.
1. North RB, Kidd DH, Farrokhi F, Piantadosi SA. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: a
randomized, controlled trial. Neurosurgery. 2005 Jan;56(1):98-107.
2. North RB, Kidd D, Shipley J, Taylor RS. Spinal cord stimulation
versus reoperation for failed back surgery syndrome: a cost effectiveness and cost utility analysis based on a randomized, controlled
trial. Neurosurgery. 2007 Aug;61(2):361-369.
3. Kumar K, Taylor RS, Jacques L, Eldabe S, et al. The effects of
spinal cord stimulation in neuropathic pain relief are sustained:
Trial Precedes Implantation
Usually, candidates for spinal cord stimulation first
undergo a percutaneous externalized trial period
of SCS with an external pulse generator for five to 10
days. The lead typically is implanted under conscious
sedation with patient feedback. The lead is positioned
and stimulation is programmed with the aim of
producing paresthesias that match the pain territory.
During the trial, patients are asked about the extent
of pain relief and satisfaction with the temporary
stimulation. Patients who report significant satisfaction and pain reduction to approximately half or less
of the baseline pain levels are often considered for
implantation with an internalized SCS system.
C l e v e la n d C L i n ic c e n t e r for s p i n e h e alt h a 24-month follow-up of the prospective randomized controlled
multicenter trial of the effectiveness of spinal cord stimulation.
Neurosurgery. 2008 Oct;63(4):762-770.
Placement of a thoracic paddle spinal cord stimulation lead connected to an
implantable pulse generator in a patient with refractory back and leg pain.
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7
Advances in Back Pain Surgery:
Replacing Discs, Not Fusing Them
By Robert F. McLain, MD
Back pain affects most of us at some point in life and, for many, it can become a chronic, disabling
problem that threatens family, employment and health. For those who need surgery, total disc replacement may offer the best hope of pain relief and functional recovery.
Current Treatment Options
Robert F. McLain, MD
Dr. McLain can be contacted
at 216.444.2744.
Depending on the cause of low back pain, some treatment strategies offer better results with fewer risks.
The key to good outcomes is picking the best treatment for each patient.
Any patient with severe back pain will need to start
treatment with conservative therapy, which includes
physical therapy, mild medications and activity modifications. Nonoperative care is effective in more than
85 percent of people with back pain, so it is always a
good place to start.
Patients who fail to improve with a full conservative
therapy program need further evaluation. Many will
benefit from pain management programs designed to
ease leg pain or back spasm, but some will be persistently impaired by focal, severe back pain, aggravated
by activity and physical therapy. When imaging studies (X-ray and MRI) show a single degenerated lumbar
disc to be the culprit – the “pain generator” – surgical
treatment can be considered.
If the disc space has collapsed and the vertebrae no
longer move normally in relation to each other, the
patient may be said to have “vertical instability” or
may demonstrate actual spondylolisthesis – a vertebral slip – between the affected vertebrae. Treatment
for lumbar instability (back pain > leg pain) has been
tried with needle procedures and laser discectomies,
with poor results. The two options with proven
effectiveness for these patients are fusion and disc
replacement surgery.
While fusion is successful in reducing back pain and
improving function in most patients, the altered
mechanics caused by stiffening the spine concern
surgeons and scientists alike and may result in later
wear and tear changes in the adjacent spine, referred
to as “transition syndrome.”
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S p i n al C olu m n | fall 2010
Wear and tear at the level above or below a fusion can
cause adjacent level disease, which may eventually
need to be treated with more surgery. Different investigators have found that, over time, 20 to 35 percent of
patients developed significant symptoms, sometimes
as early as five years after fusion. For young patients
needing surgical treatment for disc disease, this is a
particular concern.
The Rationale for Total Disc Replacement
Disc replacement surgery removes the damaged disc
and restores the normal alignment of the spine just as
a fusion should, but it also:
• Maintains motion and spinal balance at the
operated level
• Potentially slows or eliminates adjacent level disease
• Can be converted to fusion if not successful
Cleveland Clinic Center for Spine Health has been
a participant in FDA-approved trials of total disc
replacement (disc arthroplasty), and has extensive
experience with this surgical approach. We can offer
selected patients this alternative to fusion when
the risks of transition syndrome warrant a motionpreserving strategy.
Device History
The device we use, the FDA-approved ProDisc L, was
developed in France and was initially implanted in
93 discs in 64 patients in the early 1990s. Before additional procedures were performed, these patients
were followed; seven to 11 years after their surgeries,
all implants were still intact, all patients were still
mobile and 93 percent were still very satisfied with
their outcomes. Small modifications were made in
the implant until the current model became standardized in 1999. We now have follow-up of nine years
or longer on more than 30,000 patients worldwide.
C l e v e la n d C L i n ic c e n t e r for s p i n e h e alt h What the FDA Study Has Found
Surgical implantation of the artificial disc has
consistently been quicker than lumbar fusion techniques and has resulted in less blood loss and
shorter hospital stays.
Postoperatively, both fusion and disc replacement
patients showed significant improvement in pain
and increase in function, though the disc replacement patients achieved slightly better results at
both two years and five years. More disc replacement
patients than fusion patients said they would have
the operation again. Over subsequent years, fewer
of the disc replacement patients needed any other
type of surgery.
What the Cleveland Clinic Experience Has Shown
With either the Charité® device or the ProDisc device
(the two types approved by the FDA for use in the lumbar spine), excellent pain relief and return to function
can be obtained in carefully selected and prepared
patients (Figures 1 and 2). Moreover, disc replacement
options are now available to patients with neck pain
and disc degeneration. Two devices (Prestige® and
ProDisc-C) have been approved for use and several
more are awaiting FDA approval, offering patients
with unremitting neck pain an attractive new option
for pain relief and improved function.
The biggest headache current patients face is
insurance approval. Disc replacement surgery is still
considered experimental by some insurance companies, even though the FDA has declared these devices
appropriate for use and no longer investigational.
Some companies have a policy that they will not
pay for these procedures. Patients interested in disc
replacement for back problems need to check with
their insurers. If coverage can be obtained, disc
replacement surgery offers a new alternative to
standard lumbar fusion for back pain treatment.
Figure 1: A 30-year-old man presented with
chronic, unremitting low back pain. Symptoms
had persisted for approximately six years, but
had worsened the last two to three years. Leg
and foot pain was intermittent; back pain was
ranked “8/10” even at rest. Patient was unable
to work outside, had severe pain when riding in
a car, and was limited in social activities and
exercises. A painful L4/5 disc was diagnosed,
based on MRI and a discogram procedure.
Figure 2: Eight weeks after disc replacement
surgery, patient returned to work and light
exercise without restrictions. He ranked
both his back pain and leg pain “0/10.”
Robert F. McLain, MD, is a spine surgeon in Cleveland
Clinic’s Center for Spine Health. His specialty interests
include back and neck surgery, minimally invasive disc
and fusion surgery, and cervical and lumbar artificial disc
replacement. Dr. McLain is a paid consultant for Synthes,
which makes the ProDisc device described in this article.
He can be contacted at 216.444.2744 or [email protected].
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9
Immune Response in Spinal Cord Injury:
Could Drug Combination Limit Damage?
By Michael Steinmetz, MD
Researchers in Cleveland Clinic Lerner Research Institute’s Department of Neurosciences are teasing
apart the complex immune response in spinal cord trauma, with the intent of devising pharmacologic
interventions that would limit the secondary damage wrought by the response, preserve neural integrity, speed recovery and enhance restoration of function.
Michael Steinmetz, MD
Dr. Steinmetz can be
contacted at 216.445.4633.
The challenge is substantial, but there is progress.
Two pharmacologic agents already have been shown
to modulate the response and produce measurable
benefits in animal models. It may be fortuitous that
both these agents are on the market, one (rolipram) in
Europe and the other (clodronate) in the United States.
Therapy Targets Immune Response
With the current, although arguably incomplete,
understanding of the initiation and evolution of the
immune system’s involvement in secondary damage,
a Cleveland Clinic research team selected two agents
for investigation in animal models of spinal trauma.4
Initial and Secondary Trauma
Mechanical trauma to the spinal cord, albeit destructive, seldom transects the cord in its entirety.1 The
preservation of relatively few axons can support a
partial recovery.2
The immune response (i.e., neuroinflammation)
is deemed responsible for a significant portion of
the damage seen in spinal cord trauma, and is
also thought to hinder the pace and limit the extent
of recovery. The response is an orchestrated series
of events that transpires over the course of two or
more weeks.3
Clodronate is a non-nitrogenous bisphosphonate
approved by the Food and Drug Administration to
treat osteoporosis and hypercalcemia of malignancy.
Among its properties is an ability to induce selective
apoptotic cell death in monocytes and phagocytic
macrophages. Rolipram is a phosphodiesterase inhibitor approved in Europe as a treatment for depression
and other conditions. It has anti-apoptotic effects
and can reduce the production of pro-inflammatory
cytokines such as TNF and ICAM-1. The latter factor
allows the adhesion of neutrophils.
Control
Clodronate/Rolipram
These early findings are a significant step toward clinical trials. Bear in mind that both agents are approved
and have established pharmacokinetic and safety profiles. The availability of a new treatment would be of
substantial benefit to the 11,000 Americans who incur
acute spinal cord injury annually.
Michael Steinmetz, MD, is a neurological surgeon in
Cleveland Clinic’s Center for Spine Health. His specialty
interests include spine deformity, reconstructive spine
surgery, spinal cord injury and peripheral nerve surgery.
He can be contacted at 216.445.4633 or [email protected].
References
1. Tator CH, Fehlings MG. Review of the secondary injury theory of
acute spinal cord trauma with emphasis on vascular mechanisms.
J Neurosurg. 1991;75:15-26.
Two-Drug Treatment Shows Promise
2. Young W. Secondary injury mechanisms in acute spinal cord
Initially, the trauma is limited to the zone of injury.
Within hours, a region of secondary cell death begins
to expand as neurons, microglia and microglial cells
perish. The neutrophil population at the site rises,
peaks and falls precipitously over a 24-hour span.
Macrophages and microglial cells are recruited and
become predominant within 48 hours. They may reside at the site and remain active for up to two weeks.
When these cells disappear, they leave a cavity that is
surrounded by a glial scar consisting of reactive astrocytes and activated microglial cells. The process, start
to finish, is directed by a continually changing stew of
cytokines and chemokines.
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S p i n al C olu m n | fall 2010
The two drugs were studied as single agents and
in combination in 60 spinal cord-injured female
Sprague Dawley rats randomly assigned to a control
group, a group receiving clodronate encapsulated in
liposomes, a group receiving rolipram and a group
receiving the two agents in combination.
injury. J Emerg Med. 1993;11(Suppl 1):13-22.
3. Dusart I, Schwab ME. Secondary cell death and the inflammatory
reaction after dorsal hemisection of the rat spinal cord.
Eur J Neurosci. 1994;6:712-724.
4. Iannotti CA, Clark M, Horn KP, van Rooijen N, Silver J,
The combination treatment led to greater locomotor
recovery compared with the controls and single-agent
recipient animals. There was substantial axonal sparing and/or sprouting from brainstem motor nuclei
and the hindlimb motor cortex. The amount of axonal
sparing in the group receiving the drug combination
was three to four times that seen in the other groups.
Histological assessment showed a 51 percent reduction in lesion volume and a 45 percent reduction
in lesion area at the injury epicenter. The agents also
significantly increased the extent of myelinated
tissue sparing.
C l e v e la n d C L i n ic c e n t e r for s p i n e h e alt h Steinmetz MP. A combination immunomodulatory treatment
promotes neuroprotection and locomotor recovery after contusion
SCI [published online ahead of print March 23, 2010]. Exp Neurol.
doi:10.1016/j.expneurol.2010.03.010.
Five weeks after contusion spinal cord injury and treatment with
clodronate/rolipram, significant axon sparing (arrows) is seen in
the ventromedial funiculus of the spinal cord (NF green channel).
Less myelin debris (dots) and more myelinated axons (arrows)
are visualized compared with controls (MBP red channel). More
myelinated axons (arrowheads), fewer demyelinated axons (arrows)
and less myelin debris (dots) are revealed (NF/MBP co-labeling),
thus demonstrating robust neuroprotection following our treatment
paradigm (NF green channel, neurofilament staining; MBP red
channel, myelin basic protein; NF/MBP co-labeling of neurons
and myelin).
cl e v e la n d cli n ic .or g / s p i n e
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Referrals
General Patient Referral
24/7 hospital transfers or physician consults:
800.553.5056
On the Web at clevelandclinic.org
Patient Referrals to the Center for Spine Health
216.636.5860 or toll free, 866.588.2264
On the Web at clevelandclinic.org/spine
Cleveland Clinic Center for
Spine Health Locations
Cleveland Clinic
9500 Euclid Ave.
Cleveland, Ohio 44195
216.444.BACK (2225)
Hillcrest Hospital
6780 Mayfield Road
Mayfield Heights, Ohio 44124
440.312.4500
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1730 West 25th St.
Cleveland, Ohio 44113
216.363.2410
Broadview Heights Family Health Center
2001 East Royalton Road
Broadview Heights, Ohio 44147
216.986.4000
Solon Family Health Center
29800 Bainbridge Road
Solon, Ohio 44139
440.519.6800
Strongsville Family Health and Surgery Center
16761 SouthPark Center
Strongsville, Ohio 44136
440.878.2500
Westlake Family Health Center
30033 Clemens Road
Westlake, Ohio 44145
440.899.5555
Willoughby Hills Family Health Center
2570 SOM Center Road
Willoughby Hills, Ohio 44094
440.943.2500
Cleveland Clinic Center
for Spine Health Staff
Joint Appointments in the
Center for Spine Health
Gordon R. Bell, MD
Director, Center for
Spine Health
Spine Surgeon
Lilyana Angelov, MD, FRCS(C)
Brain Tumor and
Neuro-Oncology Center,
Neurological Institute
Daniel J. Mazanec, MD
Associate Director, Center for
Spine Health
Medical Spine Specialist
Thomas Bauer, MD, PhD
Department of
Anatomic Pathology
Edward Benzel, MD
Chairman, Department of
Neurological Surgery
Spine Surgeon
Edwin Capulong, MD
Medical Spine Specialist
Russell DeMicco, DO
Medical Spine Specialist
Michael Eppig, MD
Spine Surgeon
Lars Gilbertson, PhD
Research
Augusto Hsia Jr., MD
Medical Spine Specialist
William Bingaman, MD
Vice Chairman,
Clinical Areas,
Neurological Institute
Epilepsy Center,
Neurological Institute
Alfred Cianflocco, MD
Department of
Orthopaedic Surgery
Edward Covington, MD
Neurological Center for Pain,
Neurological Institute
Thomas Kuivila, MD
Department of
Orthopaedic Surgery
Tagreed Khalaf, MD
Medical Spine Specialist
Anantha Reddy, MD
Department of
Physical Medicine
and Rehabilitation,
Neurological Institute
Ajit Krishnaney, MD
Spine Surgeon
Joseph Scharpf, MD
Head & Neck Institute
E. Kano Mayer, MD
Medical Spine Specialist
Judith Scheman, PhD
Neurological Center for Pain,
Neurological Institute
Iain Kalfas, MD
Spine Surgeon
Robert F. McLain, MD
Spine Surgeon
Thomas Mroz, MD
Spine Surgeon
C le v ela n d C lin ic
C e n t er for S pi n e H e alt h
Clinical Trials
An assessment of P-15 bone putty in anterior cervical fusion
with instrumentation
Iain Kalfas, MD | 216.445.7744
A prospective, multicenter, double-blind, randomized, placebocontrolled pivotal study of ultrasound therapy as adjunctive
therapy for increasing posterolateral fusion success following
single-level posterior instrumented lumbar surgery
Ajit Krishnaney, MD | 216.445.7744
Upcoming Symposium
February 25-27, 2011
4th Annual International Symposium on Stereotactic Body Radiation Therapy and
Stereotactic Radiosurgery
Presented by:
Cleveland Clinic Brain Tumor and Neuro-Oncology Center,
Center for Spine Health and Taussig Cancer Institute
Disney’s Grand Floridian Resort & Spa
Lake Buena Vista, Florida
ccfcme.org/SBRT11
Contact Martha Tobin at 216.445.3449 or 800.223.2273,
ext. 53449, or [email protected] for seminar details.
R. Douglas Orr, MD
Spine Surgeon
Richard Schlenk, MD
Spine Surgeon
Michael Steinmetz, MD
Spine Surgeon
Santhosh Thomas, DO, MBA
Medical Spine Specialist
Deborah Venesy, MD
Physiatrist
Fredrick Wilson, DO
Medical Spine Specialist
Adrian Zachary, DO, MPH
Medical Spine Specialist
12
S p i n al C olu m n | fall 2010
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13
Services for Physicians
Physician Directory View all Cleveland Clinic staff online at clevelandclinic.org/staff.
Referring Physician Center For help with service-related issues, information about our
clinical specialists and services, details about CME opportunities and more, contact us
at [email protected], or 216.448.0900 or toll free, 888.637.0568.
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fleet of mobile ICU vehicles, helicopters and fixed-wing aircraft serve critically ill and
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care transfers, call 216.444.8302 or 800.553.5056.
Request for Medical Records 216.444.2640 or 800.223.2273, ext. 42640
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DrConnect account, visit clevelandclinic.org/drconnect or email [email protected].
MyConsult Online Medical Second Opinion MyConsult securely connects patients to top
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Outcomes Data View the latest clinical Outcomes book from many Cleveland Clinic institutes at clevelandclinic.org/quality/outcomes.
CME Opportunities: Live and Online Cleveland Clinic Center for Continuing Education’s
website, ccfcme.com, offers convenient, complimentary learning opportunities, from
a virtual textbook of medicine (Disease Management Project) and a medical newsfeed
refreshed daily to myCME, a system for physicians to manage their CME portfolios. Many
live CME courses are hosted in Cleveland, an economical option for business travel.
Spinal Column
Fall 2010
Co-Editor:
Gordon R. Bell, MD
Director, Cleveland Clinic
Center for Spine Health
Co-Editor:
Daniel J. Mazanec, MD, FACP
Associate Director, Cleveland Clinic
Center for Spine Health
Head, Section of Spine Medicine
Guest Medical Editor:
Robert F. McLain, MD
Marketing:
Colleen Burke
Sarah Delly
Managing Editor:
Terry Pederson
Graphic Designer:
Services for Patients
Irwin Krieger
MyChart MyChart is an online health management tool that securely connects Cleveland
Clinic patients to portions of their medical records where they can view test results and
medication lists, request new and review past appointments, and receive preventive care
reminders to better plan the details of their ongoing healthcare. To sign up for a MyChart
account, please visit ccf.org/mychart.
Medical Concierge Complimentary assistance for out-of-state patients and families:
800.223.2273, ext. 55580, or email [email protected]
Global Patient Services Complimentary assistance for national and international patients
and families: 001.216.444.8184 or visit clevelandclinic.org/gps
Spinal Column is published by Cleveland
Clinic’s Center for Spine Health to provide
up-to-date information about the center’s
research and services. The information
contained in this publication is for research
purposes only and should not be relied upon
as medical advice. It has not been designed
to replace a physician’s independent medical
judgment about the appropriateness or risks
of a procedure for a given patient.
Stay Connected to Cleveland Clinic
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The Cleveland Clinic Foundation
Spinal Column
9500 Euclid Avenue / AC311
Cleveland, OH 44195
Every life deserves world class care.
S pin al C olu m n | Fall 2010 INN OVAT I O N
New! Healthcare Executive
Education Programs
Cleveland Clinic is launching two healthcare executive
education programs that focus on the challenges of
leadership, management and innovation in today’s
highly competitive healthcare landscape.
“One of the unique aspects of our executive education
programs is peer learning. Attendees will learn directly
from those involved in the daily business of healthcare
excellence,” says James K. Stoller, MD, MS, a
pulmonologist and critical care medicine physician
and Chairman of Cleveland Clinic’s Education Institute.
Cleveland Clinic Excels in
U.S.News & World Report Rankings
Cleveland Clinic’s neurological
and neurosurgical programs
were ranked No. 6 in the
nation by U.S.News &
World Report in 2010.
Our Orthopaedics program
was ranked No. 4.
The 2010 “America’s Best Hospitals” survey
recognized Cleveland Clinic as one of the country’s
The Executive Visitors’ Program is an intensive two-
leading hospitals overall, with a No. 4 ranking
day program, designed for busy executives. The
nationwide. Fourteen Cleveland Clinic specialties
Samson Global Leadership Academy is a two-week
placed among the top 10 in the United States. For
immersion program that offers, among other things,
more details, visit clevelandclinic.org.
a mentoring opportunity that continues after the
program is over.
The programs are open to healthcare executives,
including physicians, nurses and administrators.
CME credit is available. To learn more, visit
clevelandclinic.org/ExecutiveEducation.
10-NEU-015