Young investigator honored for studies on spinal fluid pressure and biomarkers

Despite the significant time and resources expended on the study of spinal cord injury (SCI), few effective treatments have been found for this devastating injury.

The reasons are many—the reliance in preclinical studies on rodent models of cord injury that may not readily apply to the condition in humans; the cost and difficulty of conducting clinical trials to validate novel treatments; and the dependence of clinical researchers on functional neurologic measures to classify injury severity and measure improvement. Such functional measures are both imprecise and frequently impossible to validly assess in acutely traumatized patients.

Brian K. Kwon, MD, PhD, FRCSC, an orthopaedic spine surgeon and neuroscientist at the University of British Columbia, confronted these obstacles in three separate but related studies on the biophysical and biochemical aspects of cerebrospinal fluid (CSF) in SCI. His work, summarized in “Cerebrospinal Fluid Pressure Monitoring and Biochemical Analysis in Acute Spinal Cord Injury—A Translational Approach,” earned Dr. Kwon the 2010 Kappa Delta Young Investigator Award.

From bedside to bench
Dr. Kwon describes this three-pronged investigation as a “bedside-back-to-bench” approach that began with a patient study and moved back to laboratory analysis and animal models. Underpinning his research was the concept that controlling intrathecal pressure to improve spinal cord perfusion might have therapeutic value as a neuroprotective intervention. He also postulated that the availability of reliable “biological criteria and biomarkers that can more precisely stratify neurologic impairment and better predict neurologic outcome would be extremely valuable clinical research tools. Such criteria could both increase the number of recruitable patients for trials and lessen the number needed to achieve statistical power.

His studies yielded several findings with potential consequences for the treatment of SCI, specifically in regard to managing the hemodynamic status of patients in the acute postinjury phase and to using biomarkers to classify injury severity and predict neurologic outcome.

Most notably, he and fellow researchers discovered that, contrary to their expectations, SCI patients’ intrathecal pressure rose rather than fell following decompression, with a corresponding drop in spinal cord perfusion. Additionally, by analyzing CSF samples from these patients, they discovered that the concentration of specific proteins within the CSF could be used to biologically predict the functional severity of the injury as defined by the American Spinal Injury Association (ASIA) grading.

Lessons in pressure
In traumatic brain injury, a decrease in cerebral perfusion pressure can result from either a decrease in mean arterial pressure or an increase in intracranial pressure. In patients undergoing thoracoabdominal surgery, a reduction in spinal cord perfusion pressure when the aorta is cross-clamped can by itself lead to ischemic damage to the spinal cord and paralysis of the lower extremities. Even though CSF drainage has been shown to reduce the incidence of ischemic paralysis in patients undergoing thoracoabdominal aortic aneurysm repairs, this intervention had not been previously studied for SCI patients.

Dr. Kwon initiated a prospective, randomized clinical trial to study the role of CSF drainage to reduce pressure within the intrathecal space. In 24 patients with ASIA A (complete) or B and C (incomplete) spinal cord injuries between C3 and T11, surgeons inserted a lumbar intrathecal drain preoperatively, and patients were randomized to either having CSF drained to an intrathecal pressure of 10 mm Hg, or no drainage (ie, pressure monitoring alone).

After surgical decompresssion, the intrathecal pressure rose in all but one patient. Given that the spinal cord perfusion pressure is the difference between mean arterial pressure and intrathecal pressure, such increases in intrathecal pressure are accompanied by reductions in perfusion to the injured spinal cord. Furthermore, intrathecal pressures continued to transiently increase in the ensuing postoperative days for patients in either treatment group, suggesting that the spinal cord was subjected to further ischemic episodes.

These findings surprised Dr. Kwon and his fellow investigators. They had expected intrathecal pressures to rise upon insertion of the catheter and surgical decompression to decrease pressures. “On both accounts, we found exactly the opposite,” he reported. Although they did not observe a significant lowering of intrathecal pressure in the drainage versus the no-drainage patients, the constraints of the trial protocol on the amount and duration of CSF drainage could account for the limited reduction.

“Our observations of the rise in intrathecal pressure post-decompression suggests that a large pressure gradient exists across the injured spinal cord prior to decompression,” wrote Dr. Kwon. In the setting of a constant mean arterial pressure, the rise in intrathecal pressure “indicates a drop in spinal cord perfusion pressure…an observation that should be considered in the perioperative management of blood pressure in these patients.”

The promise of biomarkers
The clinical trial provided a unique opportunity to directly document aspects of the neuroinflammatory response to spinal cord injury. If researchers could identify biomarkers, they might be able to develop a way to better classify the severity of the injury and predict outcomes.

The second study included patients who were also enrolled in the CSF drainage trial. CSF was drawn from the patients at the time of initial lumbar puncture and catheter placement, and then postoperatively every 6 to 8 hours. The samples were assessed for the presence of neural markers such as the protein tau, the cytokine S100ß, and glial fibrillary acidic protein (GFAP).

At 6 and 12 months after surgery, patients received a functional analysis using the ASIA motor assessments and answered a structured questionnaire on neuropathic pain. The raw protein concentrations were plotted according to the baseline severity of paralysis (ASIA A, B, or C), revealing a severity-dependent expression of numerous proteins, including interleukin-6 (IL-6), IL-8, monocyte chemotactic protein-1 (MCP-1), GFAP, tau, and S100ß.

Dr. Kwon and colleagues then created a biochemical model to predict the ASIA impairment grade based on the concentrations of IL-8, GFAP, and S100ß in the CSF at 24 hours postinjury. The biochemical model accurately classified the patients’ ASIA grades in 24 out of 27 cases (88.9 percent). They then used these concentrations to predict the extent of segmental upper extremity recovery at 6 months postinjury. The cykotine model had an accuracy rate of 70 percent, compared with 65 percent for the ASIA grade. “The CSF biomarker model was at least equivalent to (if not slightly better than) our standard clinical stratification of injury severity,” they reported.

But would this injury-severity dependent pattern of expression of inflammatory cytokines be reproducible in a standard rodent model of SCI? A final study tested this hypothesis and found that cytokines such as Il-8, IL-6, and MCP-1, which were expressed differently among ASIA A, B, and C patients, were indeed differentially expressed in animals with mild, moderate, and severe injuries. This provides some validation for the use of these animal models as preclinical testing grounds.

To further investigate the role of intrathecal pressure monitoring in acute SCI and to validate the biochemical model, Dr. Kwon is leading a multicenter clinical initiative. CAMPER—the Canadian Multicenter CSF Pressure Monitoring and Biomarker Study—will provide clearer guidance on the management of blood and intrathecal pressures in acute human SCI, and validate the utility of CSF biomarkers. These insights will “hopefully not only improve patient outcomes, but will facilitate the evaluation of novel therapeutics for this catastrophic injury,” Dr. Kwon said.

The research described in this manuscript was funded by extramural competitive grants from the: Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, Paralyzed Veterans Association, Rick Hansen Man in Motion Research Fund, and Canadian Foundation for Innovation. Dr. Kwon has a consulting relationship with Medtronic Spine and Biologics.

Dr. Kwon will present his award-winning paper on Tuesday, March 9, in Auditorium A of the Morial Convention Center, as part of the Orthopaedic Research Society Annual Meeting; the Kappa Delta Young Investigator Award will be presented during the Opening Ceremonies of the AAOS Annual Meeting, on Wednesday, March 10, in the La Nouvelle Ballroom, Morial Convention Center.

Terry Stanton is the senior science writer for AAOS Now. He can be reached at tstanton@aaos.org

Bottom line

• After spinal decompression, intrathecal pressure in patients with spinal cord injury increases and spinal cord perfusion pressure drops, which could affect the perioperative management of blood pressure in these patients.
• The biomarkers identified in this research correctly classified baseline injury severity with a rate of almost 90 percent, and were comparable to current functional measures at predicting segmental upper extremity motor recovery.
• The biological changes that were observed in human SCI patients were reproduced in a standard rodent model of spinal cord injury, suggesting that at least these aspects of the model represent clinically relevant phenomena.