Riluzole May Protect Against Ischemia Reperfusion Injury During Spinal Decompression Surgery

Commentary by Michael G. Fehlings, MD, PhD, FRCSC, FACS; Samuel K. Cho, MD; Spyridon K. Karadimas, MD; and Alex M. Laliberte

cervical spine, lateralAddition of the sodium glutamate antagonist riluzole when decompression surgery is undertaken results in better long-term improvements in forelimb function in cervical spondylotic myelopathy (CSM) animal models than surgery alone, according to findings published in the journal Science Translational Medicine. The findings suggest that riluzole protects against reperfusion injury.

“In this seminal work we have, for the first time, demonstrated that postsurgical decompression reperfusion injury is an important consideration for spine surgeons in the clinical management of CSM,” said principal investigator Michael G. Fehlings MD, PhD, Professor of Neurosurgery at the University of Toronto, in Ontario. “Importantly, we provide a strong argument for the use of the FDA-approved drug riluzole to mitigate this injury and promote recovery above that seen with decompression alone. In a broader sense, we anticipate that a better understanding of the fundamental mechanisms involved in ischemia reperfusion injury (IRI) could be applicable to a number of spine surgeries, and preventative measures may improve the outcomes in a number of conditions, including correction of spine deformities.”

“The study suggests that riluzole is protective against ischemia-reperfusion spinal cord or nerve injury,” commented Samuel K. Cho, MD, Associate Professor of Orthopaedics and Neurosurgery at the Icahn School of Medicine at Mount Sinai, New York, NY. “The drug may be used in conjunction with decompression surgery to treat the unwanted neurologic complication when treating patients with cervical spondylotic myelopathy as a number of patients are known to demonstrate neurologic decline as illustrated in the study.”

“This is an outstanding investigation shedding light on one mechanism by which nerve injury can occur,” Dr. Cho added. “For a long time, we did not have an effective pharmacologic treatment for spinal cord or nerve injury. Riluzole may be a drug that can begin to fill that gap.”

Study Rationale
“Currently, surgical decompression is the only treatment option for cervical spondylotic myelopathy (CSM), a degenerative condition and the most common form of spinal cord injury,” Dr. Fehlings explained. “CSM is a debilitating disease that has a devastating effect on the patients’ ability to function and quality of life. Surgical decompression can halt disease progression and improve neurological function; however, a significant percentage of patients are left with significant neurological impairments.”

“Most importantly an appreciable, but poorly defined population develop neurological complications or deteriorate after uneventful surgical decompression,” said lead author Spyridon K. Karadimas, MD, Graduate Student at the Institute of Medical Science, University of Toronto, in Ontario said. “This left many in the neurosurgical and orthopaedic spine community puzzled and was our motivation to decipher for first time the mechanism of this phenomenon. We discovered that these postsurgery complications were the result of an IRI, which resulted in tissue and neurological deterioration. In light of this discovery, we sought a pharmacological approach to mitigate the extent of the IRI and improve recovery post decompression surgery.”

Neurological Deterioration Found in Select Patients With CSM Following Surgery
The authors examined neurological outcomes from 278 patients with CSM enrolled in the prospective AOSpine North America CSM study from 12 North American sites. Eleven patients (4%) experienced neurological complications within 20 days of surgery, including radiculopathy (C5 or non-C5 related) and perioperative worsening of myelopathy.

When comparing baseline to 6-month scores on the Japanese Orthopaedic Association (mJOA) scale, the majority of participants (79%) showed improvements in neurological status following decompression surgery, 21% remained stable, and 9.3% deteriorated.

Rat Model Shows Protective Effects of Riluzole
The authors then investigated neurobehavioral outcomes of surgical decompression in a rat model of CSM using a blinded, randomized design, and found significant decline in forelimb stride length and deterioration in manual dexterity as indicated by an increase in forepaw initial contact at week 1 postsurgery compared with rats that received sham surgery (P<0.05 for both comparisons). Rats that received riluzole plus decompression surgery showed significant improvements over the rats that received decompression alone on the following parameters: forelimb stride length, forepaw initial contact, and regularity index parameters (P<0.05 for all comparisons), suggesting that riluzole administration during surgery had a protective effect on the spinal cord, the authors noted.

Riluzole May Protect Against Ischemia-Reperfusion Injury
These findings validated the animal model and allowed the researchers to test their hypothesis that surgical decompression induces a reperfusion injury in the spinal cord parenchyma, Dr. Karadimas told SpineUniverse. “Using flow-sensitive alternating inversion recovery (FAIR)-MRI in vivo, we found a significant increase in the blood flow to the decompressed spinal cord within 24 hours of decompression surgery. Further, this increased blood flow was associated with an increase in the amount of oxidative stress and cellular damage in the preserved neurons.”

“We found that perioperative riluzole administration attenuated the induction of oxidative stress and cellular damage resulting in the protection and preservation of the neurons controlling arm and hand function,” Dr. Karadimas explained. “In vitro work confirmed these effects and suggested that they occur due to stabilization of the neuronal mitochondrial membrane potential,” said author Alex M. Laliberte, Graduate Student at the Institute of Medical Science, University of Toronto, in Ontario.

Dr. Cho told SpineUniverse that he believes that riluzole may be a viable agent to help improve outcomes in this population. “To date, we do not have many drugs to help improve neurologic function and even the ones that we currently have, such as steroids, remain controversial in terms of efficacy and have drug-related complications. When used appropriately, I believe riluzole holds promise,” Dr. Cho said.

Study Strengths and Limitations
“The main strength of this study is that it highlights ischemia-reperfusion injury as one potential mechanism underlying neurologic deterioration following decompression surgery in the spine for CSM patients and offers a viable solution to address this,” Dr. Cho commented. “This investigation contains both clinical and basic science studies that are correlative and clinically relevant. The weakness is, by study design, the clinical part is retrospective, which has inherent limitations. Also, we don't know whether the small number of patients who demonstrated neurologic decline indeed experienced ischemia-reperfusion injury or something else (eg, traction injury). The animal study potentially explains what had taken place in a mechanistic manner. However, while the animal studies help us to artificially create the disease for investigative purposes, they rarely can replace our clinically experience with real patients and may only help us explain a part of the whole story.”

Next Steps in Research
“The findings of our study have opened new avenues in CSM research,” Dr. Fehlings explained. “We are currently taking a bidirectional approach utilizing both clinical and basic science and promoting crosstalk between both areas of research. Clinically, our work has generated high expectations for the ongoing CSM-Protect clinical trial funded by AOSpine North America. This is a multicenter clinical trial with 20 centers participating across North America with the aim of testing the efficacy of perioperative riluzole to improve postsurgical recovery in humans with CSM. Moreover, we are currently developing novel diagnostic tools to identify CSM patients with high-risk of decompression-mediated IRI.”

Updated on: 08/18/16
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