“Hyperactive” Spinal Cord Circuitry Harms Immune System // After Failed Conservative Measures, Hip Arthroscopy More Cost-Effective Than Rehabilitation // and More!
Elizabeth Hofheinz, M.P.H., M.Ed. • Wed, April 27th, 2016
Spinal Cord Injury: “Hyperactive” Circuitry Harms Immune System
With the threat of infection always lurking, certain researchers set out to help a very specific group of orthopedic patients—those with higher than thoracic level 5 spinal cord injuries.
Phillip Popovich, Ph.D., is professor of Neuroscience and director of the Center for Brain at Ohio State University. He told OTW, “People who suffer a spinal cord injury (SCI) at a high spinal level (e.g., cervical SCI), are at increased risk for developing autonomic dysreflexia (AD), a potentially life-threatening condition of sudden onset high blood pressure. In people and animals with SCI, reflexes that are activated by routine stimuli including filling of the bladder or bowel often trigger AD. We recently found that these same reflexes also suppress the immune system. Since people with high level SCI also are at increased risk for developing infections (e.g., pneumonia), we set out to understand how SCI changes the autonomic circuitry in the spinal cord that controls immune function.”
“We found that after a period of one month, the number of connections between spinal cord interneurons and autonomic neurons that directly control immune function increases dramatically. Also, this newly formed circuitry is ‘hyperactive’ and discharge of neurons in this circuit causes hormones to be released into the blood and immune organs that overstimulate immune cells, causing them to die.”
“Fortunately, we were able to show that the hyperactive spinal cord circuitry can be silenced. We used a novel technique known as ‘chemogenetics’ to silence excitatory interneurons in the aberrant circuit. When the circuitry was silenced, immune cells were protected in SCI mice.”
“Autonomic complications of high level SCI including inability to control cardiovascular reflexes and immune suppression have been difficult to treat, mostly because the mechanisms causing these complications have not been defined. Our new data show that after high level SCI in mice, the spinal cord reorganizes, creating new circuitry. This ‘rewiring’ takes time, evolving over many weeks. Similar changes are likely in humans.”
“Whether chemogenetics or similar intervention(s) can be used to manipulate spinal cord autonomic circuitry in humans will require additional research. However, data from our study provide a ‘blueprint’ that may explain why the frequency of AD and infectious complications increase in some people living with SCI.”
“We still do not understand why SCI does not cause AD or immune suppression in all individuals, even in those who are affected by high level SCI. We also need to understand how and why spinal cord circuit rewiring occurs and when it does, are there critical periods during which interventions will work better? For example, can we block the rewiring?”
“We show that tremendous plasticity develops within autonomic circuitry controlling immune organs. Does a similar type of reorganization develop in other neuronal networks controlling other organs and how does the autonomic plasticity affect motor and sensory functions? Is there cross-talk between these different modalities that are affected by circuit rewiring?”
“Finally, for those in which the rewiring has already been established for many years, is it possible to reorganize this circuitry using existing drugs or rehabilitation therapies and will such interventions affect AD and immune function?”
After Failed Conservative Measures, Hip Arthroscopy More Cost-Effective Than Rehabilitation
With current healthcare costs becoming more and more untenable, many orthopedic surgeons are struggling to manage the chasm between what patients need and what insurers will pay for. Benjamin Domb, M.D., founder of The American Hip Institute, has spent his career focused on developing innovative treatments for hip pathology, and performing clinical outcomes research to refine such treatments and their indications. In a study which was recently presented at the American Orthopedic Society for Sports Medicine (AOSSM) Specialty Day on March 5, 2016, Dr. Domb waded into the medical economic aspect of the field, and found some interesting things. He told OTW, “The medical community is conscious of the growing need to understand cost effectiveness in our society. Insurers are often charged with being good stewards of the health care dollar. At times, their efforts in this mission may inadvertently affect patient access to care. There is a palpable need to perform cost effectiveness analysis in order to achieve our shared goal of helping our patients.”
“Our most recent study compared the cost effectiveness of hip arthroscopy versus structured rehabilitation without surgery, for the treatment of labral tears, one of the most common conditions we treat in hip preservation. We also examined the effects of age in cost effectiveness in both treatment arms.”
“We used the quality-adjusted life year (QALY) measure, which allowed us to ask, ‘For each additional dollar spent, how much additional quality of life can we give our patients?’ We found that arthroscopy cost an additional $2, 653 over a lifetime, but actually generated 3.94 additional quality-adjusted life years compared to rehabilitation. And it was not a huge surprise, but we found that the younger someone is, the more cost-effective arthroscopy is.”
“That naturally brings us to the question ‘How much are we, as a society, willing to pay for a patient to have an additional year with a high quality of life?'. The literature shows that the public’s willingness to pay threshold is generally accepted to be $50, 000 per quality-adjusted life year. Our study showed that the incremental cost was very low—$754 dollars per quality-adjusted life year for hip arthroscopy—far less than the accepted willingness to pay threshold.”
“The results of our study show that hip arthroscopy is cost-effective for 95% of patients. Furthermore, the data showed that the lifetime likelihood of developing symptomatic arthritis is more than doubled if someone goes through rehabilitation as opposed to arthroscopy. Our hope is that this work will promote the collaborative effort between the orthopedic community and insurance carriers to improve patients’ access to beneficial and cost-effective treatments."
Scarring After Spinal Cord Damage Does NOT Prevent Nerve Regeneration
Turns out that when it comes to spinal cord and brain injury, scientists have been barking up the wrong tree. It seems that scar tissue formed by the cells that surround neurons does NOT get in the way of cell regrowth after a spinal cord or brain injury.
Michael Sofroniew, M.D., Ph.D., a professor of neurobiology at the David Geffen School of Medicine at the University of California Los Angeles (UCLA) told OTW, “For decades, it has been thought that scar-forming cells called astrocytes prevent the regeneration of damaged nerve fibers across spinal cord injuries. Researchers assumed that if you could prevent or remove astrocyte scars, nerve fibers would spontaneously regrow. Looking for ways to remove or counteract astrocyte scars seemed like a logical strategy to try and improve repair and outcome after injury. So we tested this idea using various experimental approaches.”
“By using different transgenically targeted strategies in mice, we were able to completely prevent scar formation, or to remove chronic scars, but we never saw any regrowth of nerve fibers in spite of multiple attempts over many years of work. These results suggested that there might be other reasons for the failure of damaged nerve fibers to regenerate. So in a different set of experiments, we tested the effects of local delivery into spinal cord injuries (via slow release from biomaterial depots) of specific neurotrophic molecules that stimulate axon growth during development. We found that neurotrophic molecule delivery, combined with other manipulations to increase growth capacity, was able to stimulate robust regrowth of damage nerve fibers in spite of normally occurring astrocyte scar formation. Surprisingly, if we simultaneously prevented scar formation, the neurotrophin-stimulated regrowth was reduced or prevented. Taken together, our findings show that rather than being major inhibitors of nerve fiber regrowth, scar-forming astrocytes can be supportive of such growth.”
“Astrocyte scars are not responsible for the failure of damaged nerve fibers to regenerate after spinal cord injury. Instead, current evidence points toward a combination of reduced growth capacity of mature neurons in the adult central nervous system, combined with a lack of production of growth stimulating and growth guiding factors by the cells in the injury site. More work is needed to understand how to provide these things in a clinically translatable fashion.”