“A Start” Olfactory Mucosa Autografts in Human Spinal Cord Injury

Clinical trials to improve neurological function after spinal cord injury (SCI) have been increasing throughout the world. A great deal of enthusiasm from some corners of medical researchers, injured individuals, the media, and the lay public for new techniques aimed at “cure” have led some to the expectation that a cure is imminent (1–3). To date, however, none of the recent trials has shown dramatic changes in neurological or functional recovery. The pilot study by Lima et al, (4) published in this issue, describes a surgical intervention that has received some media attention over the last few years. In this report, 7 subjects, all initially classified as ASIA A, aged 18 to 32 years and from 6 months to 6.5 years post-injury, underwent olfactory mucosa autograft transplantation into their spinal cord with the scar tissue reportedly removed. Followup was performed at 6, 12, and 18 months after surgery, with some improvements noted in upper and lower extremity motor scores and overall sensory scores, with two subjects converting from ASIA Impairment Scale (AIS) A to C status. Improvements were also reported for some subjects in bowel and bladder function and “subjective impression of neurological changes.” Adverse events were reportedly minimal. The authors conclude that “olfactory mucosa autograft transplantation into the human injured spinal cord is feasible, relatively safe and potentially beneficial.” There are a number of limitations of this preliminary study that are important to keep in mind. The first issue relates to the performance of a large-scale human study (although only 7 patients' results are detailed in this study, 41 subjects have reportedly undergone this procedure) without a more definitive safety analysis being reported. Recommended guidelines for studies on human subjects with SCI have been published that outline certain criteria for the planning, initiation, and conduct of translational research in the nervous system (5). These include: Preclinical studies in which animal data should be acquired prior to human studies that would be considered predictive of lasting clinical benefit. The greater the invasiveness of the procedure, the higher the standard of preclinical safety and efficacy should be. Safety assessments should be documented and should optimally include outcome measures for pain, as well as assessing maintenance of function above the lesion. There should be evidence of functional benefit demonstrated on accepted objective measures of functional outcome. Functional improvement in the animal model should be of sufficient magnitude and duration to justify the potential risk of a clinical trial. Whenever possible, experimental trials should use placebo control groups. The introduction of the paper describes “a small animal trial using olfactory mucosal transplants in subacute spinal transection model revealed tissue continuity across the lesion site and no signs of overgrowth.” However, this is “unpublished data.” The authors continue that “further support for the potential of the olfactory mucosa in experimental animal studies of SCI will soon be reported.” It is surprising that human studies would be undertaken without reported animal model findings to define the functional or neurological benefits of the intervention. The time period of inclusion into the study was from 6 months post-injury and included subjects with a neurological injury classified as AIS A and B. For clinical trials performed on individuals with chronic SCI, especially when including AIS B subjects, it is more common to wait until individuals are at least 1 year post-injury. Without intervention, patients, most especially individuals with AIS B, can show recovery in bowel and bladder function, as well as improvement to ASIA C status from 6 months to the 1-year time period postinjury. All of the subjects reported were classified as AIS A. Two subjects (Patients 1 and 2), however, who underwent the procedure at 6 months post-injury, showed significantly more recovery; and gained 35 points (the most of any subject) and 15 points (third greatest improvement), respectively, on follow-up sensory examination. For motor testing, Patient 1 improved 7 points on follow-up lower extremity motor (LEM) testing, which was equal to the greatest degree of recovery of the subjects. Greater detail regarding the surgical procedures would allow greater understanding by other researchers regarding the tissue implanted, for example, quantifying the amount of olfactory mucosa removed for implantation, the technique for removal of the tissue and description of the histology. Unfortunately, the examiners were not blinded and there was no mention of inter-rater reliability of the assessors. All patients reportedly had lower extremity (LE) motor recovery, including subjects who remained with complete tetraplegia (AIS A). Such large zones of partial preservation are uncommon, although possible. Quality of life (QOL) changes were described as another benefit to the subjects; however, “no measures were used to quantify this change.” Postoperative EMG findings were reported for 3 subjects who had indication of LE voluntary contraction; however, no identification of these individuals was made or whether these subjects were tested preoperatively in these same muscles to show evidence of electrodiagnostic change. Bowel and bladder changes were described for only a few patients. No comparisons were made between pre- and postoperative urodynamics, and the finding of a change from intermittent catheterization to “Valsalva voiding” is not necessarily an indication of neurologic recovery. To fully study the effect on the bladder, urodynamic testing performed in all subjects would have offered more objective data. We are experiencing an exciting time in the field of SCI research, with so many studies currently underway and many anticipated trials in the near future [Cethrin (BA-210), HP-184, anti-nogo antibodies, minocycline, among others]. Research to discover therapies for SCI has made steady progress over the last several years (5), and continued progress is anticipated through novel approaches by individual centers, eventually leading to multi-center trials. While the limitations of this study have been elucidated, its publication has important implications. It is hoped that much can be learned from this trial and a randomized controlled trial can be discussed after analysis of the patients who have already undergone the treatment.