October 22, 2014
An exclusive report about this work was shown last night on the UK BBC Panorama program, with film footage spanning 3 years, showing the patient in rehabilitation before the transplant and then during the 2 years after the transplant. The patient was shown walking, albeit slowly and leaning on a walker. A video clip can be seen here.
“It is immensely gratifying to see that years of research have now led to the development of a safe technique for transplanting cells into the spinal cord. I believe we stand on the threshold of a historic advance and that the continuation of our work will be of major benefit to mankind,” Professor Raisman said in a statement.
“I believe we have now opened the door to a treatment of spinal cord injury that will get patients out of wheelchairs. Our goal now is to develop this first procedure to a point where it can be rolled out as a worldwide general approach,” he added. In the Panorama documentary, he made a point of saying that he does not intend to patent any part of the technique and is keen for other groups to replicate the research.
The case has received much publicity, with headlines including “miracle surgery” and “cure for paralysis,” but experts in the field were generally cautious.
Michael G. Fehlings, MD, head of the spinal program at Toronto Western Hospital, Ontario, Canada, said the results were “promising.” He commented to Medscape Medical News: “The field of regenerative neuroscience is advancing. However, the results in a single case always need to be interpreted with caution. Larger studies with multiple patients, blinded assessments, and appropriate control groups are needed. Nonetheless, the work suggests that cellular treatments for spinal cord injury in combination with intensive rehabilitation could be a viable treatment option in the future.”
But Wolfram Tetzlaff, MD, director of the International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, Canada, is more skeptical.
He told Medscape Medical News that “It is entirely possible that untethering [releasing scar tissue pressure] and rehabilitation could have done this. Larger cohorts of patients and control groups with similarly spared tissue getting just this type of rehabilitation (without cell injections) would be needed for confirmation.”
“Sadly this media hype gives other people living with spinal cord injury the feeling that they should get this treatment tomorrow,” he added. “Any risky intervention like this needs validation in a trial. What it should leave us with is the hope that indeed improvements are possible even in cases deemed ‘complete’ and that with more funding incremental steps towards therapies will eventually happen.”
The technique involved transplanting olfactory ensheathing cells (OECs) into the spinal cord. These cells were discovered by Professor Raisman in 1985, and he showed that they could repair spinal injuries in rats in 1997.
To obtain the OECs used in the transplant, the patient underwent surgery to remove one of his olfactory bulbs. Quite separately from his paralysis, the patient had chronic allergic sinusitis and nasal polyps and had no sense of smell, but when the polyps were cleared by sinus surgery his sense of smell recovered. In the UCL press release, the researchers admit they are unclear about how exactly this happened, but they speculate that the right olfactory bulb was able to interpret smells from the left nostril.The first human transplant took place 2 years ago in Darek Fidyka, a 38-year old man in Poland. He had been left paralyzed after a knife stabbing, which resulted in a clean cut through the spinal cord at the upper vertebral level Th9. There was a gap of 8 mm between the two ends of the spinal cord, clearly visible on MRI, which was shown on the Panoramaprogram. Another MRI scan taken at 5 weeks after transplant showed that the gap was now less obvious, while another MRI scan at 5 months after transplant showed no visible gap.
MRI scans obtained before, 5 weeks after, and 5 months after transplant. BBC Panorama
Once the olfactory bulb had been removed, it was placed in a cell culture for 2 weeks to produce OECs. These were then injected into the spinal cord above and below the injury, and four strips of nerve tissue were taken from the ankle and patched across the 8-mm gap. These formed “bridges” for the spinal nerve fibers to grow across with the aid of OECs, the UCL release explains.
In their publication, the authors report that the patient improved from American Spinal Injury Association (ASIA) class A, clinically complete spinal cord injury, to ASIA class C, with motor function preserved below the neurologic level, and more than half of key muscles below that level at a muscle grade of less than 3.
He had improved trunk stability, partial recovery of voluntary movements in the lower extremities, and an increase of muscle mass in the left thigh with partial recovery of superficial and deep sensation, the authors report. Further, there was some indication of improved visceral sensation and vascular autoregulation in the left lower limb, they note. “The pattern of recovery suggests functional regeneration of both efferent and afferent long-distance fibers.”
Imaging confirmed that the grafts had bridged the left side of the spinal cord, where most of the nerve grafts were implanted, they add, “and neurophysiological examinations confirmed restitution of the integrity of the corticospinal tracts and the voluntary character of recorded muscle contractions. To our knowledge, this is the first clinical indication of beneficial effects of transplanted autologous bulbar cells.”
The UCL release also gives details of the patient’s recovery. “Before the study, Darek had been in various rehabilitation programs for 13 months after injury with no sign of improvement. As these programs were incomplete, he was also subjected to an additional eight-month rehabilitation program before the experimental treatment to check if he would recover without surgery, so-called ‘spontaneous recovery.’ The researchers say that the chances of a spontaneous recovery after this time are less than 1%.” This program of exercise — 5 hours per day, 5 days a week — has continued after the transplant.
Three months after the surgery, Darek’s left thigh muscle began to grow and after six months he was starting to walk within the rehabilitation center with the help of a physiotherapist and leg braces. Now, two years on, he is able to walk using a frame although it is tiring. His bladder sensation and sexual function have also improved. He said: ‘I think it’s realistic that one day I will become independent.'”
Consultant spinal injuries surgeon, Wagih El Masri, clinical professor of spinal injuries at Keele University, United Kingdom, was not involved in the research, but traveled to Poland to clinically assess the patient. “Although the clinical neurological recovery is to date modest, this intervention has resulted in findings of compelling scientific significance,” Professor El Masri told the BBC.
“I have waited 40 years for something like this,” he added.
All of the researchers emphasize that more work is needed, and the team now plans to treat another 10 patients, in Poland and Britain, over the coming years, although that will depend on the funding received.
Dr Tetzlaff stressed that it is premature to draw conclusions because this is a study with only one patient, and larger cohorts with blinded assessors are needed. He pointed out: “This patient presented functionally complete but had a 2-mm bridge of spared tissue at the site of injury. These bridges can be nonfunctional when compressed by scarring, and performing the type of surgery [untethering] they did might have done just that. In addition, this patient received extensive physiotherapy (5 hours daily/5 days a week) for 8 months before and 21 months after and showed this motor recovery by 11 months (which is modest but significant). This rehabilitation regimen likely contributed to this recovery in an injury that was not complete. For these reasons alone it is impossible to conclude presently whether these cells and bridges had an effect. The 19-month FA-MRI of this particular patient would indicate there was a wide gap, suggesting this was not a regeneration effect.”
He added: “We hear similar anecdotal reports from our colleagues in China, who also have the resources to apply 6 hours of rehab/6 days a week (with the help of family members living in/near the hospitals). What this indicates is that some functionally complete patients would likely benefit from more and longer rehabilitation regimen than we can presently offer, sadly. Rehabilitation is the only effective treatment presently aside from the initial stabilization surgery.”
Jane Sowerby, a spokesperson from the UK spinal cord charity Back Up, who herself has a spinal cord injury, also urged caution. She said while the study was “fascinating,” wider application is still a long way off and “it’s potentially dangerous for people to pin all their hopes on this being a miracle cure.”
She added: “There’s been such huge media coverage of this, I just worry that people are going to assume that we’re all going to be walking again by Christmas, which obviously isn’t going to be the case. It’s important for people that have recently had a spinal injury to really think about the present and get involved with a charity like Back Up rather than thinking about things that may be a long way off in the future.”
This research was supported by the Nicholls Spinal Injury Foundation and the UK Stem Cell Foundation.
Cell Transplant. Published online October 21, 2014. Abstract