On a rainy Sunday night in November 2006, Franci Sterzer, 33, and her daughter, Sierra, 14, arrived home to Canal Flats, tired but happy after a hockey tournament in Missoula, Mont. Their town, in the Kootenay Rockies, about 75 kilometres north of Cranbrook, B.C., has its share of bad weather, and when Franci got up on Monday morning, she noticed that the slick roads had frozen over.
“I didn’t feel like taking the kids to the school bus,” she says, “but we were going to Mexico in December and I didn’t want them to miss any more school.” So at 7:30 a.m. on Nov. 20, Franci and her kids – daughter Sierra and sons Aspen, 12, and Mapston, 9 – hopped into the family’s Chevy Avalanche sport utility truck, buckled their seatbelts and headed south along Highway 93/95 to catch the school bus in Skookumchuck.
The 20-minute drive was uneventful until Franci came to a bend in the road and hit black ice. “It was such a huge patch that it seemed to never end. I kept sliding and hit the ditch. Things got blurry from there,” she says.
The Avalanche flipped over and landed upside down. Franci was trapped inside, unable to move, with the back of her head pinned against the roof. Aspen was injured, too, with a concussion and cuts to his forehead. Sierra kicked out the window, scrambled out with Mapston and flagged down the first car. The driver had a CB radio but didn’t know how to use it, so Mapston picked up the radio and called for help.
When the paramedics arrived, they extricated Franci from the vehicle on a spinal board, then took her and Aspen to the nearest hospital in Cranbrook.
Severe spinal injury
Because Franci had suffered a severe spinal injury she needed specialized trauma care and was airlifted to Calgary’s Foothills Medical Centre, arriving at about 4:30 p.m. Her husband, Karl, and the kids had to stay behind with Aspen. “It was extremely tough. We wanted to be with my wife,” he says.
Franci had fractured and dislocated one of the lower vertebrae in her neck, C7 (the seventh cervical vertebra), and it was compressing her spinal cord. Several hours later she underwent decompression surgery to lift the bony fragment off her spinal cord, as well as a bone graft and plating to realign and stabilize her spine.
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Reducing secondary damage
But surgery alone can’t stop the secondary damage to the cord that occurs in the hours, days and weeks after the primary injury. Spinal tissues continue to discharge toxic chemicals that kill and disable nerve cells some distance away from the core injury, compounding the damage and limiting the possibilities for recovery.
Right now those possibilities are expanding, thanks to a virtual explosion of spinal cord research – ranging from promising animal experiments to the first clinical trials in patients. And Canadian scientists are at the forefront of efforts to develop and test new drugs and rehabilitation methods to reverse the “permanent” effects of spinal cord injuries.
So, while Franci was in the intensive care unit awaiting surgery, Dr. Steve Casha asked if she would participate in a pilot study of an experimental drug that could potentially reduce the secondary damage and enhance her recovery. With the blink of an eye (the only way she could communicate) Franci was enrolled in the world’s first clinical trial using minocycline for spinal cord injury.
The next morning, Karl and the kids flew to Calgary. “Franci was in really tough shape, but it was important for her to know the kids were OK. Aspen stood up on a chair so she could see him first. That was a huge relief for her.”
Like Franci, at least half of new spinal cord injury patients suffer damage to cervical segments of the spinal cord, causing paralysis in both the upper and lower body. Before her devastating accident, Franci was very fit and active. “She started the first female hockey team in Canal Flats,” says Karl. “She ran, hiked, golfed, lifted weights and did yoga and wakeboarding.”
She also ran the gift shop and did the accounting for the family’s thriving log-home and resort-building business. After her injury, Franci was paralyzed from her chest down and could only partially move her arms and hands. “Her biggest challenge was being able to breathe,” says Karl. “Franci worked really hard to get breathing on her own.”
In the past, the best that people with severe spinal cord injuries could hope for was quality care to preserve their post-injury capabilities, rather than effective treatments to restore mobility. “The floodgates have opened. There was nothing five years ago. There are now dozens of different treatments that are currently being validated,” says John Steeves, a spinal cord researcher at the University of British Columbia (UBC) who holds the position of The John and Penny Ryan B.C. Leadership Chair in Spinal Cord Injury Research and is the director of ICORD (International Collaboration on Repair Discoveries) in Vancouver.
These new research initiatives offer patients like Franci the still dim, but growing, hope of being able to walk again – or at least gain more movement and sensation, and become more independent.
Scientists today believe that a cure for spinal cord injuries will depend on a combination of treatment strategies that includes neuroprotection, regeneration and rehabilitation.
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Neuroprotection: Drugs that rescue spinal tissue
“Neuroprotection salvages cells that would otherwise die,” says Dr. John Hurlbert, a spinal neurosurgeon who launched the minocycline trial with Dr. Steve Casha, a fellow University of Calgary neurosurgeon. “It’s easier to save neurons than to regenerate them.”
Minocycline does that by reducing neuroinflammation and blocking the release of toxic chemicals that would otherwise destroy healthy cells near the primary injury site. The drug must be given within 12 hours to keep those cells from dying and then administered twice daily for seven days.
For newly injured patients such as Franci, the hope is that neuroprotective drugs can stop the secondary wave of cell suicide that sweeps through spinal cord tissue and lead to a fuller recovery. The more tissue that is preserved, the more movement and sensation the patient is likely to regain in the weeks, months and years after the injury.
Franci is one of 50 patients participating in the minocycline study; half were treated with the drug and half were given a placebo. Although Franci won’t know whether she was treated until the study is completed next year, she and her husband remain optimistic. “We have an intuition that Franci is on minocycline,” says Karl. That belief could be based simply on hope, or on the progress in her hand and finger movements in the months following her injury.
Neuroprotection and regeneration: Repair the cord, grow new nerve endings
Cethrin, a new drug developed by Lisa McKerracher, formerly a neuroscientist at the Université de Montréal, has both neuroprotective and regenerative properties. Scientists have learned in the last decade that spinal cord cells can potentially grow new connections, but certain inhibitory molecules released after a spinal injury prevent regeneration.
Ten years ago, McKerracher developed a protein molecule, called Cethrin, that blocks Rho (which receives signals from those inhibitory molecules). Preclinical studies showed that Cethrin greatly improves recovery after a spinal injury because it prevents cells from dying and promotes regrowth of injured axons (nerve cell fibres that carry messages).
In 2005, Bioaxone Therapeutic (a biotech company started by McKerracher) launched a clinical trial of the new drug at hospitals in Toronto, Montreal and Vancouver, and in five cities in the United States. Thirty-seven patients with complete spinal cord injuries had the drug topically delivered onto their spinal cords within eight hours of the injury. (Patients – like Franci – who have complete injuries have no movement or sensation below the injury site and are much less likely to regain them than patients with incomplete injuries.)
The results are very encouraging. About 31 per cent of patients recovered some sensation and/or movement below the level of the injury, going from a complete to an incomplete injury. The drug is safe, and those patients will have a much better chance of regaining more mobility in the future. “The data look better than anyone could have expected from a safety trial,” says McKerracher.
The Cethrin trial was led by spinal surgeon Dr. Michael Fehlings, holder of the Krembil Chair in Neural Repair and Regeneration at the University Health Network’s Toronto Western Hospital. “The degree of improvement in patients treated with Cethrin exceeds expectations, and Cethrin shows great promise,” says Fehlings, noting that seven patients improved substantially, with at least two regaining some movement in their previously paralyzed legs.
In January of this year, Alseres Pharmaceuticals acquired the rights to develop and commercialize the drug, and the company plans to launch a large clinical trial early in 2008 to definitively assess the benefits of Cethrin for spinal cord patients.
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Regeneration: Growing new nerve connections
Successful repair of spinal cord injuries will depend, in part, on the regrowth and replacement of damaged connections between spinal nerve cells. In 2006, Novartis launched in Europe the first clinical trial of a purely regenerative drug in spinal cord patients.
In the initial feasibility phase, 15 patients were given this antibody drug, known as anti-Nogo, and now a larger trial to investigate safety and effectiveness is under way. This drug works by blocking Nogo (so called because it tells nerve connections not to grow), an inhibitory protein that stops spinal cells from sprouting new connections. In animal studies, primates whose spinal cords were partially severed regained 80 per cent of their hand movements after being treated with anti-Nogo antibodies.
Clinical trials are expected to begin at Toronto Western Hospital and other spinal injury centres in Canada and the U.S. early in 2008.
Restoration: Cell transplants offer great promise
Cell transplants, which we hear a lot about, are being looked at as part of a long-term strategy for repairing and possibly curing spinal cord injuries. The concept is simple: replace some or all of the cells that have been destroyed as a result of a spinal cord injury to help patients regain mobility.
“The promise is that you might have regeneration of damaged nerve fibres. The big challenge is to get the right cells into the right place and working,” says Dr. Armin Curt, a neurologist and chair of SCI Rehabilitation Research at UBC.
Major progress has been made in the past decade in testing transplants of different types of cells in animal models of spinal cord injury. Some of the most promising types of cells being tested include embryonic and adult stem cells, Schwann cells (from peripheral nerves) and olfactory glial cells (from the nasal lining). With Schwann and olfactory glial cells, the strategy is to transplant them and harness their regenerative properties to repair the injured cord.
With stem cells, the hope is that embryonic or adult stem cells can be coaxed into becoming functioning cells in the damaged area of the spinal cord. In a 2006 experiment, for example, Fehlings of Toronto Western Hospital transplanted stem cells from the brains of adult mice into rats whose spines had been crushed. The stem cells restored myelin (an insulating layer around nerve fibres that transmits signals from the brain) in the damaged area and the rats gained more mobility. Fehlings predicts that stem cell therapies for spinal cord injury could be safely tested in human patients within five to 10 years.
Cell transplants offer exciting potential but are controversial because of unregulated procedures now being performed on spinal cord patients in China, Russia, Portugal and other countries.
A 2006 study by Curt and two other leading neurologists (published in Neurorehabilitation and Neural Repair) assessed seven patients who received olfactory ensheathing cell transplants in China. After surgery, three patients developed meningitis and none of the seven showed measurable improvements in their condition. More research is needed to show safety and effectiveness, says Curt, before cell transplants are ready for testing in patients.
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Active rehabilitation: reawakens movement
Milos Popovic, a biomedical engineer at the Toronto Rehabilitation Institute, uses functional electrical stimulation (FES) to activate nerves connected to muscles affected by paralysis. Popovic developed a Walkman-size FES system as a training tool to help patients with limited walking ability regain voluntary control of weakened or paralyzed leg muscles.
After regular FES sessions on a treadmill for three to four months, the patient’s ability to walk is greatly improved, even without the use of the electrical stimulation device. With repeated electrical stimulation of the leg muscles, the nervous system relearns how to move those muscle groups. “The nervous system has some plasticity, so you can retrain it with FES,” explains Popovic.
John Haddad, 39, is one of five patients with a chronic incomplete spinal cord injury who participated in a 2005 pilot study published in Spinal Cord. In 1996, John had a benign tumour removed from his spine. After the operation, he could only walk a short distance using braces and two canes, and he needed his wheelchair to go to the store. Seven years after the operation John began FES treatment.
“The FES has made my mobility much better. I walk up stairs all the time now, and I can go a lot farther than before. It’s taken me from using my wheelchair to not using it,” says John, who continues to use two canes because he has no feeling in his legs. “The canes tell me where the ground is.”
This therapy is particularly exciting because it helps patients with chronic spinal cord injuries – most of whom are not expected to recover more movement. “I’ve proven that you can improve a lot. It’s given me drive because I’ve got more mobility,” says John.
Intensive rehabilitation helps to retrain circuits in the brain and spinal cord to maximize movement. Researchers believe that intensive rehab methods, such as FES therapy and partial body-weight support treadmill training (please see “Training the Spinal Cord to Walk,” page 106), will have an even greater impact when combined with neuroprotective and regenerative treatments, such as minocycline, Cethrin and anti-Nogo, or with cell transplants.
“You want to combine a new medication with rehab to get an enhanced benefit,” says Dr. Mohan Radhakrishna, a specialist in physical medicine and rehabilitation at McGill University Health Centre in Montreal.
Page 5 of 6Moving forward
When Franci Sterzer hit that patch of black ice last November, her life changed forever. But unlike many victims of spinal cord injury before her, she has choices that offer her a possibility of meaningful recovery. As a participant in the first minocycline trial for spinal cord patients, she hopes that this neuroprotective drug will improve her prospects for regaining more mobility in the years following her injury.
In the first six months of treatment and rehab at Foothills Medical Centre, Franci progressed from being unable to breathe on her own to significant gains in the use of her hands, wrists and fingers. “In a relatively short period of time, Franci’s progress has been good enough that she doesn’t have to use an adaptive aid for her right hand,” says Yvette Andreas, a research nurse at Foothills Medical Centre. “Her fine motor skills have been continually progressing, and she’s better able to grip things. She can use a pen to write, and now she’s doing some painting.”
Andreas won’t know which patients were treated with minocycline until the study is completed next year. But, she says, “There have been some changes in some patients that make us hopeful. They’ve gained some recovery that you might not normally have expected.” If Franci was given the drug, the potential benefits from intensive rehabilitation should also be greater because more spinal tissue would be preserved.
Franci’s increased ability to use her hands, wrists and fingers has given her more independence. “I’m encouraged by the progress I’ve made in hand mobility,” she says, “but I’m uncertain about the unknown. Will the progress stop or continue?” The brightest glimmer of hope may lie in the flickers of movement in her lower limbs. “Franci is able to move her toes voluntarily. Our short-term goal is to get more controlled movements on a regular basis,” says Karl. “It’s uncharted territory. Our ultimate goal is for her to walk again.”
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