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Repairing damaged spinal cords: hopes for the future
THE LANCET
SCIENCE AND MEDICINE
Repairing damaged spinal cords: hopes for the future
E
very year, 700 people in the UK and 10 000 people in the USA injure their spinal cord. The prospect of recovery for most of these people is remote, so the demonstration of a new repair strategy, albeit only in rats, by scientists at the Karolinska Institute in Sweden, has generated considerable interest. The American Association for the Advancement of Science describe the result as “a major stride in spinal-cord repair”, but Martin Berry, a professor of anatomy at Guy’s Hospital, London, UK, is more cautious, saying that it might all be a “bit overoptimistic”. Is the Swedish approach likely to work in human beings and what other approaches are being developed? To repair the spinal cord the damaged axons have to be persuaded to regenerate. Martin Schwab at the University of Zurich, Germany has previously demonstrated that proteins made by oligodendroglial cells inhibit axonal growth in central nervous system white matter. To get round this inhibition, the Swedish scientists used multiple intercostal nerve grafts to bridge gaps in transected rat spinal cords, thus redirecting nerve pathways from white to gray matter. The grafted area was stabilised with fibrin glue containing acidic fibroblast growth factor (figure). Hind-limb function in the rats started to improve significantly 3 weeks after the bridge procedure but none of the animals recovered full coordinated locomotion (Science 1996; 273: 510–13). This latest research is valuable, say clinicians, in that it consolidates both Schwab’s work, and that of Albert Aguayo (McGill University, Montreal, Canada) who has shown that spinal axons can invade and grow in peripheral nerve conduits outside the cord. But the new repair strategy is “still quite far from being applied to the more complex requirements of higher mammals”, says William F Collins, (Yale University School of Medicine, Yale, USA). Ann Logan (Birmingham University, UK) adds that the researchers “did no anatomical analysis. All the conclusions were based on behavioural tests which won’t discriminate between neuroprotection and true regeneration”. And as Susan Hall, (Guy’s Hospital, London, UK) says “There is an enormous difference between a discrete experimental lesion produced in the rat by transecting the spinal cord with a scalpel, and the indiscriminate destruction of cord tissue seen in traumatic
814
injuries such as motor cycle accidents”. A further potential flaw in the Swedish study, suggests Berry, is the use of peripheral nerve grafts to aid spinal-cord repair. “The general feeling”, he says “is that axons become entrapped within the graft and do not bridge the gap. There’s no reason axons should leave the graft because concentrations of neurotrophins in the graft are higher than they are in surrounding CNS”. One alternative bridging technique is being investigated in animal models by Mary Bartlett Bunge and co-
workers at the Miami Project to Cure Paralysis, Miami, USA. This group is developing cables of Schwann cells to act as “stepping stones” for injured nerves to grow across (figure). What is the current status of human spinal cord repair? In 1977 George Bonney (St Mary’s Hospital, London, UK) successfully re-implanted a spinal nerve. Thomas Carlstedt (Royal National Orthopaedic Hospital, Stanmore, UK) has continued this work, and has successfully reimplanted avulsed spinal nerve roots in 3 out of 5 patients with severe brachial plexus injuries. In the successful cases, surgery was performed within a month of injury. “If a nerve is cut off from its target it seems it can’t survive. The nerve cells within the spinal cord start to deteriorate with time.” Carlstedt says the next step is to find ways to prevent this decline. Scientists and clinicians alike are clear that a single tactic will not reverse the complex effects of spinal- cord injury. “We need a combination of approaches, including transplantation, provision of neuroprotective and growth-promoting agents, and perhaps specialised surgical
techniques”, says Naomi Kleitman of the Miami Project. One major problem with the existing approaches, both in animal models and human beings, is that nerve regrowth can be fairly non-specific. Lars Olson, one of the Swedish scientists, says that the pyramidal-tract fibres in the rodent experiments regenerated long distances to appropriate areas of the spinal cord, but Carlstedt sees a rather haphazard picture in human beings. “There are several tens of thousands of neurons within the spinal cord and normally each neuron has a specific target site in the muscle. We can’t influence that with this technique. When the nerves are introduced to the peripheral nerve conduit they are simply going for a good environment. It’s like vehicles going out on a highway but they don’t know if they are going to Edinburgh or Bath.” In practice this results in a kind of “mass movement” when patients attempt to use reinnervated muscles—eg, on abduction of the shoulder there is also some flexion at the elbow. As well as trying to encourage axons to grow towards appropriate targets, thus restoring motor function, Carlstedt is also seeking ways to restore sensory input. But for now, treatment of spinal- cord injury remains unsatisfactory, says Collins. Steroids can be beneficial if given within 7 hours of injury but their overall effect is minimal for those with severe injury. Collins believes the current situation warrants clinical studies of experimental surgical interventions such as myelotomy and local cooling of the injured spinal cord. He also points to the importance of efficient medical care at the roadside and during transportation after spinal injury. Correcting shortfalls here “could be one of the most effective changes in the treatment of spinal-cord injury”. Catherine Read
Vol 348 • September 21, 1996
SCIENCE AND MEDICINE
Repairing damaged spinal cords: hopes for the future
E
very year, 700 people in the UK and 10 000 people in the USA injure their spinal cord. The prospect of recovery for most of these people is remote, so the demonstration of a new repair strategy, albeit only in rats, by scientists at the Karolinska Institute in Sweden, has generated considerable interest. The American Association for the Advancement of Science describe the result as “a major stride in spinal-cord repair”, but Martin Berry, a professor of anatomy at Guy’s Hospital, London, UK, is more cautious, saying that it might all be a “bit overoptimistic”. Is the Swedish approach likely to work in human beings and what other approaches are being developed? To repair the spinal cord the damaged axons have to be persuaded to regenerate. Martin Schwab at the University of Zurich, Germany has previously demonstrated that proteins made by oligodendroglial cells inhibit axonal growth in central nervous system white matter. To get round this inhibition, the Swedish scientists used multiple intercostal nerve grafts to bridge gaps in transected rat spinal cords, thus redirecting nerve pathways from white to gray matter. The grafted area was stabilised with fibrin glue containing acidic fibroblast growth factor (figure). Hind-limb function in the rats started to improve significantly 3 weeks after the bridge procedure but none of the animals recovered full coordinated locomotion (Science 1996; 273: 510–13). This latest research is valuable, say clinicians, in that it consolidates both Schwab’s work, and that of Albert Aguayo (McGill University, Montreal, Canada) who has shown that spinal axons can invade and grow in peripheral nerve conduits outside the cord. But the new repair strategy is “still quite far from being applied to the more complex requirements of higher mammals”, says William F Collins, (Yale University School of Medicine, Yale, USA). Ann Logan (Birmingham University, UK) adds that the researchers “did no anatomical analysis. All the conclusions were based on behavioural tests which won’t discriminate between neuroprotection and true regeneration”. And as Susan Hall, (Guy’s Hospital, London, UK) says “There is an enormous difference between a discrete experimental lesion produced in the rat by transecting the spinal cord with a scalpel, and the indiscriminate destruction of cord tissue seen in traumatic
814
injuries such as motor cycle accidents”. A further potential flaw in the Swedish study, suggests Berry, is the use of peripheral nerve grafts to aid spinal-cord repair. “The general feeling”, he says “is that axons become entrapped within the graft and do not bridge the gap. There’s no reason axons should leave the graft because concentrations of neurotrophins in the graft are higher than they are in surrounding CNS”. One alternative bridging technique is being investigated in animal models by Mary Bartlett Bunge and co-
workers at the Miami Project to Cure Paralysis, Miami, USA. This group is developing cables of Schwann cells to act as “stepping stones” for injured nerves to grow across (figure). What is the current status of human spinal cord repair? In 1977 George Bonney (St Mary’s Hospital, London, UK) successfully re-implanted a spinal nerve. Thomas Carlstedt (Royal National Orthopaedic Hospital, Stanmore, UK) has continued this work, and has successfully reimplanted avulsed spinal nerve roots in 3 out of 5 patients with severe brachial plexus injuries. In the successful cases, surgery was performed within a month of injury. “If a nerve is cut off from its target it seems it can’t survive. The nerve cells within the spinal cord start to deteriorate with time.” Carlstedt says the next step is to find ways to prevent this decline. Scientists and clinicians alike are clear that a single tactic will not reverse the complex effects of spinal- cord injury. “We need a combination of approaches, including transplantation, provision of neuroprotective and growth-promoting agents, and perhaps specialised surgical
techniques”, says Naomi Kleitman of the Miami Project. One major problem with the existing approaches, both in animal models and human beings, is that nerve regrowth can be fairly non-specific. Lars Olson, one of the Swedish scientists, says that the pyramidal-tract fibres in the rodent experiments regenerated long distances to appropriate areas of the spinal cord, but Carlstedt sees a rather haphazard picture in human beings. “There are several tens of thousands of neurons within the spinal cord and normally each neuron has a specific target site in the muscle. We can’t influence that with this technique. When the nerves are introduced to the peripheral nerve conduit they are simply going for a good environment. It’s like vehicles going out on a highway but they don’t know if they are going to Edinburgh or Bath.” In practice this results in a kind of “mass movement” when patients attempt to use reinnervated muscles—eg, on abduction of the shoulder there is also some flexion at the elbow. As well as trying to encourage axons to grow towards appropriate targets, thus restoring motor function, Carlstedt is also seeking ways to restore sensory input. But for now, treatment of spinal- cord injury remains unsatisfactory, says Collins. Steroids can be beneficial if given within 7 hours of injury but their overall effect is minimal for those with severe injury. Collins believes the current situation warrants clinical studies of experimental surgical interventions such as myelotomy and local cooling of the injured spinal cord. He also points to the importance of efficient medical care at the roadside and during transportation after spinal injury. Correcting shortfalls here “could be one of the most effective changes in the treatment of spinal-cord injury”. Catherine Read
Vol 348 • September 21, 1996