A frequent question and probably the main reason that thousands of people come to the CareCure Forums (http://sciwire.com) is to find out whether there has been progress in the discovery and development of therapies that restore function after spinal cord injury. A few years ago, it would have been easy to summarize all available, promising, and potential therapies in one article. Now, it is impossible to do so. What are the current and promising therapies that can and may restore function for chronic spinal cord injury? So many therapies have been claimed to restore function after spinal cord injury that some people believe that the "cure" is here, that doctors simply need to apply available therapies, and that no more research is necessary. At the same time, many people believe that no therapy can restore function within their lifetime. In my opinion, both beliefs are wrong. This article will summarize the promise and limits of therapies that are available or may soon be available to restore function in spinal cord injury.
Let me first define restorative therapies, as opposed to a curative or prosthetic therapies. Restorative therapies refer to treatments that can bring back useful function. It differs from curative therapies which should restore function to the point that a person cannot be spinal-injured. Prosthetic therapies are those that substitute devices for functions. For example, a person might be able to get from point A to B just as well and as fast on a wheel chair as walking but this would not be restorative therapy. Likewise, a person might get a suprapubic catheter that would allow unassisted emptying of the bladder and that may function almost as efficiently as being able to void but restorative therapies would be aimed at restoring micturation.
For discussion purposes, I will categorize restorative therapies into three types: rehabilitative, regenerative, and replacement therapies. Rehabilitative therapies aim to restore function by maximizing the function of remaining systems. Regenerative therapies restore function by regrowing axons and other cells that allow axons to function. Replacement therapies seek to replace lost neuronal circuits and functions. While these distinctions may appear to be academic and nitpicking, they do involve different strategies and are at different stages in development. Finally, of course, restorative therapies differ from preventative therapies that seek to reduce further losses of function. Each of these categories of therapies will be discussed in three sequential installments. This article will focus on rehabilitative therapies. I will update these articles regularly as progress occurs in the field, as well as provide documentation for the different therapies.
Significant advances have been made in the past decade in rehabilitative therapies. For many years, rehabilitation focused on maximizing function that survived the injury, teaching people to use their remaining systems more effective with the aid of devices. Most rehabilitative approaches assumed that there would be no further return of function. There has been a sea-shift of attitudes as people are beginning to realize that the brain and spinal cord are capable of remarkable recovery. Until recently, most doctors in rehabilitative centers began treatment by telling patients that they must accept their loss, and learn how to make the most of what they have remaining. This is beginning to change.
The first and most important development in rehabilitative therapy was the recognition that most people recover to some extent after spinal cord injury. Although doctors have known for years that people with any preservation of motor or sensory function shortly after injury are likely to recover substantially over the first year or two after injury, they regarded this as a glass half-empty rather than a glass half-full. The very language used to describe spinal cord injury implied pessimism. For example, many clinicians substituted the word "transection" to describe patients with "complete" neurological loss of function below the injury level. The role of rehabilitation has changed from palliation to maximizing recovery.
Beginning in 1990, clinical trials of acute spinal cord injury showed that recovery is the rule and not the exception after spinal cord injury, even in cases of co-called "complete" spinal cord injury. The second National Acute Spinal Cord Injury Study (NASCIS 2) showed that untreated patients with "complete" spinal cord injury typically recovered 8% of lost motor and sensory function by 6-12 months after injury. People with even slight preservation of motor or sensory function below the injury site recovered 59% of what they had lost. When these patients received high-dose methylprednisolone within 8 hours after injury, those with "complete" injuries on average recovered 21% of function while those with "incomplete" injuries recovered 75%. In the 1980's, 64% of people with spinal cord injury were "complete" on admission but only 36% were "complete" in the 1990's.
Many people believe that the absence of voluntary movement indicate the lack of functioning axons crossing the injury site. This may not be true for the following reasons. First, neurological examinations usually focus on voluntary activity and seldom look for voluntary inhibition. A majority of descending axons in the spinal cord are inhibitory rather than excitatory. This is why there is generally increased excitability of the lower spinal cord after injury, due to disinhibition. While many people may not be able initiate movement, they can often suppress spasticity or spasms. Second, people who have complete neurological loss below the injury site may have some residual function not detected by standard neurological examinations and may still have axons crossing the injury site (Dimitrijevic, 1988a, 1988b; Sherwood, et al. 1992).
Progress in rehabilitative therapies came on several fronts. The first was the recognition that regular standing and other exercises improved the bone, muscle, cardiovascular, and pulmonary function in people. This was not a discovery since physicians have long known that bone, muscle, heart, and lungs of people deteriorated when they did not use them. The second was the use of electrical stimulation and other devices to exercise paralyzed muscles. The third was the discovery that as many as 40% of people who have never walked independently after spinal cord injury can learn to walk independently with intensive supported locomotor exercise on treadmills. Other therapies that employ biofeedback or exercise have shown that intensive training can reverse "learned non-use". The concept of intensive training to restore function is beginning to be accepted in rehabilitation.
Standing. Physicians have long known that immobilization causes bone and muscle loss, as well as reduced cardiovascular and pulmonary capacity. It seemed logical that early and vigorous efforts to get patients with spinal cord injury out of bed and standing would prevent such losses. In the 1980's, it was not possible to do this because surgical approaches to stabilizing the spinal column did not permit rapid mobilization. However, in the past decade, surgically implanted fixation devices now allow a vast majority of patients to be up within days after injury. Despite this, many rehabilitation centers are still skeptical and do not vigrously encourage their patients to stand. While several studies suggest that standing exercises do not restore bone and muscle function, it should be pointed out that these studies used only short and intermittent standing often started months after spinal cord injury. More recent studies suggest that weight-bearing can restore bone and muscle function but restoration is slow, especially when weight-bearing exercises are too little too late.
Spasticity. Spinal cord injury disconnects the brain from the spinal cord below the injury site. If they have not been damaged, spinal cord circuits below the injury site become hyperexcitable and this manifests in spasticity (increased reflexes) and spasms (spontaneous organized movements). Spasticity is aggravated by bladder infections, decubiti, kidney stones, and other sources of noxious input into the lower spinal cord. For many years, doctors have regarded spasticity as undesirable and used drugs to suppress spasticity. They often do not distinguish between spasticity and spasms. Spasticity results from disinhibition of reflex circuits such that the muscles are hyperactive, resist movement, and show repetitive responses (clonus) to stimulus. Drugs such as baclofen and tizanidine effectively reduce spasticity but are not particularly effective against spasms unless they are given in such high doses that they weaken the muscles to the point of flaccidity. A better and more common practice today is to eliminate conditions that aggravate spasticity and titrate antispasticity drugs to reduce spasticity to a tolerable level without weakening muscles.
Exercise. A person with spinal cord injury can exercise muscles above the injury site. Paraplegic patients, for example, can exercise vigorously with available devices. For many years, physical therapists have been less aggressive in exercising people with cervical injuries. Because they do not have enough functioning muscles to engage in activities that can stimulate the cardiovascular and pulmonary system, they often spend 95% of their waking hours recumbent or sitting. However, many strategies are now available for exercising people with high spinal cord injury. For example, people with cervical spinal cord injury can do progressive weight-bearing on tilt tables. Many physical therapy techniques can be used to strengthen weak muscles in the arms and legs. Tetraplegics can swim. The goal is to start exercises as soon as possible and as often as possible. Combined with weight-bearing, titrating anti-spasticity medication so that spasticity can be used to help exercise the muscles, even people with high cervical spinal cord injury can maintain their body.
Stimulation. Electrical stimulation have been used to activate muscle for centuries. Although much data indicate that muscle stimulation can maintain and increase muscle bulk and strength (Gorman, 2000), they are still not consistently applied in spinal cord injury. Surface stimulation activates only superficial muscles. Implanted stimulation systems are more effective for activating deeper muscles, both the surgery and the devices are expensive. Implanted intradural stimulation reduces spasticity (Barolat, et al. 1995) but may not be cost-effective (Midha & Schmitt, 1998). Sacral root stimulation for bladder function is both effective and cost-effective (Brindley, 1994; Egon, et al., 1998; van der Aa, et al., 1999; Wielink, et al. 1997; Van Kerrebroek, et al. 1996, 1997) but it unfortunately requires cutting of sacral dorsal roots to reduce spasms associated with stimulation. Newer stimulation systems may be able to do so without sacrificing the roots (Sievert, et al., 2002).
hand function (Mulcahey, et al., 1997), and standing . Third, FES can be combined with exercise programs to increase muscle bulk and strength. Although still expensive, combination exercise and FES devices are now available for home use. Modern stimulators are also computerized and safer. As experience grows, functional electrical stimulation may become practical and more popular.
Ambulation. Wernig, et al. (1992, 1995, 1998, 2000, 2002) in Bonn, Germany reported that they were able to restore functional locomotion in as many as 40% of people who had never walked after spinal cord injury. They did intensive locomotor training by placing people in harness supports and walking them for hours on treadmills. Called laufband (German word for treadmill) therapy, this approach was initially greeted with skepticism. However, many groups have recently reported similar positive results (Dobkin, et al. 1995; Berman, et al. 2000; Hess, et a; 2001; Protas, et al. 2001; Field-Fote, 2001; Abel, et al. 2002), even after brief training in people with incomplete spinal cord injuries (Trimble, et al. 2001). The benefits of such therapies were thought to be limited to incomplete paraplegics who had better postural control. However, Dietz, et al. (1999; 2001; Wirz, et al. 2001) in Switzerland recently reported that the restoration of locomotor function paradoxically may be better in people with cervical spinal cord injuries. Indeed, measurable improvements in locomotor function can be shown even in people with so-called "complete" spinal cord injury.
Forced use. Several recent studies also suggest that when brain and spinal circuits are not used for months or years after injury, they turn off or become dormant. Thus, even though there may be sufficient axons to initiate and control function, the circuits that they influence are no longer functioning. Taub & Morris (2001; Kunkel, et al. 1999) recently reported successful use of "constraint-induced movement therapy" to enhance recovery after stroke, even many years after injury, attributing the recovery to reversal of "learned non-use" (Taub, et al. 1999). Even though several studies suggest that such training may help restore function in people with stroke, (Page, et al. 2001), both patients and therapists continue to be skeptical concerning the efficacy of contraint-induced movement therapy (Page, et al., 2001, 2002). Some (van der Lee, 2001) believe that the beneficial effects of the treatment stems from the increased attention and training time. Such a phenomenon may well be the reason why as many as 40% of people can be trained to walk again, even many years after spinal cord injury.
Biofeedback. One approach to reversing "learned non-use" is biofeedback exercises. Biofeedback therapy uses electrical recordings of muscle activity (EMG) for voluntary muscle movement training. In any training session, a muscle will show a range of activity. The goal of biofeedback is to train the person to activate a muscle group consistently at the upper limits of that range of activity. When the person does so, the criterion is increased. Biofeedback may be useful for restoring a variety of motor functions (Brudney, et al., 1979; Brucker, 1996) although some studies suggest that biofeedback is not superior to conventional physical therapy (Kohlmeyer, et al. 1996). Biofeedback does require the presence of connections and may produce motor improvements that do not generalize to other function. For example, I know a hemiplegic pianist who used biofeedback to improve his piano playing to the point that he is believe to be playing better than before his injury but he cannot use his hand to write or feed himself.
Summary. Rehabilitative therapies can restore much more function than most people think. A majority of people, even after severe spinal cord injuries, have attained significant functional recovery due to some or all of the above therapies. Exercise and use of paralyzed muscles can restore function, even years or decades after injury. A recent poll of the members of the carecure community, for example, indicate that more than half of the people report return of additional function below the injury more than 2 years after injury. Many people recover both motor and sensory function five or even ten years after injury. Such recoveries are seldom noticed or believed by many physicians who usually do not follow spinal cord injury patients for such long periods. We should not be surprised by the finding that non-use leads to loss of function. The surprising finding is that intensive use can restore function after years or even decades of non-use.
(to be continued)
Part 2 Regenerative Therapies
Part 3 Replacement Therapies