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Spinal Cord Injury: Progress, Promise, and Priorities (2005)

Chapter: 4 Current Therapeutic Interventions

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Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
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4
CURRENT THERAPEUTIC INTERVENTIONS

As a result of recent advances in science and technology, individuals with a spinal cord injury have improved survival rates, increased opportunities for independent living, and longer life spans—all difficult to imagine possible even a few decades ago. Beginning at the accident scene, immobilization of the spine prevents or reduces the severity of a spinal cord injury, and advances in emergency response have improved the medical care for other urgent and life-threatening problems often associated with spinal cord injuries, including significant blood loss, blocked respiratory pathways, major head or body system trauma, and a dramatic drop in blood pressure. Improvements in rehabilitative care and treatment options have also provided significant functional enhancement and improved daily function.

Organized according to the stage of the injury and the targets for therapeutic intervention, this chapter describes the current standards of care and the treatment options for reducing the sequelae and secondary complications associated with spinal cord injuries, including improving sexual, bowel, and bladder functions; minimizing pulmonary embolisms, depression, and spasticity; alleviating pain; and enhancing function. The following chapter provides details of the progress that is being made in neuronal repair and regeneration and discusses the committee’s recommendations for moving forward in developing therapeutic interventions.

CURRENT STANDARDS OF CARE

Clinical practice guidelines are used in all areas of medicine to promote the best available treatments backed by scientific evidence. Given the com-

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

plexity of spinal cord injuries, only a limited number of guidelines have been developed or are under development. Clinical practice guidelines for spinal cord injuries have come largely from two professional groups, both of which rated the evidence by similar criteria to arrive at formal treatment recommendations. Guidelines from the American Association of Neurological Surgeons and the Congress of Neurological Surgeons (AANS/CNS) deal with acute care, and those developed by the Consortium for Spinal Cord Medicine deal with acute and chronic care (Table 4-1) (PVA, 2002). Other groups have developed additional evidence-based clinical guidelines (AHRQ, 1998). Panels accord the greatest weight to evidence from randomized, prospective, controlled clinical trials and the least weight to evidence from case reports describing one or more patients who improved with treatment. A lack of clinical guidelines for a particular treatment does

TABLE 4-1 Clinical Practice Guidelines for Treatment of Spinal Cord Injury

Current Guidelines

 

Acute Care

 

Acute management of autonomic dysreflexia: Individuals with spinal cord injury presenting to health care facilities (1997, 2001)a

 

Pressure ulcer prevention and treatment following spinal cord injury: A clinical practice guideline for health-care professionals (2000)a

 

Diagnosis of occipital condyle fractures by computed tomography (CT) imagingb

 

Isolated fractures of the axis in adultsb

 

Management of pediatric cervical spinal injuriesb

 

Chronic Care

 

Neurogenic bowel management in adults with spinal cord injury (1998)a

 

Depression following spinal cord injury: A clinical practice guideline for primary care physicians (1998)a

 

Outcomes following traumatic spinal cord injury: Clinical practice guidelines for health-care professionals (1999)a

 

Prevention of thromboembolism in spinal cord injury (1997a, 2002b)

Guidelines Under Development

 

Respiratory managementa

 

Preservation of the upper extremity functiona

 

Bladder managementa

 

Acute management of spinal cord injurya

 

Sexuality and reproductive healtha

 

Treatment of spasticitya

aConsortium for Spinal Cord Medicine.

bAmerican Association of Neurological Surgeons and the Congress of Neurological Surgeons.

SOURCES: Apuzzo, 2002; PVA, 1998, 2000, 2001, 2002.

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

not mean that the treatment is ineffective; rather, some treatments have not been entered into clinical trials to examine efficacy.

THERAPIES FOR ACUTE INJURIES

Acute care begins at the scene of an injury, continues through transport of the patient, and ends with early evaluation and care at a trauma center. The complex medical challenges faced in treating patients who suffer a spinal cord injury begin at the injury scene where often the patient not only needs to be immobilized because of concerns about a spinal cord injury but also requires immediate attention for other urgent and life-threatening problems: significant blood loss, blocked respiratory pathways, major head or body system trauma, or a dramatic drop in blood pressure. One indicator of the progress that has been made in acute care is that patients increasingly arrive at the emergency department with less severe injuries. Most patients (55 percent) in the 1970s came to regional centers with complete spinal cord injuries, whereas today approximately 39 percent arrive with complete injuries (AANS/CNS, 2002a). The transformation to less severe injury is most likely the result of improved emergency medical services (EMS) at the accident scene and more careful handling and patient care during transport (Garfin et al., 1989). Apart from immobilization at the accident scene, few therapies for acute spinal cord injuries have been proven to be effective and safe.

Immobilization at the Scene and Transport to Acute Care

At the scene of the injury, the primary considerations related to the spinal cord injury are to stabilize the spine and to ensure rapid transport to the nearest acute-care facility. These goals are vital to preventing further injury, considering that it has been estimated that in the past between 3 and 25 percent of spinal cord injuries took place after the initial trauma, either during transport or early in the course of patient evaluation (Hachen, 1974). In the United States, the practice of immobilizing the neck and spine of all trauma patients at the scene has become nearly universal. Immobilization at the scene is supported by clinical experience and by biomechanical evidence that it reduces the pathological motion of the spinal column.

A major improvement in EMS arrival and transport times has led in recent decades to striking decreases in rates of mortality, injury severity, complications, and lengths of hospital stays (Hachen, 1974; Tator et al., 1993). In the mid-1990s, a large clinical trial conducted in multiple states noted the rapid times of EMS arrival at the scene (e.g., 4 minutes for 25 percent of cases) and arrival to the first emergency department in about 1 hour (Geisler et al., 2001). The elapsed time from the injury to the arrival at

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

a specialized trauma center averaged 6.2 hours. Also, the quality of the care administered during transport has improved. Before 1968, many deaths took place in transit as a result of inadequate respiratory or cardiovascular support. Current treatment guidelines call for rapid transport to the closest facility with the capacity to evaluate and treat spinal cord injuries (AANS/CNS, 2002c).

Despite the progress in care at the scene of the injury, there are as yet no demonstrably effective pharmacological therapies that can be administered at the scene or during transport. Further attention needs to be given to the development of acute-care therapeutic interventions and to evaluation of other emergency response efforts that might improve patient outcomes, such as methods to relieve compression of the spinal cord and prevent further cell death, edema, and ischemia.

Decompression of the Spinal Cord

Decompression of the spinal cord, if it is performed during the appropriate time window, may provide a benefit to individuals with spinal cord injuries. In many patients, surgery is performed soon after the injury to remove the tissue debris, bone, disc, and fluid that compress the spinal cord. The goal is to alleviate pressure and to improve the circulation of blood and cerebrospinal fluid, particularly for those with central cervical spinal cord injuries (Dobkin and Havton, 2004). Yet there are many unknowns about the value and timing of this procedure. Studies of decompression in rodents after a spinal cord injury demonstrate that the longer compression of the spinal cord exists, the worse the prognosis for neurological recovery (Dimar et al., 1999).

A meta-analysis found that although decompression clearly improves neurological recovery in animal models, the findings for humans are less impressive (Fehlings et al., 2001). Studies favoring decompression have mostly been case studies, which are less robust types of analyses than randomized controlled trials. No prospective clinical trials of the benefits and risks of decompression have been conducted. Furthermore, in the studies that have already been completed, the timing of surgery was not uniform, so the optimal timing remains unknown. Nevertheless, the best indication about timing comes from a large case series that found that the greatest benefits were obtained when decompression was performed within 6 hours of the injury (Aebi et al., 1986). Some evidence, on the other hand, indicates that decompression of the spinal cord may be harmful and is best avoided, as long as the individuals are provided with nonsurgical therapies (Fehlings et al., 2001). Weighing the evidence as a whole, two professional groups adopted the position that decompression does not constitute the standard of care but should remain an option (Silber and Vaccaro, 2001;

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

AANS/CNS, 2002c). The Christopher Reeve Paralysis Foundation is in the process of developing an international clinical trials network (see Chapter 6) and is examining the feasibility of performing a clinical trial to examine the optimal timing for spinal cord decompression.

Neuroprotection

Several human clinical trials of potential neuroprotective therapies after spinal cord injury were conducted in the 1980s and 1990s (Mirza and Chapman, 2001); however, none of these conclusively demonstrated a benefit for increasing function after a spinal cord injury. The most high profile clinical trials were of the medications methylprednisolone and the ganglioside GM-1. After careful review of the results by two separate panels, neither of the two medications received endorsement as a standard of care (Fehlings and Spine Focus Panel, 2001; AANS/CNS, 2002c).

The three clinical trials of methylprednisolone, a corticosteroid, were sponsored by the National Acute Spinal Cord Injury Study (NASCIS) (Bracken et al., 1984, 1990, 1997). The trials were launched after it was reported that methylprednisolone preserved neurological function in animal models by inhibiting ischemia, axon degeneration, and inflammation, among other effects. The first human clinical trial in the early 1980s compared high- versus low-dose methylprednisolone (Bracken et al., 1984); the second clinical trial compared the effects of methylprednisolone with those of another agent and a placebo (Bracken et al., 1990); and the third clinical trial compared the timing of methylprednisolone treatment (Bracken et al., 1997). Concerns have been raised about the robustness of the statistical analyses and the heterogeneity of the populations with spinal cord injuries used in the studies, which made it difficult to compare due to differences in the baseline characteristics of the study populations (Bracken and Holford, 2002) (see Chapter 6 and Appendix E). Consequently, it has been stated that the data describing improved recovery from methylprednisolone treatment are weak and that the improvements observed may represent random events (Hurlbert, 2000). In some cases the trials documented serious side effects, the most prominent of which were higher infection rates, respiratory complications, and gastrointestinal hemorrhage.

Another pharmacological therapy, the ganglioside GM-1, a lipid that is abundant in mammalian central nervous system membranes, was also reported to show improvement in animal models but has not been found to be useful in humans. Its potential therapeutic value was suggested by its ability to prevent apoptosis and to induce neuronal sprouting in animal models. However, the findings from a large-scale clinical trial were negative when the results for the treated group were compared with individuals who received placebo (AANS/CNS, 2002c).

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

Similarly, experiments with rodents (Behrmann et al., 1994) and cats (Faden et al., 1981) have demonstrated that thyrotropin-releasing hormone (TRH) can significantly improve long-term motor recovery after a spinal cord injury. However, a large-scale randomized clinical trial designed to examine the effects of TRH analogs in individuals with acute spinal cord injuries was not fully completed (Pitts et al., 1995), and such an evaluation has not been revisited.

TREATING COMPLICATIONS OF SPINAL CORD INJURIES

Prevention or Elimination of Chronic Pain

Chronic pain, one of the most common sequelae of spinal cord injuries, is not adequately controlled by currently available treatments. Inadequately controlled pain not only erodes quality of life, functioning, and mood but also can lead to depression and, most tragically, suicide (Hulsebosch, 2003; Finnerup and Jensen, 2004). Some clinicians have been slow to recognize that chronic pain is real, has serious consequences, and should not be dismissed as grounds for psychiatric referral (Hulsebosch, 2003).

To assist with the development of treatments for the chronic pain associated with spinal cord injuries, an International Association for the Study of Pain task force was formed to define distinct categories and sources of pain (Vierck et al., 2000). Two categories were defined: at-level neuropathic pain and below-level neuropathic pain. At-level neuropathic pain is correlated to the amount of damage to the gray matter above and below the primary injury site (Yezierski, 2000) and the amount of secondary cellular damage caused by the release of neurotransmitters (glutamate and N-methyl-D-aspartate [NMDA]) (Tator and Fehlings, 1991) and inflammatory cytokines (Bethea et al., 1998; Vierck et al., 2000). Below-level neuropathic pain is associated with axonal disruption, loss, or damage along the spinothalamic tract (Bowsher, 1996).

Experts in spinal cord injury-associated pain consider the development of pain therapies to be a major and feasible research priority, considering the body of research that has been amassed over the past 10 years about pain mechanisms in individuals with spinal cord injuries, as well as related research on other forms of neuropathic pain. Neuropathic pain, as explained in Chapter 2, results from direct damage to neural tissue, whereas nociceptive pain is caused by damage to nonneural tissues (bone, muscles, and ligaments). Nociceptive pain is what most healthy people are familiar with, and it is more treatable and controllable with standard pain therapies like anti-inflammatory agents and analgesics. Neuropathic pain is often treated with antidepressants and anticonvulsants, but their efficacies spe-

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

cifically for the treatment of spinal cord injury-associated pain are weak (Finnerup and Jensen, 2004).

Few randomized controlled clinical trials of pain therapies for individuals with spinal cord injuries have been published in the medical literature, and none of the trials that have been conducted found commonly used pain therapies to be highly effective (Table 4-2) (Finnerup and Jensen, 2004). Explicit guidelines for the treatment of both pain and spasticity (see the next section) for clinicians and caregivers are lacking. However, evidence is accumulating that opioid agents given in combination with other agents may have therapeutic value (Mao et al., 1995; Wiesenfeld-Hallin et al., 1997; von Heijne et al., 2000).

The use of some therapies that encourage axonal elongation may be inadvisable because they could also cause chronic pain. For example, in addition to promoting axon regrowth, brain-derived neurotrophic factor has been found to elicit pain (Kerr et al., 1999), likely by enhancing synaptic input into the superficial dorsal horn, where nociceptive pain processing

TABLE 4-2 Randomized Controlled Trials of Pharmacological Treatments for Pain in Individuals with Spinal Cord Injuries

Active Drug

Number of Patients Tested

Outcome

Reference

Valproate

20

No effect

Drewes et al., 1994

Gabapentin

7

No effect

Tai et al., 2002

Lamotrigine

22

No effect

Finnerup et al., 2002

Amitriptyline

84

No effect

Cardenas et al., 2002

Trazodone hydrochloride

18

No effect

Davidoff et al., 1987

Lidocaine

21

Better than placebo

Loubser and Donovan, 1991

Lidocaine

10

Better than placebo

Attal et al., 2000

Mexiletine

11

No effect

Chiou-Tan et al., 1999

Morphine

9

No effect

Attal et al., 2002

Morphine

15

No effect

Sidall et al., 2000

Clonidine

15

No effect

Sidall et al., 2000

Morphine and clonidine

15

Better than placebo

Sidall et al., 2000

Ketamine

9

Better than placebo

Eide et al., 1995

Alfentanil

9

Better than placebo

Eide et al., 1995

Propofol

8

Better than placebo

Canavero et al., 1995

Baclofen

7

Better than placebo

Herman et al., 1992

 

SOURCE: Adapted from Finnerup and Jensen, 2004.

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

takes place (Garraway et al., 2003). Primary sensory neurons (also known as primary afferents) in the spinal cord convey pain information from the primary sensory neuron to the brain. After a spinal cord injury, these neurons become hyperexcitable; namely, they fire more readily than before the injury. To explain hyperexcitability, a recent study with animals revealed that projection neurons possess more sodium channels of a particular type (Nav1.3) (Hains et al., 2003). Strategies to reduce the formation of this sodium channel may reduce hyperexcitability and pain. Furthermore, suppression of the activation of a key enzyme, known as MAP kinase, which aids the transmission of signals from the projection neuron’s membrane to its nucleus (Kawasaki et al., 2004), may prevent the onset of pain.

Relief of Spasticity

Spasticity refers to the debilitating muscle spasms and other types of increased muscle tone that occur after a spinal cord injury. Spasticity is similar to pain in that both are highly common after spinal cord injuries and have multiple possible mechanisms that might account for their onset (see Chapter 2). The key difference between them is that spasticity results from the heightened activity of reflex pathways (proprioceptive sensory neurons and motor neurons), whereas pain reflects the heightened activities of pain pathways.

Spasticity affects, to various degrees, the vast majority of people with spinal cord injury (Kaplan et al., 1991). Treatment begins with stretching and other rehabilitation techniques. If it remains uncontrolled, drug interventions are used, and if it is severe, the treatment is surgery and administration of the drug baclofen by implanted pumps (Kirshblum, 1999). Baclofen and tizanidine have inhibitory effects on motor neurons because their actions mimic that of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). No treatment for spasticity is uniformly successful or provides a complete cure, most likely because of spasticity’s multiple underlying causes, but it can be controlled in many individuals (Burchiel and Hsu, 2001). The drug fampridine, a potassium channel blocker, appears to alleviate some degree of spasticity and is being evaluated in clinical trials. One of the issues in the development of drugs used to control spasticity is that they may have the undesirable effect of inhibiting spontaneous activity that might be necessary for axon regrowth (McDonald and Becker, 2003) and may deprive patients of useful muscle contraction.

Thromboembolism

Thromboembolism is a potentially life-threatening condition frequently encountered in the early weeks after a spinal cord injury. Deep vein throm-

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

boses (DVTs) are blood clots that form deep within the veins, usually in the legs and thighs, and result from slowed or halted blood flow (venous stasis) in immobilized individuals with spinal cord injuries. The most feared complication of DVT is pulmonary embolism, which can bring sudden death. Pulmonary embolism occurs when a blood clot within a deep vein dislodges and travels to the pulmonary artery, where it obstructs the passage of oxygenated blood to the rest of the body. Widespread adoption of preventive regimens in the early 1990s decreased the incidence of DVT in individuals with spinal cord injuries in acute care or rehabilitation from 14 to 9.8 percent and the incidence of pulmonary embolism from nearly 4 to 2.6 percent (Chen et al., 1999).

Today, the incidences of both DVTs and pulmonary embolism have declined because of greater awareness of the conditions and several controlled clinical trials that found that combination strategies are effective in preventing DVT and pulmonary embolism. A panel rating the quality of evidence found several treatment modalities that warranted designation as a standard of care because they had been found to be effective in controlled clinical trials (AANS/CNS, 2002b). The standards for preventing DVT call for prophylactic treatment with low-molecular-weight heparins (an anticoagulant) or adjusted-dose heparin, the use of rotating beds, or a combination of these modalities. Low-dose heparin, in combination with compression stockings or electrical stimulation, is also recommended as a standard of care. High doses of heparin have been found to lead to higher incidence of bleeding. Several other preventive treatments were also listed as options for care (AANS/CNS, 2002c).

Bladder Dysfunction

Bladder dysfunction affects virtually all individuals with spinal cord injuries (see Chapter 2). Its treatment depends on the site and the type of injury, including the extent of sacral injury. Three types of bladder problems are common after a spinal cord injury. The first, flaccid bladder, results from injury to the sacral cord, which controls reflexive contraction of the bladder. The injury leaves the bladder’s detrusor muscle incapable of being contracted and thus causes urine to back up in the kidneys. The treatment is intermittent catheterization, in which a tube is inserted into the bladder to permit passive drainage at regularly scheduled intervals to prevent urine from overfilling the bladder. Bladder overfill causes damage to the bladder wall and heightens the risk of infection (Burns et al., 2001). In order to reduce the incidence of urinary tract infections, intermittent catheterization should be performed by the patient (Cardenas and Mayo, 1987).

The other two types of dysfunction are detrusor hyperreflexia and detrusor-sphincter dyssynergia. The goal of treating detrusor hyperreflexia

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

is to prevent incontinence. Treatment of detrusor-sphincter dyssynergia is aimed at ensuring adequate drainage, low-pressure storage, and low-pressure voiding. Both of these bladder conditions can be treated with anticholinergic or other types of medications that suppress contraction of the detrusor muscles. However, in many cases these medications do not suppress contractions. Bladder augmentation (augmentation cystoplasty) is often recommended for patients who have destrusor hyperreflexia or reduced compliance that fails to respond to anticholinergics (Sidi et al., 1990). New treatments have been introduced for these conditions, including pharmacological therapies to reduce the hyperactivity of the detrusor muscle (such as botulinum toxin or capsaicin) and functional electrical stimulation (see below). For example, a Food and Drug Administration (FDA)-approved device, known as the Vocare bladder system, uses surgically implanted electrodes to stimulate the sacral nerves controlling bladder function. The patient manually controls the stimulator using an external transmitting device. The benefits of these therapies have yet to be fully investigated (Burns et al., 2001). In another strategy, male patients may undergo sphincterotomy or stent placement to use the hyperreflexia to empty the bladder. The Consortium for Spinal Cord Medicine will soon be describing the strength of the evidence in a clinical practice guideline under development.

Neurogenic Bowel Treatment

Neurogenic bowel, the absence of voluntary control over stool elimination, affects the vast majority of individuals with spinal cord injuries. Some studies have found that as many as 95 percent of individuals with spinal cord injuries require at least one therapeutic procedure so that they can defecate (Glickman and Kamm, 1996). The majority of individuals with spinal cord injuries rate bowel dysfunction as a major life-limiting problem (Kirk et al., 1997). Before they leave the hospital, most patients are taught how to care for neurogenic bowel. Care is designed to regularize bowel movements and prevent constipation, incontinence, other gastrointestinal symptoms, and serious complications from impacted bowels (see the section on autonomic dysreflexia below). It consists of a program with several components that are individualized to patients with one of two types of neurogenic bowel: reflexic bowel and areflexic bowel. Both types require dietary fiber and fluid intake, oral medications, and rectal suppositories. Treatments help to stimulate the transport of stool through the bowels and hold moisture within the stool. Key differences in treating reflexive bowel versus areflexic bowel include the type of rectal stimulant, the consistency of the stool, and the frequency of bowel care. Clinical practice guidelines for the management of neurogenic bowel were developed in 1998 (Spinal Cord Medicine Consortium, 1998).

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

Autonomic Dysreflexia

Autonomic dysreflexia is a potentially lethal complication of a spinal cord injury that affects people with injuries at or above the thoracic level (usually T6 or above). The condition is manifest by severe headache (caused by an abrupt elevation of blood pressure), hypertension, profuse sweating, and activation of other autonomic reflexes. Symptoms come from overactivity of the autonomic (involuntary) nervous system cells in the spinal cord because of the blocked nerve impulses from the brain that normally keep these cells under restraint. The most frequent triggers of autonomic dysreflexia are an impacted bowel or an overfull bladder. The overactive sympathetic nerve and its branches cause a narrowing of the blood vessels, which, in turn, dramatically elevates blood pressure. Death from seizures, stroke, and abnormal heart beat rhythm can ensue if autonomic dysreflexia is not urgently treated.

Because autonomic dysreflexia is most often set off by bladder distention or bowel impaction, many individuals with spinal cord injuries have learned means of self-care to avoid emergency treatment by sitting upright to check urinary drainage or empty their bowel. An array of nonpharmacological and pharmacological agents are also available for emergency medical treatment (PVA, 2001).

Pressure Ulcers

Pressure ulcers are a highly frequent and serious complication of a spinal cord injury that affect physical, psychological, and social functioning. Ulcers are lesions caused by unrelieved pressure (if the force is perpendicular) or shear (if the force is tangential) to the tissue surface. The constant pressure can also interfere with the pressure in the capillaries and can therefore affect the exchange and elimination of nutrients and metabolites. Prolonged circulatory interference ultimately leads to cell death. In severe cases, individuals can develop a severe internal infection (septic shock), which can lead to organ failure. Stage I lesions are marked by discoloration and changes in tissue consistency on the skin surface, whereas the most serious lesions, stage IV lesions, are marked by extensive tissue necrosis and damage to muscle, bone, or supporting structures. About 32 percent of individuals with spinal cord injuries admitted to specialized care centers have been reported to develop pressure ulcers during the acute care stage, and at 2 years of follow-up the prevalence of pressure ulcers was 8.9 percent (Yarkony and Heinemann, 1995). The Consortium for Spinal Cord Medicine’s clinical practice guideline advocates a range of prevention strategies, including the avoidance of prolonged positional immobilization, use of support devices on beds and wheelchairs, and dietary changes. Treat-

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

ments include a range of cleansing strategies, debridement, and surgery for deep stage III or stage IV ulcers. The use of electrical stimulation to enhance healing of stage III or stage IV pressure ulcers is also recommended, on the basis of data from three randomized controlled clinical trials (PVA, 2000).

Treatment of Sexual Dysfunction and Fertility

Male Sexual Dysfunction and Fertility

Treatment research has largely focused on erectile dysfunction rather than the other two components of male sexual function, ejaculation and orgasm. The greatest strides have been with oral medications for erectile dysfunction. Although most men with spinal cord injuries have erections, their quality is often not sufficient to sustain intercourse. Sildenafil (Viagra), which has been available since 1998, has been shown to have a high degree of efficacy, with up to 94 percent of men with spinal cord injuries in one study reporting improved erections and intercourse (Derry et al., 2002). Other new drugs with pharmacological and side effect profiles somewhat different from those of sildenafil have also become available (Anderson et al., 2004). Oral medications are now considered the first line of therapy and have largely supplanted less safe, more cumbersome, and costly treatments, such as penile prostheses (Benevento and Sipski, 2002). Local erectogenic neurotransmitters administered by injection, topical, or urethal forms are in development (Elliot, 2002).

Fertility problems, which are common in men with spinal cord injuries, result from poor sperm quality or ejaculatory dysfunction. Much progress has been made in enhancing male fertility through the development of penile vibratory stimulation, which has become routine for men with spinal cord injuries who wish to have children (Benevento and Sipski, 2002). Vibratory stimulation is considered preferable to another treatment, electroejaculation, because it is less invasive and may be performed at home or in a clinic setting. Studies have shown that nearly all men given one of these two treatments successfully ejaculate, after which approximately one-third of the couples achieved pregnancies (Sonksen et al., 1997). However, this success rate is still largely dependent on overcoming the low sperm quality in men with spinal cord injuries, which often requires very invasive forms of assisted reproduction, ranging from artificial insemination to in vitro fertilization and intracytoplasmic sperm injection.

Female Sexual Dysfunction and Fertility

Sexual dysfunction in women with spinal cord injuries received scant attention until the 1990s. The problems include insufficient vaginal secre-

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

tions and failure to reach orgasm (especially in women with sacral injuries) (Benevento and Sipski, 2002). Women with spinal cord injuries benefit from sildenafil, which promotes increased subjective arousal (Sipski et al., 2000). In the trial, the drug worked most effectively when it was combined with manual or visual stimulation, and there were few adverse effects.

Fertility is generally preserved in women with spinal cord injuries (Charlifue et al., 1992), primarily because it does not rely on spinal circuits. Rather, fertility is controlled by the hypothalamic release of hormones that stimulate the ovaries. Pregnant women with spinal cord injuries tend to have babies with lower birth weights and tend to have more complications during pregnancy and delivery, including bladder and bowel problems, autonomic hyperreflexia, decubitus ulcers, urinary tract infections, edema, anemia, spotting, fatigue, cardiac irregularity, and preeclampsia (Charlifue et al., 1992; Jackson and Wadley, 1999).

Treatment of Bone Disorders

The reduced mobility and other pathological changes that occur in individuals with spinal cord injuries often lead to decreases in bone density (hence, a greater risk of bone fractures) and heterotopic ossification. The latter refers to the formation of bone in soft tissues near paralyzed joints. Bone density loss, particularly in the lower limbs, occurs during the first 6 months after the injury and then plateaus over the next 12 to 16 months (Demirel et al., 1998). The drug alendronate (Fosamax) has recently been found in a 2-year clinical trial to stop bone density loss at all bone sites at which measurements were taken (Zehnder et al., 2004). The drug, a bisphosphonate, works by inhibiting bone resorption by osteoclasts.

Heterotopic ossification can range from an incidental finding on an X-ray to massive bone formation surrounding a joint, producing total ankylosis. The most common location is the hips. Heterotopic ossification is treated with range-of-motion exercises, the drug etidronate, nonsteroidal anti-inflammatory drugs (NSAIDs), and irradiation. The use of NSAIDs, especially within the first 2 months of an injury, has been found to reduce the incidence of heterotopic ossification by a factor of 2 to 3 (Banovac et al., 2004). Severe cases are treated surgically, and the chance of recurrence may be reduced by the use of the nonsurgical therapies listed above.

Depression

Depression after a spinal cord injury is common and disabling. A key longitudinal study was conducted to track more than 100 individuals with spinal cord injuries for 2 years after discharge from the hospital (Kennedy and Rogers, 2000). It found that nearly 30 percent of the individuals were

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

depressed at the time of discharge; the rate of depression then dropped, before climbing over the next 6 months. Rates peaked at 60 percent by year’s end and then declined to 16 percent by the end of the second year. The treatment of depression in any group of individuals with a chronic physical illness, particularly those with spinal cord injuries, is expected to reduce unnecessary suffering and disability and to motivate adherence to complex programs of self-care, rehabilitation, and treatment.

Effective treatments are available for depression (APA, 1994). In 1998, the Consortium for Spinal Cord Medicine published a clinical practice guideline detailing specific steps for assessment, diagnosis, and treatment of depression (PVA, 1998).

RETRAINING AND RELEARNING MOTOR TASKS

The plasticity of the nervous system, or the nervous system’s ability to adapt and reorganize itself, sometimes allows the body to partially recover some of the motor function lost as a result of a spinal cord injury. As described throughout this report, a great deal of the research and clinical effort has been focused on restoring lost motor function through pharmacological or surgical methods. However, physical training and rehabilitation techniques and neuroprostheses also provide individuals with additional tools that they can use to recover from a spinal cord injury.

Body Weight Support Training

It is important that patients do not overcompensate with motor function that has been spared, thus limiting the capacity of the nervous system to adapt (Barbeau, 2003). Therefore, body weight support techniques have been developed that assist in locomotion, while minimizing compensation. One therapy that is used to improve walking in individuals in both the acute and the chronic stages of their injuries is body weight-supported treadmill training. During this therapy, individuals are placed in a harness to unload between 0 and 50 percent of their weight and are then put on a treadmill to simulate walking (Wernig et al., 1995, 1998; Protas et al., 2001; Dobkin et al., 2003a). Therapists then systematically reduce the amount of weight support, while training patients to walk on the treadmill at faster speeds.

Although this technique is promising, it is still unclear how effective body weight support treadmill training is at improving function in individuals with incomplete chronic spinal cord injuries. It is believed that body weight-supported training enhances the relearning of motor skills in the presence of spared pathways and facilitates the remaining pathways to

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
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relearn to interpret the complex sensory information associated with walking (Wernig et al., 1995; Harkema et al., 1997; Hulsebosch, 2002; Dietz and Harkema, 2004; Edgerton et al., 2004). These therapies produce a wide range of biochemical and physiological changes in the nervous system and musculature. Long term improvement in electromyogram (EMG) activity in paralytic legs has been observed (Wirz et al., 2001), which has been correlated to functional reorganization of neuronal centers in both the brain (Dobkin, 2000) and residual pathways in the spinal cord (Dietz and Harkema, 2004). Levels of neurotransmitters also change their levels in response to body weight support training (Edgerton et al., 2001). However, it is not clear if the observed physiological changes correlate with improvements in muscle control and function. To confirm these preliminary findings, an ongoing prospective large scale randomized clinical trial (The Spinal Cord Injury Locomotor Trial) has been designed to evaluate body weight-supported treadmill training and to compare that therapy with conventional physical therapy (Dobkin et al., 2003a,b). This study consists of two groups of patients, an experimental group that received body weight support and gait training, and a control group that received conventional standing and mobility training. Results from this study have not yet been published in a peer review journal; however, preliminary findings suggest that the treatment group was not associated with any improvement in the outcome measures compared to the “standard of care” gait training provided to the control group (Dobkin et al., 2003b, 2004). Three additional clinical trials are under way (NIH, 2004). Preliminary results from one of these phase II studies suggest that aggressive treadmill training may facilitate functional improvements, but this trial has not been completed and these results have yet to be published in a peer-reviewed journal (Hulsebosch, 2002).

A major difficulty with body weight support treadmill training is the effort required by therapists to guide the movements of individuals’ legs (Hesse, 1999). Therefore, a number of approaches have been developed to assist, including robotic-assistive stepping devices such as the Lokomat (Hocoma AG, Volketswil Germany), in which the movements of an individual’s legs are controlled by a preprogrammed physiological gait pattern. Other rhythmic leg exercises can be achieved with modified exercise bicycles.

A related approach is to incorporate functional electrical stimulation (see below) in combination with body weight-supported walking in individuals with incomplete injuries (ASIA C) (Postans et al., 2004). One study has demonstrated improvements in interlimb coordination with the use of afferent electrical stimulation during treadmill training (Field-Fote, 2001). Individuals with spinal cord injuries will likely receive the greatest benefit

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
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by combining body weight-supported treadmill training with other approaches, such as robotic devices (Dobkin and Havton, 2004), drugs, and surgery.

Functional Electrical Stimulation

Functional electrical stimulation (FES) is the approach most commonly used to artificially improve muscle function. FES devices have two key components: a control unit and stimulating electrodes. The control unit translates commands from voluntary movements or sensors into signals that are sent to the stimulating electrodes, which are taped onto the skin or surgically positioned near the specific nerves that innervate muscle groups (Bhadra et al., 2001). The stimulating electrodes provide mild shocks to muscle groups, causing them to contract (Barbeau et al., 2002). These contractions help maintain muscle mass and can initiate muscle movements, such as controlling movements of the hands or legs (Peckham et al., 2002). Modulating the magnitude of the stimulus parameters affects the strength of the muscle contraction and coordinated functional movements can be generated by controlling the relative stimulation strengths of collections of muscles (Dobkin and Havton, 2004).

FES is used in multiple ways to improve function, including cardiovascular conditioning, improving gait control and speed, restoring hand control and breathing, and controlling bowel and bladder function. FDA has approved neuroprostheses for the restoration of hand function, bowel and bladder control, and breathing, and clinicians at many spinal cord injury centers are trained in their use. In addition, an FDA-approved walking system uses a nonimplanted FES and an FES cycle ergometric device that allow periodic exercise of paralyzed leg muscles.

As noted earlier in the chapter, electrical stimulation for bladder function control involves a neuroprosthesis sold in the United States as Vocare. It is an FDA-approved medical device that provides the user with the ability to void upon demand as a result of the stimulation provided by the implanted device. Electrodes are placed on the sacral roots either intradurally (which is the most popular location in Europe) or extradurally (which is the location used more frequently in the United States). Voiding of the bladder is controlled by an implanted radio receiver controlled by an external device that delivers energy and control to the implant. This system allows individuals with spinal cord injuries to manage difficult bladder problems and drain many urine management devices (catheters and condoms). It also reduces the incidence of bladder infections. The device has been implanted in more than 1,500 patients around the world, and 90 percent of those with the implant reportedly used it 4 to 6 days per week. Thus, the cost of the

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

device compared with that of conventional care is recovered in about 7 years (Creasey and Dahlberg, 2001).

FDA has approved a neuroprosthesis for hand control, called Freehand, which provides two grasping patterns to individuals with C5 or C6 tetraplegia. It consists of a stimulator-receiver implanted in the chest and eight electrodes implanted at the motor points of hand and forearm muscles. Shoulder movement is used to proportionally control the degree of hand opening and closing. Fifty-one individuals with C5 or C6 tetraplegia were enrolled in a multicenter clinical study of the safety, effectiveness, and clinical impact of the Freehand system (Peckham et al., 2001). The results showed that the neuroprosthesis increased the pinch force of every subject, and it enabled 98 percent of the participants to grasp and move more objects in a standardized grasp-release test. An advanced system is under clinical investigation. This advanced system provides greater upper limb function and incorporates implanted control methods, thereby eliminating the need for the external shoulder sensor.

Tendon transfer surgery is often used either alone or in conjunction with neural prostheses (Kirshblum, 2004) for upper-extremity locomotion. This surgical procedure involves transferring one or more tendons of muscles with retained voluntary function to restore lost movements. The procedure is reversible and generally restores function equivalent to that provided by one or two spinal roots. Enhanced function is provided through additional stimulation channels, which are used to activate the muscles of the hand for fine control, elbow extension, and hand rotation. This system has been implanted in seven subjects (Peckham et al., 2002). An advanced neuroprosthesis that uses an implantable controller for restoration of hand and upper-arm control has been demonstrated to improve finger control in a group of individuals and has improved their performance of activities of daily living (Hobby et al., 2001). Recently, one participant received implants in both arms to further improve function.

For respiratory control, electrical stimulation can be used to stimulate the phrenic nerve, which controls the contractions of the diaphragm muscles. This technique, known as phrenic nerve pacing, was introduced in the 1960s (Escher et al., 1966). Phrenic pacing systems have allowed users to decrease or even discontinue the use of mechanical respirators and enable more normal breathing. The technique has been applied to more than 1,000 patients worldwide and has become a clinically accepted intervention in selected individuals (DiMarco, 1999). An alternative to direct stimulation of the phrenic nerve has also been developed. It is less invasive, as electrodes are implanted laparoscopically into the diaphragm (DiMarco et al., 2002; Onders et al., 2004). To date, 10 individuals have received the implant, and 9 of these individuals have been able to comfortably tolerate

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

extended periods (hours) of respirator-free pacing. If the utility of the device is confirmed in additional individuals, diaphragm pacing with intramuscular electrodes placed by laparoscopic surgery may provide a less invasive and less costly alternative to conventional phrenic nerve pacing.

The objective of some lower-extremity FES systems is to enable individuals with paraplegia to stand and transfer themselves. The functional goals associated with standing include reaching for high objects, having face-to-face interactions with other people, and transferring between surfaces independently or with minimal assistance. At present there are no commercial or FDA-approved systems for FES-aided standing; however, one implantable system has reached the multicenter clinical trial stage of development (Davis et al., 2001).

The only FDA-approved FES system for ambulation available is a surface stimulation system (Parastep). Individuals with paraplegia wear a microprocessor-stimulator unit at the waist and use a walker with controls built into the handles. This system allows these individuals to stand and walk with a reciprocal gait for limited distances. Use of the system has additional medical benefits, such as providing increased blood flow to the lower extremities, a lower heart rate at subpeak work intensities, increased muscle mass, and reduced spasticity and also has psychological benefits (Klose et al., 1997; Graupe and Kohn, 1998).

FES devices can also be used to maintain an individual’s muscle fitness and potentially encourage the recovery of function. Decreased muscle mass is a secondary condition that, if left untreated, can diminish the potential for complete recovery. A common cause of muscle atrophy is the loss of motor neurons in the spinal cord that drive muscle contraction. Other, usually less severe but more widespread atrophy occurs over time because of the disuse of paralyzed but still innervated muscles. FES can help reverse disuse atrophy by stimulating muscle activity, but it relies on intact nerve-muscle connections and cannot easily be used to stimulate denervated muscles.

FES devices have received a mixed reception from both clinicians and individuals with spinal cord injuries. Originally, the controllers and stimulating electrodes were large and cumbersome and did not provide very fine control; however, technological advances are leading to reductions in the sizes of these devices and reductions in the numbers of surgical procedures required for implementation. In addition, the implanted electrodes have improved reliabilities and longevities. Some individuals with spinal cord injuries and their clinicians are dissuaded from using FES devices because of the surgical procedures required to implant the systems and, in the case of Vocare, the additional damage to the nervous system that results from the requirement to transect some of the sensory nerves that enter the spinal cord (Creasey et al., 2001). However, the potential benefit to an individual’s

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

quality of life and the decreased health care costs over the lifetime of the individual likely offset the large initial expense of FES devices (Creasey et al., 2000).

Considerable research and development have been invested in the development of computer-controlled FES devices (Taylor et al., 2002), and future advances are likely to be linked to advances in technologies and their appropriate application to individuals with spinal cord injuries. For example, numerous electrode interfaces that provide more selective activation of nerves will provide finer movements. Others use physiological principles to block neural firing and will be used to block pain and suppress spasticity. Additionally, smaller stimulators are being developed. These will provide individuals with devices that can be fully implanted.

There is also a considerable effort to develop brain-computer interfaces that can be used to convert thoughts into electrical signals that can control and stimulate muscles (Friehs et al., 2004). These interfaces are most likely to initially have impact on the most severely disabled individuals who have lost other communication channels, but retain the ability to control their cortical firing. Cortical control may be used for control of the environment and for communication by such individuals, and may also be used as an interface for robotic manipulators and FES systems. Current approaches include, from least invasive to most, extracting control information from the electroencephalogram (Keirn and Aunon, 1990; Wolpaw and McFarland, 2004), placing electrodes subcranially over the brain, or placing electrodes into the brain. Research on all approaches is ongoing both in animal models and in patients, and two-dimensional control of cursors on a monitor screen has been demonstrated. Additional technologies are being developed to assist individuals with spinal cord injuries that severely restrict their movements, including an eyeglass-type infrared-controlled computer interface (Chen et al., 1999) and a wireless environmental control system using Morse code (Yang et al., 2003).

The overall acceptance of implantable neuroprostheses in upper extremity functional restoration has been very good, with over 80 percent of patients achieving regular use of the devices (Peckham et al., 2001). In addition, more than 95 percent of those who received implants reported satisfaction with the neuroprosthesis (Polacek et al., 1999). Neuroprothesis devices, such as the Freehand system, also have the potential to reduce the overall cost of care for spinal cord injured people (Creasey et al., 2000). Although it has been a difficult challenge, some insurance companies and the U.S. Department of Veterans Affairs reimburse individuals for associated costs. Ensuring that such benefits become available to individuals with spinal cord injuries in the future will require an effective delivery model, which requires collaboration between various clinical specialties (physical medicine and rehabilitation physicians, hand surgeons, and therapists) to

Suggested Citation:"4 Current Therapeutic Interventions." Institute of Medicine. 2005. Spinal Cord Injury: Progress, Promise, and Priorities. Washington, DC: The National Academies Press. doi: 10.17226/11253.
×

identify individuals who would benefit from neuroprotheses, as well as greater knowledge within the spinal cord injury community of the availability and benefits of neuroprotheses. However, the development of FES products, like pharmaceuticals, presents a financial challenge to companies, and this challenge may constrain the future development of such systems (Cavuoto, 2002; Dobkin and Havton, 2004).

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An estimated 11,000 spinal cord injuries occur each year in the United States and more than 200,000 Americans suffer from maladies associated with spinal cord injury. This includes paralysis, bowel and bladder dysfunction, sexual dysfunction, respiratory impairment, temperature regulation problems, and chronic pain. During the last two decades, longstanding beliefs about the inability of the adult central nervous system to heal itself have been eroded by the flood of new information from research in the neurosciences and related fields. However, there are still no cures and the challenge of restoring function in the wake of spinal cord injuries remains extremely complex.

Spinal Cord Injury examines the future directions for research with the goal to accelerate the development of cures for spinal cord injuries. While many of the recommendations are framed within the context of the specific needs articulated by the New York Spinal Cord Injury Research Board, the Institute of Medicine’s panel of experts looked very broadly at research priorities relating to future directions for the field in general and make recommendations to strengthen and coordinate the existing infrastructure. Funders at federal and state agencies, academic organizations, pharmaceutical and device companies, and non-profit organizations will all find this book to be an essential resource as they examine their opportunities.

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