Archives of Physical Medicine and Rehabilitation
Volume 88, Issue 3, Supplement 1 , Pages S76-S83, March 2007

Spinal Cord Injury Medicine. 5. Long-Term Medical Issues and Health Maintenance

  • Anthony E. Chiodo, MD

      Affiliations

    • Department of Physical Medicine and Rehabilitation, University of Michigan Hospital, Ann Arbor, MI
    • Corresponding Author InformationCorrespondence to Anthony E. Chiodo, MD, Dept of PM&R, Univ of Michigan Hospital, 325 E Eisenhower, Ann Arbor, MI
    • ,
  • William M. Scelza, MD

      Affiliations

    • Department of Physical Medicine and Rehabilitation, Carolinas Rehabilitation, Charlotte, NC
    • ,
  • Steven C. Kirshblum, MD

      Affiliations

    • Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry–New Jersey Medical School, Newark, NJ
    • Spinal Cord Injury Services, Kessler Institute for Rehabilitation, West Orange, NJ
    • ,
  • Lisa-Ann Wuermser, MD

      Affiliations

    • Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN
    • ,
  • Chester H. Ho, MD

      Affiliations

    • and Louis Stokes Cleveland Department of Veterans Affairs Medical Center and Department of Physical Medicine and Rehabilitation, Case Western Reserve University, Cleveland, OH.
    • ,
  • Michael M. Priebe, MD

      Affiliations

    • Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN

Article Outline

Abstract 

Chiodo AE, Scelza WM, Kirshblum SC, Wuermser LA, Ho CH, Priebe MM. Spinal cord injury medicine. 5. Long-term medical issues and health maintenance.

This self-directed learning module highlights long-term care issues in patients with spinal cord injury (SCI). It is part of the study guide on SCI in the Self-Directed Physiatric Education Program for practitioners and trainees in physical medicine and rehabilitation. The most common secondary medical complications include pressure ulcers, pneumonia, and genitourinary issues. Health care maintenance is important to prevent medical complications, for general health as well as for issues specific to SCI. Women with SCI have gender-specific issues regarding amenorrhea, sexuality, fertility, and menopause. Options exist to assist disabled men with sexuality and fertility complications. Pain is a common complication after SCI. Many new areas of research in the field of SCI are discussed.

Overall Article Objective

To discuss long-term care issues in patients with spinal cord injury, including health maintenance, secondary conditions, women’s health, sexual function, pain, and spinal cord regeneration and recovery.

Key Words: Pain, Rehabilitation, Sexual disorders, Spinal cord injuries, Women’s health

 

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5.1 Educational Activity: To formulate a list of secondary medical conditions that commonly occur in a 20-year-old man with a C4 American Spinal Injury Association grade A spinal cord injury who is 1 year postinjury 

SECONDARY MEDICAL COMPLICATIONS are extremely common in patients with chronic spinal cord injury (SCI). The Model Spinal Cord Injury Systems data indicate that the incidence of secondary conditions changes based on the number of years that a person has had an SCI. Pressure ulcers are the most common secondary condition, with the incidence increasing with time postinjury.1 Pneumonia rates are highest in tetraplegia and in older patients.1 Rehospitalization rates have remained static over the last 10 years.2 The most common reasons for rehospitalization include genitourinary complications, pressure ulcers, and respiratory complications. Urinary complications and pressure ulcers are more frequently reported in people with complete injuries. Pneumonia is more common in people with tetraplegia, whereas pressure ulcers are more common in people with paraplegia. Patients from skilled nursing facilities, those with lower motor scores on the FIM instrument, or who are using state or federal health insurance plans have a higher rehospitalization rate.2

Pressure ulcers are common but tend to cluster in a select population of patients. In 1 study 75% of participants failed to report recurrent pressure ulcers (never had any or had them only immediately after SCI onset), whereas 13% reported a clear pattern of recurring pressure ulcers of 1 or more per year. Only pressure ulcer history, cigarette use, and use of sleep medication predicted future recurrent pressure ulcers.3 Treatment options outlined in the Consortium Guidelines4 are presented in abbreviated form in appendix 1.

Urologic issues are detailed in the Consortium Guidelines, and bladder management strategies are abbreviated in appendix 2.5 The use of prophylactic antibiotics to prevent urinary tract infections (UTIs) after SCI continues to be unsupported by prospective studies.6 Intradetrussor botulinum toxin type A is effective in treating spastic bladder in SCI.7 Intravesical resinofiritoxin is also effective but is not currently approved by the U.S. Food and Drug Administration (FDA).8 Major risk factors for the development of urolithiasis among patients with SCI include recurrent UTIs, indwelling catheters, vesicoureteral reflux, prior kidney stones, and immobilization hypercalciuria.9 Shock wave lithotripsy success is 50% to 90%, and percutaneous nephrolithostomy is as successful as in the able-bodied population.10 Chronic indwelling catheters, smoking, and kidney stones are risks factors for bladder cancer. Gross hematuria should be aggressively evaluated as the most common sign of bladder cancer. False-negative rates for cystoscopy approach 20%. Fifty percent survival is seen at 17 months from the time of diagnosis.10 Although renal failure rates have declined dramatically over the last 50 years, the best test to monitor renal function has not been experimentally determined.

Diseases of the respiratory system are the leading cause of death after SCI. Of deaths from respiratory diseases, 72.3% are specifically due to pneumonia.2 Pneumonia is the leading cause of death for each age group and all time periods postinjury and is highest in tetraplegia. Mortality rates because of respiratory diseases have been increasing in people with SCI. Pulmonary management issues are detailed in the Consortium Guidelines.11 Sleep disordered breathing is seen in as many as 60% of people with tetraplegia within 4 weeks of injury.12 Sleep apnea in patients with SCI is as responsive to continuous or bilevel positive airway pressure treatment as the general population.13

Musculoskeletal issues including loss of bone mineral density (BMD), fractures, and overuse injuries are other important secondary conditions. In a study of men with SCI, 61% met the World Health Organization criteria for osteoporosis, 19.5% were osteopenic, and 19.5% had normal BMD.14 Fracture after SCI occurred in 34%. Considered simultaneously with age, duration of SCI, and level of SCI, BMD was the only significant predictor of the number of fractures.14 Ten milligrams of alendronate daily has been shown to have some limited positive effect on osteoporosis in chronic SCI patients measured by dual-energy x-ray absorptiometry,15 but there is no strong evidence for routine use in this population to decrease risk of fracture. Functional electric stimulation cycling applied shortly after SCI does not significantly attenuate bone loss.16

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5.2 Educational Activity: To detail the recommendations for health maintenance after SCI for this 20-year-old man with SCI 

People with SCI require regular and comprehensive health care throughout their lifetimes. This care includes routine health monitoring and treatment for non-SCI problems as well as for SCI-specific problems. The altered physiology and the absence of many typical symptoms for common problems after SCI pose a unique problem for health care providers.

The Canadian Task Force on Preventive Health Care and the U.S. Preventive Services Task Force for Periodic Health Examinations have provided guidelines for routine screening and preventive health care.17 These guidelines are, for the most part, appropriate to use as a starting point for people with SCI. Every periodic health examination should include the following components: current concerns and medications, review of systems (ROS), social history, medical history, family history, physical examination, counseling, and a plan for age-appropriate screening, immunizations, and treatment for problems identified. Areas of focus should also include the unique issues of SCI and aging with a disability.

Some of the important aspects to record include screening for gingivitis, decreased vision, hearing, flexibility, and cognitive slowing, as well as a screen for depression and suicide risk. Questions of smoking and counseling for smoking cessation, alcohol and drug use, exercise, risks for sexually transmitted diseases, and current employment status also should be included.

An expanded ROS is needed to address the specific problems common in SCI. Questions about bladder and bowel control, blood pressure control, skin integrity, pain, spasticity, sexual function, equipment needs, and changes in strength, sensation, and functional ability are important SCI-specific problems to address. In 1 study,18 subjects with SCI reported that 1 of the most important components of the comprehensive annual physical examination was the ability to talk to their physician about problems, especially muscle strength and weakness, bladder issues, pain, bowel and digestion problems, and equipment needs.

In addition to a general physical examination, a skin examination for abnormal moles and an examination of the oral cavity in smokers, ex-smokers, and alcoholics are recommended. A digital rectal examination for men over age 50 years, clinical breast examination for women aged 50 to 69 years, pelvic examination with Papanicolaou smear, gonorrhea and chlamydia swab if at high risk, and examination for ovarian masses are gender-specific, evidence-based recommendations. The general physical examination for people with SCI should be expanded to include an SCI-specific neurologic examination to document changes in motor or sensory function, a skin examination to assess for risk and/or presence of pressure ulcers, and a musculoskeletal examination to identify problems related to aging with SCI and pain.

Counseling for smoking cessation, advice for daily personal and annual professional dental care, sun exposure, and safety issues including use of safety belts, drinking and driving, bicycle helmet use, and hearing protection if exposed to loud machinery is recommended. Counseling is recommended for lifestyle issues including diet and nutrition, physical activity, and advice against alcohol abuse and prevention of sexually transmitted diseases if earlier screening identifies a problem. Counseling regarding wheelchair and other equipment maintenance and safety, pressure ulcer prevention, and compliance with the person’s bladder management program are issues that should be included for people with SCI.

Recommendations for the general periodic health examinations include screening for colon cancer with either fecal occult blood testing or flexible sigmoidoscopy for those over age 50 years and colonoscopy if at high risk. Mammography is recommended for women every 1 to 2 years between ages 50 and 69 years. A tuberculosis skin test, human immunodeficiency virus testing if at high risk, fasting glucose every 3 years for those over age 40 years or annually for people with risk factors for type 2 diabetes, screening for nutritional deficiencies with complete blood count, B12, albumin and iron levels if at risk, fasting lipid profile for men over 40 years and for women over 50 years, and prostate-specific antigen testing in men between ages 50 and 70 years or after age 45 years if at increased risk are also recommended. These screening interventions appear to be appropriate for people with SCI who will fall into high-risk categories for many of the diseases being screened, including diabetes, lipid abnormalities, and osteoporosis. However, few studies have formally evaluated these recommendations in the SCI population. Routine laboratory screening in a population of people with chronic SCI resulted in low diagnostic and therapeutic yield (<1.5%) except for serum glucose and lipid tests.19 In 1 study20 of 100 non-SCI outpatients, ROS and physical examination had a higher therapeutic yield than chest radiography, electrocardiography, and routine laboratory tests, except for the lipid profile. Further research is needed to define which screening tests are appropriate for the SCI population.

Because people with SCI are at significant risk for renal complications, regular screening of the urinary tract is important. Eighty-five percent of urologists in the United States surveyed recommended annual renal ultrasound, and 20% recommended renal scintigraphy as the preferred screening examination for the upper urinary tract. For surveillance of the lower urinary tract (LUT), 65% used annual video-urodynamics and 25% recommended cystoscopy, whereas 35% performed no routine surveillance and only examined the LUT when patients had recurrent UTIs or abnormalities were found on renal ultrasound or scintigraphy.21 However, routine screening with renal ultrasound was found to be cost effective only if used in SCI patients with genitourinary symptoms or signs.22, 23 The addition of abdominal radiography did not increase the sensitivity or specificity of renal ultrasound for identifying renal stones in people with SCI.24 Creatinine clearance is unreliable as a monitor for renal function because of its poor repeatability, primarily because of the difficulty of obtaining correctly collected 24-hour urine specimens.25

Rubella vaccination is recommended for women with no history of previous immunization who become pregnant. Immunization for pneumonia and influenza are especially important for people with SCI who are considered to be a high-risk population.26

Communication among medical providers for a person with SCI is critical to prevent duplication of some services while overlooking others. In 1 study,27 93% of people with SCI had a family doctor, 63% were followed up by an SCI specialist, and 56% were followed up by both. There was significant duplication in general medical and preventive services, although lifestyle and emotional issues were not addressed in more than 75% of the sample.

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5.3 Educational Activity: To address the health issues for a tetraplegic 30-year-old woman with traumatic SCI 

With the exception of a relatively brief period of amenorrhea in the acute and subacute periods after injury, the hypothalamic–pituitary axis returns to normal. Management of menstruation is a common concern after SCI, because erratic onset is particularly problematic with an insensate perineum. Although women report lower rates of menstrual cramping after SCI, nearly 25% report increased spasticity, bladder spasm, and dysautonomia during menstruation.28 Advances in hormone-based contraceptives, particularly those producing quarterly menstrual periods rather than monthly, may prove helpful.

There are no data to suggest a decline in fertility among women after SCI. Issues of contraceptive choice, however, remain clouded by insufficient data regarding additional risks in the presence of SCI. Although the risk of oral contraceptive–associated thromboembolism increases with age and smoking in nondisabled people, few data exist to determine if chronic paralysis increases risk as well. Concerns that an insensate uterus would result in failure to detect problems with an intrauterine device in the early stages have led to little use of this device in SCI. Compared with their nondisabled peers, women with disabilities are more likely to use surgical methods, including hysterectomy, or a natural method, and are less likely to use hormonal or barrier methods.29

Pregnancy in women with SCI is generally categorized as high risk, primarily from a high rate of complications specific to SCI, including UTI, autonomic dysreflexia (AD), and functional deficits.30 The SCI physician should work in collaboration with the obstetrician to manage these issues. Women with SCI may be more likely to have low–birth-weight infants but are no more likely to have a preterm infant or an infant with congenital abnormality.28 They are more likely to have a forceps delivery or Cesarean section, but no more likely to experience a miscarriage or stillbirth. Surprisingly, despite recommendations that labor and delivery in women with SCI, specifically those prone to AD, be managed with epidural/spinal anesthesia,30 50% of labors among women with SCI were managed without any anesthetic.28

Women with SCI experience menopause at similar ages and with most symptoms similar to women without SCI. As with menstruation, women with SCI report increased spasticity, bladder spasm, and dysautonomia during menopause. However, women with SCI also report a higher rate of psychologic symptoms and sleep disturbances compared with women without SCI.

Physiologic parameters of sexual function in women with SCI have been described in recent years. Libido is generally preserved after injury.31 Genital vasocongestion creates the lubrication and engorgement necessary for intercourse. Preservation of psychogenic genital vasocongestion is associated with the preservation of sensation in the T11-L2 dermatomes.32 Reflexogenic vasocongestion can be induced via manual genital stimulation in women with upper motoneuron injuries. Approximately 50% of all women with SCI are able to achieve orgasm, although time to orgasm is prolonged compared with women without SCI.33 Functional magnetic resonance imaging studies suggest that the vagus nerve, which bypasses the spinal cord, carries genital sensory afferents to the brain, mediating the orgasm response.34 However, lower motor neuron injury affecting the S2-5 levels greatly reduces the ability to achieve orgasm. Sildenafil has been shown to improve subjective arousal when used with manual stimulation and may improve genital vasocongestion as well.33

There are no data to suggest that women with SCI have different rates of disease affected by estrogen, such as breast or uterine cancer. Although rates of screening for these cancers has consistently been shown to be lower among women with disabilities than among nondisabled women,35 more recent data show less disparity based on disability alone, with differences accounted for by race and socioeconomic status.36 Heart disease is now the leading cause of death among women with SCI who have survived the first year of injury, as it is with men and women without SCI.

Premenopausal women with SCI do not appear to have any greater risk of osteoporosis than men with SCI. It is unclear to what degree women with chronic SCI experience subsequent menopause-related bone loss. One cross-sectional study37 has suggested that postmenopausal women with SCI have lower bone mass below the level of injury than premenopausal women with SCI, but there are no longitudinal data to confirm these findings. Whether women with osteoporosis who sustain an SCI have further bone loss from immobilization is also unclear. Little evidence exists to guide treatment of SCI-related bone loss, regardless of sex or menopausal status, and studies on the use of bisphosphonates in both acute and chronic SCI are conflicting.15 Although these studies include women, the numbers have been too small to draw conclusions in this subpopulation.

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5.4 Clinical Activity: To counsel a 20-year-old man with C4 American Spinal Injury Association grade A SCI on options regarding sexual function and fertility 

As a person assimilates into the community after an injury, issues relating to his/her sexuality and fertility are crucial components to a healthy transformation. For men, SCI significantly impacts erectile and ejaculatory dysfunction. It is reported that although 92% of men with SCI are able to achieve an erection, only 44% with complete injuries and 56% with incomplete injuries are successful with intercourse and less than 5% of men can have an unassisted ejaculation.38

Treatment options for erectile dysfunction (ED) include devices, implants, intracavernosal injections, and pharmacologic agents. Vacuum suction draws blood into the erectile tissue and a constrictor ring is placed at the base of the penis. This device can be used only for less than 30 minutes, and the potential for skin breakdown limits its use. Penile implants can be in the form of a malleable metal rod or an inflatable implant activated by a pump implanted into the abdomen or scrotum. The potential for penile erosions caused by decreased or absent sensation and the high risk of infection make implantable devices unfavorable, especially with the advancements in pharmacologic options. Phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil) are now the most commonly used agents to treat ED. These agents enhance the nitrous oxide–mediated vasodilatation of the erectile tissue. Stimulation is required to activate the erectile response, and these agents are more efficacious in men who have reflexogenic erections. In reviewing randomized control trials, it is estimated that up to 94% of subjects with SCI reported their erections were improved with sidenafil.39 Side-effect profiles include hypotension, headache, facial flushing, and visual disturbances. Simultaneous use of nitrate-based medications or alpha receptor blockers should be avoided because of a potentiated hypotensive event. Side-effect profiles of the phosphodiesterase type 5 inhibitors can closely mimic symptoms of AD (ie, headache, facial flushing). Patients taking these medications should advise their clinicians and avoid the use of nitrates to treat AD, should pharmacologic means be necessary. Intracavernosal injections with alprostidil, a prostaglandin derivative, are an effective means to treat ED after SCI. Injections can cause priapism and are not routinely recommended to use more than 3 times a week to prevent penile fibrosis. An intraurethral form of the prostaglandin did not prove to be effective. ED treatments have little effect on one’s ability to have an ejaculation.

Newer technologies and advances in fertility care now make it increasingly possible for men with SCI to father children, with success rates as high as 40%.40 Barriers to fatherhood include anejaculation, poor semen quality, and the need for assistive reproductive technologies to achieve a pregnancy. Thus, interventions directed by urologists and reproductive endocrinologists must be used. Penile vibratory stimulation has long been known to produce ejaculation and is the first line of treatment if a person is unable to ejaculate on his own. The vibrator is held over the frenulum of the penis until ejaculation occurs. Recent research shows that parameters of 2.5mm amplitude and frequency of 100Hz are optimal.41 For injuries at T10 and above, intact bulbocavernosus reflex and a triple flexion response to plantar stimulation are good prognostic factors for success with this stimulation method. If unsuccessful, electroejaculation can be attempted. Rectal probes will directly stimulate deep pelvic nerves to stimulate ejaculation. For men with intact sensation, and those with injuries at T6 and above susceptible to AD, this procedure must be performed in a monitored setting. Electroejaculation is generally more reliable, with success rates of 80% to 90%. As a last resort, direct testicular extraction of sperm can be performed.

Poor sperm quality is a routine finding in men with SCI. Sperm counts may be normal, but their quality and motility can be poor. The precise etiology of the abnormal semen characteristics is not known and likely multifactorial. Time since injury has not been shown to influence sperm quality. As a result, assistive reproductive technologies are generally required to achieve pregnancy. The simplest is intrauterine insemination, a direct injection of a sperm into the uterus. A home technique can also be performed with the semen being directly inserted into the vagina with a syringe. In-vitro fertilization (IVF) requires the use of fertility drugs and invasive procedures to obtain eggs that will be fertilized outside the womb and reimplanted into the uterus 48 to 72 hours later. Intracytoplasmic sperm injection (ICSI) requires only a few healthy motile sperm that are directly injected into an egg under microscopic guidance for fertilization and are then reimplanted as with IVF. Given the poor semen quality in men with SCI, ICSI has greatly improved the chances of a couple achieving pregnancy.42 The cost of these technologies is expensive.

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5.5 Clinical Activity: To assess a 20-year-old tetraplegic man who presents with diffuse pain 

Subjective pain in the SCI population varies from 64% to 80%. Forty-seven percent of SCI patients reported onset of chronic pain within the first year after their SCI.43 Chronic pain affects mood, function, and quality of life. Most patients are typically dissatisfied with current treatment efforts, and at least 19% in 1 study and 39% in another study reported experiencing severe pain.44 Pain severity is associated with completeness of injury, depression, and unemployment and is not associated with level of injury.45

Two common classifications for pain are currently used in SCI. The International Association for the Study of Pain (IASP) taxonomy has 3 tiers based on pain type. The Bryce and Ragnarsson Classification46 (table 1) is similar to the IASP but has a greater number of pain categories, which are based on location and etiology.

Table 1. The Bryce and Ragnarsson SCI Pain Classification System
LocationTypeEtiologic Subtype
Above level
Nociceptive1Mechanical/musculoskeletal
2AD headache
3Other
Neuropathic4Compressive neuropathy
5Other
At level
Nociceptive6Mechanical/musculoskeletal
7Visceral
Neuropathic8Central
9Radicular
10Compressive neuropathy
11Complex regional pain syndrome
Below level
Nociceptive12Mechanical/musculoskeletal
13Visceral
Neuropathic14General
15Other

NOTE. From Bryce and Ragnarsson.46 Reprinted with permission.

Nociceptive pain is caused by injury at a specific site, with the nerve activation occurring at the site of injury at local nerve endings. Visceral pain is not well defined but arises from damage to, or irritation or distention of, internal organs (ie, bowel, bladder) or supporting ligaments. It is reported in 15% of patients with chronic SCI, with 38% characterizing it as severe. In contrast, neuropathic pain is caused by injury of a nerve; that is, pain at the level of the injured spinal cord, at the nerve root, or at the site of a local nerve injury (eg, carpal tunnel syndrome). Sympathetic pain is a type of neuropathic pain caused by activation of the autonomic nervous system in response to a noxious stimulus.

Neuropathic pain is reported below the level of injury in 19% to 24% of patients with SCI, with 27% of them rating it as severe. At the level of injury, 11% to 36% of SCI patients had neuropathic pain, with 39% reporting the pain as severe.43 Neuropathic pain is more common in patients older than 40 years and in patients whose injuries are motor and sensory complete.47 Neuropathic pain is more commonly seen in patients injured by gunshot wounds. Studies point to neuropathic pain as being the most difficult to treat; this is especially true of neuropathic pain at or below the level of injury.48

Approximately 42% of SCI patients reported musculoskeletal pain, with 22% rating it as severe. Upper-extremity pain after SCI is most likely associated with repetitive overuse during transfers, pressure relief, and wheelchair mobility; 65% of the time, it interferes with a patient’s ability to transfer.49 The most common upper-extremity pain problems occur in the shoulders (75%), wrists (53%), hands (43%), and elbows (35%). Shoulder pain is associated with time since injury, limitations in shoulder range of motion, lower overall health, and lower function.50, 51 It is also associated with acromioclavicular joint narrowing, rotator cuff muscle imbalances, and adductor weakness in the general and elite athlete SCI populations. It is suspected that imbalances lead to glenohumeral motion abnormalities that trigger impingement, inflammation, and pain. Anterior muscular tightness with posterior muscular weakness is also a common association.

The diagnostic investigation of pain in SCI must be specific to the symptoms being evaluated. A thorough history, physical examination, radiologic studies, and electrodiagnostic evaluation may help delineate the exact diagnosis. Identifying the etiology of the pain is crucial to determining appropriate treatment.

Treatment of neuropathic pain in SCI can be complex and should have a multifaceted approach. This approach includes the use of modalities, medications, psychotherapy, and surgical interventions. The clinical use of anticonvulsants, antidepressants, antispasticity, and other adjunct medications is common, with some benefit shown in the SCI population. Although opioids were historically rated as an effective treatment, more recent studies show that they have little effect on neuropathic pain and are associated with decreased leisure activity and increased affective complaints.52 Surgical procedures include spinal cord stimulators, intrathecal medications, and the dorsal root entry zone procedure with intramedullary electric guidance.

Treatment of musculoskeletal shoulder pain includes shoulder stretching and strengthening, which specifically improves muscle balance, biomechanics, and endurance training. These activities are associated with a decrease in the severity and frequency of shoulder pain and improvement in function.53 Local injections and systemic medications such as nonsteroidal anti-inflammatories and opiates are used. Activity restriction is recommended but may be difficult because of functional needs. Many already limit their activities because of pain, which has a significant impact on functional skills and independence.

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5.6 Educational Activity: To discuss the current research on interventions for neurologic recovery in SCI for a 30-year-old tetraplegic woman after traumatic SCI 

Numerous changes occur within the spinal cord after initial injury that hinder return of function. Many of these changes have been elucidated in this last decade. According to recent findings, potential treatments fall into 1 or more of 5 categories54: (1) protection, to prevent death of neuronal cells undamaged by the initial injury; (2) stimulating axonal growth, to enhance the intrinsic regenerative capacity of spinal and supraspinal neurons or to block or remove endogenous inhibitors; (3) bridging, to provide a permissive substrate for elongating axons and replacing lost tissue; (4) enhancing axonal transmission, to alleviate conduction block in spared or regenerated axons; and (5) rehabilitation, to enhance functional plasticity in surviving tissue or to promote repair.

Many animal studies have focused on these experimental aspects of treatment. Appendix 3 lists some of the areas of research in each of the categories of treatment after SCI. The text below summarizes recently completed trials, current or ongoing trials, or trials planned for human clinical investigation in the near future.

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Experimental treatments 

Protection 

Methylprednisolone was previously discussed in Activity 2.1.55 Although the initial report of the second National Acute Spinal Cord Injury Study indicated no beneficial effects of naloxone, a subsequent report found that patients with incomplete lesions treated with naloxone within 8 hours had significantly greater recovery than patients treated with placebo.56 An initial small study treating patients with monosialoganglioside (Sygen) within 48 hours of injury for an average of 26 days found greater mean recovery at 1 year, including some improved recovery in muscles that had no strength at entry of the study.57 A subsequent large multicenter study reported a trend toward improvement in neurologic recovery in people with American Spinal Injury Association (ASIA) grade B at 26 weeks after being treated for 8 weeks, as well as a significant effect in people who received Sygen who did not have surgery. No significant effect was noted at the principle endpoint of 26 weeks in the total group of patients studied.58

Improving perfusion to the cord in the acute phase after injury includes the use of a lumbar drain to decrease intraspinal resistance to perfusion, elevation of mean arterial pressure, and calcium channel blockers. Calcium channel blockers decrease vasospasm and improve blood flow with improved axonal function; however, they also cause systemic hypotension that may compound the ischemic deficit. In animal models, minocycline, a semisynthetic tetracycline antibiotic, showed improved hindlimb function and strength59; human trials may begin soon.

The ProCord (Activated Macrophage) study60 was an international multicenter trial for people with an acute, neurologically complete SCI. Macrophages isolated from the patient’s blood were activated through a process proprietary to Proneuron and then injected directly into the patient’s injured spinal cord by day 14 after injury. In a phase 1 trial initiated in 2000, a greater number of a small group of those subjects improved from neurologically complete to incomplete status by 1 year.60 In the phase 2 trial, subjects with a neurologically complete SCI between C5 and T11 were randomized in a 2:1 ratio of treatment to control subjects. Control subjects did not receive the procedure, but all subjects received standard SCI rehabilitation and follow-up testing for 1 year. After two thirds of the subjects were recruited, the trial was halted because of financial constraints.

Stimulating Axonal Growth 

A phase 1 clinical trial61 was performed on 10 subjects with neurologically complete injury (AISA Impairment Scale [AIS] grade A) between the levels of C5 and T10, using oscillating field electric stimulation (OFS). The OFS device was implanted within 18 days of the injury and was removed at 15 weeks. At 1 year, the degree of pain as measured by the visual analog scale pain score was decreased, with improvement noted in light touch and pinprick sensation as well as some muscle strength improvement. The FDA has given permission to extend the study.

Cethrin (BA-210), a Rho pathway antagonist that may promote neuroregeneration and neuroprotection in the central nervous system, is currently in clinical trial.62 Cethrin is applied to the surface of the dura mater of the spinal cord together with Tissel, a fibrin sealant normally used to repair small dural tears, within 7 days of injury. The study is being performed in centers in the United States and Canada for people with a neurologically complete SCI.

Bridging 

Peripheral nerves have been implanted at the site of the injury with mixed results.63 Olfactory ensheathing glial (OEG) cell grafting in humans is being performed in a number of centers around the world. Preliminary results of a study64 investigating OEG in Australia were published, with no reports of neurologic improvement at 1 year in 3 subjects but without any noted adverse events. Lima reported on the first 7 patients who underwent autologous OEG transplantation at the site of the lesion. These patients with neurologically complete injuries had some sensory and motor function recovery.65, 66 Results of fetal stem cell implants in China were published (not a controlled study),67 with reports of almost immediate and dramatic improvement in some cases. Clinical follow-up was limited and the results have been questioned.68

Enhancing Axonal Transmission 

Preliminary work with 4-aminopyridine (Fampridine), a potassium (K+) channel blocker, in subjects with chronic incomplete SCI (phase 1 and 2 studies) showed trends toward improvement in pain and spasticity. Phase 3 multicenter trials were completed and did not show significant results, although there were improvements in multiple sclerosis (MS) trials and further study is currently underway in MS subjects.69

A phase 2 trial has been completed using HP-184, a K+ and sodium channel blocker, although data have not yet been published. The phase 1 trial in 48 subjects with chronic incomplete SCI resulted in increased motor index scores.70 The phase 2 trial has recruited 240 subjects with chronic incomplete SCI (AIS grades C and D), with injury levels C4-T10. Outcome measures include changes in motor index score and gait.

A number of the above-mentioned surgical procedures may enhance axonal regeneration as well as serve as a bridge for axonal recovery. Some of the animal work listed in Appendix 3 has shown promise, and human-based studies are being planned.

Rehabilitation 

New rehabilitation techniques and research are covered in Educational Activity 3.5.

Research to discover therapies for SCI has made steady progress, and a number of clinical trials are being proposed for subjects with SCI. Recommended guidelines have been proposed for the planning, initiation, and conduct of these trials.71 These guidelines include the following: the proposed clinical trial should be based on supportive preclinical animal efficacy data that would be considered predictive of lasting clinical benefits; there should be a high benefit-to-risk ratio, especially with invasive studies; outcome measures should be objective and should include safety, pain issues, and maintenance of function both above and below the lesion; and placebo control groups should be included when possible.

Great excitement exists in the field of SCI medicine over research that has moved from the laboratory to human clinical trials. Despite the excitement with respect to cure and the optimism regarding the development of therapies, at present no pharmacologic, surgical, or rehabilitative therapy exists that can cure all of the impairments caused by the injury. Most likely, a combination of the treatments discussed above will be required to address the complex issues of SCI. Further study is required, not only to find treatments to enhance neurologic and functional recovery but also to decrease medical complications and optimize the quality of life of people with SCI.

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APPENDIX 1. Wound care management issues in SCI 


1.Prevention considerations
a.Inspection

b.Pressure relief

c.Seating and positioning (including pressure mapping)

d.Cushion and support surface prescription

e.Psychologic and social factors


2.Correction of underlying factors
a.Nutrition

b.Incontinence

c.Spasms and contractures

d.Smoking

e.Heterotopic ossification

f.Wound infection

g.Bowel and bladder management


3.Débridement options
a.Autolytic

b.Enzymatic

c.Mechanical

d.Sharp

e.Surgical


4.Wound care
a.Moist dressings

b.Débridement

c.Infection control

d.Vacuum-assisted closure system

e.Growth factors

f.Impact of caregiver time


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APPENDIX 2. Bladder management in SCI 

Pharmacologic interventions

Anticholinergic medications

α-blockers

Botulinum toxin

Intermittent catheterization

Credé and Valsalva maneuvers

Indwelling catheterization

Reflex voiding

Urethral stents

Transurethral sphincterotomy

Electric stimulation and posterior sacral rhizotomy

Bladder augmentation

Continent urinary diversion

Cutaneous ileovesicostomy

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APPENDIX 3. Research categories in the treatment of SCI 

Protection against SCI

Previously studied methods

Methylprednisolone, naloxone, calcium channel blockers, GM-1

Present and future studies

Minocycline, erythropoetin, riluzole, sulfonylureas, hyperdynamic therapy, and cerebral spinal fluid drainage

Stimulating axonal growth

Electric stimulation (oscillating field stimulator), Nogo-blocking antibody, myelin associated glycoprotein, oligodendrocyte myelin glycoprotein, Rho inhibitors (eg, Cethrin), activated macrophages, chondroitin sulfate proteoglycans, inosine, heparan sulfate proteoglycans, keratan sulfate proteoglycans, nerve growth factors, estrogen, and serotonin selective reuptake inhibitors

Bridging

Peripheral nerve grafts, Schwann cells, olfactory ensheathing glial cells, and nanotubes

Enhancing axonal transmission

Schwann cells, olfactory ensheathing glial cells, 4-aminopyridine, HP-184, neuroprogenitor cell transplants (stem cells)

Rehabilitation

Electric stimulation, weight-supported ambulation

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 No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated.Reprints are not available from the author.

PII: S0003-9993(06)01570-X

doi:10.1016/j.apmr.2006.12.015

Archives of Physical Medicine and Rehabilitation
Volume 88, Issue 3, Supplement 1 , Pages S76-S83, March 2007

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