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Spinal Cord Injury Medicine and Rehabilitation Argyrios Stampas, MD1

Keith E. Tansey, MD, PhD2

1 Department of Physical Medicine and Rehabilitation, University of

Texas at Houston, TIRR Memorial Hermann, Houston, Texas 2 Departments of Neurology and Physiology, Emory University and SCI Clinic, Atlanta VA Medical Center, Atlanta, Georgia

Address for correspondence Keith E. Tansey, MD, PhD, Departments of Neurology and Physiology, Emory University and SCI Clinic, Atlanta VA Medical Center, 615 Michael St, Atlanta, GA 30322 (e-mail: [email protected]).

Abstract

Keywords

► spinal cord injury ► secondary complications ► neural plasticity ► functional recovery

The rehabilitation of spinal cord injury (SCI) is a complicated process, but one in which new research is developing novel and increasingly promising methods of restorative neurology. Spinal cord injury medicine addresses not only the neurologic injury, but all the secondary complications in other organ systems whose regulation is disrupted after SCI. To some degree, the rehabilitation of SCI is focused on return to the community and functional goals are paramount, regardless of whether they can be achieved through some mechanism of compensation or due to a growing effort at engendering neurologic plasticity and recovery. The authors present a typical case of cervical incomplete SCI and discuss the medical complications and considerations for care during acute rehabilitation. They also review current methods of planning and executing rehabilitation, along with emerging methods that are leading to, in varying degrees, greater neurologic recovery. Finally, new approaches in SCI rehabilitation, namely neuromodulation, are discussed as efforts are made to further augment neural plasticity and recovery in SCI.

Despite efforts to reduce spinal cord injury (SCI), the incidence of traumatic SCI has remained stable over the past several decades, with approximately 12,000 new cases per year being reported in the United States.1 The demographics have changed, with an increasing average age of injury and a slightly decreasing, but still predominant, percentage of males. There has also been an increasing percentage of incomplete tetraplegia and a decreasing percentage of motor and sensory complete injuries. Accidents continue to be the major cause of SCI, whether automotive, falls, sports, or workrelated. It is reported that approximately 270,000 persons in the United States live with traumatic SCI, and a more recent investigation indicated a prevalence of over 1 million living with any etiology of spinal cord dysfunction in the United States.2 In the face of these statistics, our understanding of spinal cord biology and the changes that occur after SCI continues to grow, and the ultimate goal of researchers and clinicians in the field is to achieve neurologic restoration after this catastrophic injury. We describe a statistically common traumatic case, a young male adult with a cervical SCI

Issue Theme Neurologic Rehabilitation; Guest Editors, Karunesh Ganguly, MD, PhD, and Gary M. Abrams, MD, FAAN

resulting in incomplete tetraplegia, and detail his hospital and rehabilitation course, with particular emphasis on physical exam findings, prognosis, and their use in guiding rehabilitation and functional recovery.

Clinical Case and Current Methods of Care A 25-year-old right-handed man with no significant past medical history sustained a traumatic neck injury from diving into shallow water under the influence of alcohol. Paramedics arriving at the scene stabilized his neck and noted no movements of his extremities. His breathing appeared labored and he was intubated. Upon arrival to the regional trauma center, intravenous (IV) methylprednisolone (MP) was started. Although once considered a standard in the acute treatment of SCI, review of the original studies and failure to show repeatable results by other large studies have resulted in a decrease of MP use worldwide.3–6 In the United States, the use of MP is based upon individual practitioner or trauma program preference. If MP has an effect, it may be to limit the

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1396006. ISSN 0271-8235.

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Semin Neurol 2014;34:524–533.

extent of secondary tissue damage. In isolated cervical spinal cord injuries, this might result in regaining function over a spinal level or two, something with significant consequences for functional recovery. However, MP would be of little functional benefit in thoracic injury, as the gain or loss of a few thoracic levels will not significantly change recovery of walking, bowel or bladder function, or even respiratory ability. Furthermore, there are situations in which MP could be considered contraindicated, such as with risk for infection (aspiration pneumonia in this case), extensive surgery (poor wound healing), old age, high trauma score, psychiatric disorder, and/or other medical conditions such as poorly regulated diabetes. Finally, steroids have been shown to be detrimental in traumatic brain injury (TBI) and it is becoming more evident that there is a significant co-occurrence of TBI and cervical SCI, ranging from 59% to 77%.7 The workup in the emergency room revealed a C7 burst fracture with retropulsion of bony fragments into the spinal canal. Magnetic resonance imaging (MRI) performed a few hours later showed cord edema from C6–T1 with a small amount of T2 hyperintensity spanning those levels. The lack of intramedullary hematoma (hypointensity on T2) in the cervical spinal cord supports better motor recovery, compared with its presence.8 The cervical spine was surgically decompressed and stabilized with hardware within 24 hours of injury, which has recently demonstrated better functional

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outcomes.9 There are also fewer morbidities and shorter days on ventilation, in the intensive care unit, and for overall hospital length of stay with early stabilization of spinal cord injuries.10 The surgery in this patient was uneventful, and he was extubated without difficulty, subsequently breathing room air. His neurologic exam was notable for some improvements, including trace upper extremity (UE) movement and intermittent lower extremity movements. The International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) exam was performed between 72 hours and 1 week (►Fig. 1), at which point prognosis for ambulation can be accurately predicted.11 In complete paraplegia, there is about a 5% recovery of ambulation, whereas in incomplete tetraplegia and incomplete paraplegia, that recovery is 47% and 76%, respectively.12 All with lower extremity motor scores of more than 20 (out of a possible 50) at 1 month recover some degree of walking ability (see also13). The patient’s ISNCSCI exam was most notable for sacral preservation, with voluntary anal contraction, sensation of light touch and pin prick in the S4–5 dermatome, and sensation of deep anal pressure (►Fig. 1). This exam finding is defined as an incomplete spinal cord injury, American Spinal Injury Association (ASIA) Impairment Scale (AIS) C, motor incomplete. Given his age (< 50 years old), and his exam of AIS C, he has an approximate 90% chance to ambulate at the

Fig. 1 Initial International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) score sheet at 72 hours.

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1-year mark.11 Statistics on life expectancy with SCI have been collected and are most influenced by age at injury, completeness of injury, and spinal cord level.2 In this case of an injury occurring in the second decade of life resulting in incomplete tetraplegia, the average remaining years are over 50, only slightly below life expectancy for those without SCI. As people with SCI have been nearing more normal life expectancy, the costs of living with SCI have also been evaluated and are an important consideration. The first year of injury (based on 2012 dollars), will cost a patient with low tetraplegia AIS C $739,874, and $109,077 each subsequent year for a lifetime cost of $3,319,533.2 Lacking serious medical complications, the patient was promptly transferred to an acute inpatient rehabilitation facility that specializes in spinal cord injury. Evaluation was performed by an interdisciplinary team of rehabilitation nurses; respiratory, physical, occupational, and speech therapists; neuropsychologists; social workers; as well as by neurorehabilitation physicians. Patient education was provided regarding respiratory care (quad coughing), autonomic function (blood pressure and heart rate changes and other symptoms that could be associated with autonomic dysreflexia), and skin care (to prevent pressure sores). Functional goals by the different disciplines are currently individualized based largely on the ISNCSCI exam (neurologic level and AIS classification), and grossly include mobility, activities of daily living (ADLs), and bowel and bladder management. The importance of the ISNCSCI exam to help guide reasonable expectations of functional outcomes cannot be overstated, as it helps plan a realistic and effective rehabilitation program. In 1999, an expert panel of SCI professionals developed tables of expected functional outcomes in motor complete SCI, based upon the ISNCSCI exam, the neurologic level of injury (NLI), and Functional Independence Measures (FIM) scores.14 Fifteen years later, despite increased knowledge regarding neural restoration in SCI, these tables have remained relatively unchanged. This should not be viewed as a failure of the promising neural restorative therapies that will be discussed later, but an inability to demonstrate the quality of neural restoration therapy in functional improvement, especially in more severe SCI. That is to say, functional recovery measures often do not discriminate between compensatory changes versus neurologic recovery. Efforts to develop outcome measures that describe neural recovery and their clinical meaningful benefits continue to progress as new therapies are developed.15 In fact, the Spinal Cord Injury Measure (SCIM), in its third version, has excellent correlation with FIM, and is 26% more sensitive to change than the FIM. It has excellent correlation with the Berg Balance Scale, the Walking Index for Spinal Cord Injury, and the 10 Meter Walk Test, and an inverse relationship with the Falls Efficacy Scale.16 That said, it is still very difficult to get from neurologic injury characterizations (imaging, electrophysiologic testing, neurologic exam) to behavioral testing (gait, UE, and balance assessments) to functional status (SCIM-III or FIM) to participation and quality of life in any one individual. The ISNCSCI exam repeated on the patient in the inpatient rehabilitation facility demonstrated further neurologic recovSeminars in Neurology

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ery (►Fig. 2), but these improvements over 9 days likely represent mostly spontaneous recovery rather than the consequences of extensive rehabilitation. There are expected outcomes for motor recovery based upon motor scores at the 1-month mark for both complete and incomplete injuries in both the upper and lower extremities.17–19 In this case of incomplete tetraplegia, functional strength (3/5) is expected to be achieved in 73% of muscles groups, with a score of at least a one-fifth on the Medical Research Council (MRC) Scale for testing muscle strength at 1 year. Roughly 25% of muscles scoring 0/5 on motor strength testing will recover functional strength at 1 year. The expected combination of upper motor neuron (UMN) and lower motor neuron (LMN) signs is found in the majority of incomplete cervical spinal cord injuries, especially around the NLI. In this case, UMN findings are primarily found in the bilateral lower extremities with brisk reflexes, crossed adductor reflexes, and present Babinski signs. In the upper extremities, there can be a mix of both UMN and LMN findings. In this patient, a Hoffman sign was found in the right hand, but there were also diminished brachioradialis and absent triceps reflexes, along with weakness, slight atrophy, and lack of spasticity elsewhere. The MRI helps confirm the clinical suspicion that the gray matter at these spinal levels was involved. Exiting nerve roots may also be damaged, but these are often difficult to visualize or even distinguish electrophysiologically. Lower motor neuron muscles will have increased fatigability, and different rehabilitation strategies are often employed to promote their recovery.20 Although seemingly uncomplicated in this case of a healthy 25-year-old, SCI increases the risk of acute care adverse events with associated morbidity, most commonly pneumonia, urinary tract infections, delirium, neuropathic pain, and pressure ulcers.21 Few other neurologic diseases or injuries acutely affect as many nonneurologic organ systems as does SCI. These include (systems): neuropathic pain, spasticity, mood disorders (neurologic and psychological), dysautonomia and deep vein thrombosis (DVT) risk (cardiovascular), compromised cough/stiff chest wall, atelectasis, and pneumonia (respiratory), decreased gut motility/constipation (gastrointestinal), spastic bladder, detrusor-sphincter dyssynergia, urinary tract infections (UTIs), and erectile dysfunction (ED) (genitourinary), pressure ulcers and bone loss and heterotopic ossification (HO) (integument and skeletal), to name a few of which the rehabilitation team must be mindful of during their rehabilitation course. It is not only the lack of sensation that masks the usual symptomatology, but risks are greater in this group due to their immobility, aspiration risk, urine retention, peripheral trauma, and to a central nervous system (CNS) injury-induced immunedeficiency syndrome.22 Suffice it to say, the traumatic SCI population requires close physician monitoring throughout their hospitalization, including inpatient rehabilitation. Estimates of DVT in this population reach nearly 100%, but are largely asymptomatic and often undetected by conventional Doppler ultrasound.23,24 In a large study of patients with acute SCI, there was a higher occurrence of DVTs in

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Fig. 2 Subsequent International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI ) score sheet 9 days later.

patients with paraplegia versus tetraplegia, motor complete injury versus incomplete, and males over females.25 Although the occurrence of DVTs were not age related, pulmonary embolism (PE) was associated with ages over 61 and not influenced by degree or level of injury. Inferior vena cava filters are often placed intraoperatively in many patients thought to be at increased risk of developing PE, but who are not candidates for anticoagulation with low-dose unfractionated heparin (LDH) or low-molecular-weight heparin (LMWH). Because the risk of developing a thrombus with a chronic vena cava filter is as high as 40%, removable filters have been shown to be both efficacious and safe in SCI.26 The duration of DVT prophylaxis in spinal cord injury remains controversial, but the Consortium for Spinal Cord Medicine developed clinical practice guidelines establishing duration of treatment, generally lasting the course of inpatient rehabilitation.27 In this case of incomplete tetraplegia without other risk factors (lower limb fracture, previous thrombosis, cancer, heart failure, obesity, age over 70), the duration of DVT prophylaxis is 8 weeks. Heterotopic ossification (HO) may share a similar clinical presentation with DVT with extremity swelling, erythema, warmth, and pain. When near a joint space, HO may limit functional range of motion. Medications for treatment of HO in the early phase, including during the acute rehabilitation admission, consist of nonsteroidal anti-inflammatory drugs

(NSAIDs), which require special consideration given anticoagulation and the possibility of exacerbating gastric stress ulceration and possible hemorrhage. The rehabilitation facility is an opportune site for this morbidity, as range of motion exercise is part of the treatment plan for HO. The prevalence of pain in SCI and its interference with activities of daily living is well established. In a Model System Study involving SCI during acute rehabilitation, nearly every participant had some element of pain.28 Pain in SCI can be broadly divided into categories above the level of injury, at the level of injury, and below the level of injury, and each then subdivided into nociceptive (musculoskeletal or other endorgan origin) and neuropathic pain (from the SCI and/or root injuries). Up to 15 different subtypes of pain that commonly occur in SCI have been identified.29,30 Treatment of pain should be done aggressively, not only to allow for the willing participation in rehabilitation therapy, but to prevent chronic pain31,32 and the likely association with depression.33 This patient has musculoskeletal pain at his neck radiating to the back of his head and neuropathic pain at and below the level of injury, with dysesthesias (manifesting as burning, tingling, hot/cold sensations or electric shocks) in a cape-like distribution radiating from his neck to the shoulders, down his arms into his fingertips, with associated allodynia (painful perception of nonnoxious stimuli) and hyperalgesia (amplified nociceptive perception). The cape-like pattern is Seminars in Neurology

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consistent with a central cord syndrome, in which gray matter injury impacts crossing fibers of the spinothalamic pathway. Neuropathic pain management in spinal cord injury relies on evidence from other neuropathic pain etiologies, including diabetes and trigeminal neuralgia. Similarly, first-line agents include tricyclic antidepressants such as amitriptyline, serotonin reuptake inhibitors (SSRIs) such as duloxetine, and anticonvulsants, such as gabapentin and pregabalin, or even carbamazepine. Pregabalin has an Food and Drug Administration- (FDA-) approved indication for the treatment of neuropathic pain in spinal cord injury. Nonsteroidal antiinflammatory drugs are also used because of their wellknown analgesic effects in the periphery, as well as similar effects in the CNS with subsequent central analgesia. Opioids are most often reserved for intractable pain in spinal cord injury. In the acute rehabilitation setting where time is of the essence, they are utilized for breakthrough pain periods while effective doses of first- and second-line medications are titrated. The use of opioids in SCI, especially for chronic pain, is controversial for multiple reasons. The well-known reasons that exist for other pain etiologies, such as dependence/abuse, constipation, sedation, and decreased efficacy over time, are also seen in the SCI population. Moreover, studies have shown that morphine, although initially providing analgesia, can result in worsening neuropathic pain as well as delayed motor recovery, both in the acute and chronic period.34 Spasticity (or the upper motor neuron syndrome) is another morbidity that may interfere with the rehabilitation of spinal cord injury.35 Spasticity includes hyperreflexia, hypertonia, flexor, extensor or adductor spasms, and cocontractions or dyssynergias during voluntary movements. Furthermore, the hypertonia can be present at rest and disappear during movement or the exact opposite. Hypertonia may be beneficial in assisting with transfers and improving bed mobility, but in excess may interfere with mobility and ADLs, as well as predisposing to chronic pain, fractures, dislocations, and skin ulceration. The treatment of spasticity must also maintain this fine balance, as excessive treatment may result in worsening function due to weakness, fatigue, and somnolence. The Modified Ashworth Scale is a commonly used test to assess spasticity in SCI. The Tardieu Scale is a newer test more commonly used by therapists, with measurements of the joint angle at which “catch” exists, as well as describing the resistance to passive movement at both slow and fast speeds. Specific to the SCI population is the Spinal Cord Assessment Tool for Spastic Reflexes (SCATS), a relatively new tool, which assesses three common spastic motor behaviors in the lower extremities: clonus, flexors spasms, and extensor spasms. The Penn Spasm Frequency Score (PSFS) is a subjective score patients can provide, ranking the frequency of their spasms. This patient has spasms in his trunk and legs, less than once per hour, scoring a 2 on the PSFS, and causing significant discomfort and interference with function. They occur when changing position, when his bladder is full, and during his bowel program. New or increasing spasticity is a sensitive symptom of noxious stimuli below the level of Seminars in Neurology

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injury, most commonly UTIs, constipation, skin breakdown, but can occur even with the new prescription of an SSRI. The decision to proceed with spasticity management is not a trivial one, as the desirable aspects of spasticity are also treated with the negative ones. There is no gold-standard treatment option, and the majority of the medications have significant side effects. Oral medication classes include gamma-aminobutyric acid (GABA) agonists like benzodiazepines and baclofen, α-2-adrenergic agonists, such as tizanidine and clonidine (blood pressure permitting), and occasionally, dopamine agonists. In many ways, the antispasticity mediations may counter the desirable effects of rehabilitation by causing CNS depression and further weakness. On the other hand, they may reduce nonspecific responses to sensory input or residual, altered supraspinal inputs to improve motion fluidity. There are also physical modalities that can improve spasticity, including passive range of motion, vibration, massage, application of heat or cold, acupuncture, weight-bearing, and both electrical and magnetic stimulation. In this case, because of the frequency of spasticity and its interference with his activities, baclofen was initiated and therapy was scheduled beginning with FES ergometry or vibration plate prior to the initiation of mobility and gait training. Autonomic dysfunction can cause further interruptions in the rehabilitation of SCI, with resulting morbidity and even mortality.36 Autonomic dysreflexia is a medical emergency in SCI with a NLI of T6 and above, most commonly in complete injuries. It is caused by noxious stimuli below the NLI, most often via visceral afferents (bladder, bowel) or cutaneous afferents (decubitus ulcers). The ensuing sympathetic overflow can result in a hypertensive emergency (often with reflex bradycardia), cardiac dysrhythmia, and/or stroke in addition to lesser symptoms of nasal stuffiness, sweating, and anxious feelings. The algorithm for management of this medical emergency aims at relieving the most common noxious stimuli with careful blood-pressure monitoring and management as needed. It is best to use short-acting antihypertensive medications such as nitroglycerin paste (which can be wiped off when the noxious stimulus is found to avoid overshoot hypotension). Some painful stimuli such as cystitis cannot be alleviated simply with the initiation of antibiotics, so also treating the pain will help with decreasing the autonomic effects. In this case of incomplete tetraplegia, autonomic dysreflexia is not a major concern, but other dysautonomic findings may be present, such as orthostatic hypotension or dysautonomia with visceral afferent activation (during bowel evacuation programs or with UTIs). Dysautonomic findings in this patient with incomplete tetraplegia include orthostatic hypotension and hypotension at rest, with systolic blood pressures (SBP) under 100 mm Hg. Conservative treatment measures include encouraging oral hydration, ace wrapping of the bilateral lower extremities, and/or use of an abdominal binder. Eating large meals is discouraged in favor of smaller, more frequent ones, and it may be helpful to have the patient sleep somewhat inclined in bed. Therapy interventions include slowly increasing the angle to upright on a tilt table and the use of electric stimulation of the legs prior to sitting or standing. Salt can

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be added to the diet to help with increasing blood pressure as part of a short-term solution. Orthostatic reflexes tend to recover, but if medications are required, midodrine is the only FDA-approved medication for orthostatic hypotension, and is rarely required for chronic use. Although SBP can remain hypotensive and BP measurements may continue to indicate orthostatic hypotension, symptoms of decreased brain perfusion often resolve. Somewhat beneficial findings of dysautonomia include sweating, flushing, and piloerection (goose bumps), which can function as substitute signals to urgently empty the bladder or bowel or the need for skin pressure relief. Bowel and bladder education and management, as well as pressure relief, are subjects in which nurses and therapists work together to help accomplish. The neurogenic bladder with detrusor-sphincter dyssynergia that occurs with an injury above the sacral micturition center is unique to spinal cord injury.37 A urodynamic study is needed in all patients with spinal cord injury to assess the intradetrusor pressures and the risk of vesicoureteral reflux. Anticholinergic medications commonly prescribed for overactive bladder can help reduce the upper motor neuron symptoms of neurogenic bladder, while α-1-adrenergic blockers can decrease bladder neck contraction during voiding causing the dyssynergia. Botulinum toxin is also used to partially paralyze the bladder, requiring the use of catheterization for emptying. External sphincterotomy is a surgical option for those with detrusorsphincter dyssynergia resulting in frequent, intolerable symptoms, but it is falling out of favor with less-invasive procedures, including stents, balloon dilatation, and intraurethral botulinum toxin A.38

Rehabilitation Treatment As briefly mentioned above, acute inpatient rehabilitation focuses on functional improvements using outcome measures that largely neglect quantitative measures that discriminate between neural restoration and compensatory improvements. As lengths of stay throughout the health care spectrum diminish, functional compensatory changes are likely to remain the priority for acute inpatient rehabilitation goals, leading to a safe discharge back to the community. Outpatient therapy and community programs, where clients sometimes pay out of pocket for SCI therapy, are filling the void as a result of the changes in health care. Rehabilitation therapy goals are driven by the individual patient, the exam findings, and the expected outcomes as previously discussed. There is little other evidence to provide guidelines on specific treatment approaches for specific patient profiles. Therapists try different approaches, using different modalities, different doses of those modalities, different orders of treatment modalities or different combinations of those treatments, to tailor the therapy to that which is most tolerable and efficacious to achieve the patient’s functional goals. This approach has generated years of “practice-based evidence” (and sometimes near religiously held beliefs). It may be the best we have to offer patients with SCI, but it rarely allows for scientific study, to objectively

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determine what interventions work in which individuals and to what extent. The Model Systems Program, from which the expected outcome data originate, describes a multidisciplinary, comprehensive approach toward SCI rehabilitation, allowing for a plethora of variables to confound the data concerning the effect of any specific therapy. There is clearly an opportunity for rigorous study of specific therapies and their effects during acute inpatient rehabilitation, but this will likely require better “phenotyping” of a patient’s baseline neurophysiological profile across a spectrum of measures and then testing appropriate subgroups of patients with specific interventions.39 One hurdle to this approach is the necessity to keep all other variables constant between a test group and a control group of patients, something therapists struggle with as they consider going against what their clinical experience tells them is best for patients. Deviating from their clinical expertise may be considered an unethical way to treat patients (despite the lack of evidence for much of what they do). Traditional functional therapy, used in the population from which the Model Systems outcome data was collected, originally relied more heavily on compensatory mechanisms to achieve functional goals. Spastic limbs were used as innate orthoses, weakened limbs were splinted or braced, and the emphasis was on teaching the body how to adapt to its new physiology. The results of this comprehensive, interdisciplinary approach gave birth to the Model Systems, which is now the standard of care expectation among all CARF-accredited SCI rehabilitation institutions. As our knowledge about neurologic repair and recovery has expanded, and with development of promising new treatment strategies, the mission of the Model Systems has evolved to focus more efforts on research. Over the past two decades, the attention in neurorehabilitation has shifted more to emphasize neurologic recovery. Observations from animal work using activitybased training have been translated to human practice, and the Model Systems efforts have been augmented by individual rehabilitation centers’ efforts and networks of centers such as the NeuroRecovery Network of the Christopher and Dana Reeve Foundation.

Recent Developments and the Therapeutic Pipeline The evidence supporting the capacity for neural plasticity and repair in neurorehabilitation, and for restorative neurology in general, is based upon basic science and animal model studies, and now more studies being performed in humans to support translation of this evidence. Much of neural repair depends upon molecular, cellular, and neural circuit processes involved in neural development, response to neural injury, and response to neural activity, including neural and gliogenesis, cell survival and migration, axonal outgrowth, pathfinding, and myelination, and ultimately functional synapse formation with probable postsynapse formation modulation of synaptic strength.40 This is in addition to the need for dealing with inflammation, overcoming the glial and extracellular matrix scar, and the need for vasculogenesis after SCI. Seminars in Neurology

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In the case of activity-based therapy, training can provide the stimulus required for some cellular processes important for plasticity and repair. Evidence from rat models of spinal cord injury illustrates activity-modulated release of brainderived neurotrophic factor (BDNF) in the lumbar spinal cord and increases in amplitude of muscle activity when one compares sedentary to gait-trained rats,41 probably due to the ability of neurotrophins to also function as neuromodulators.42 Additional studies utilizing a running wheel or an enriched environment have also shown benefits in recovery from experimental SCI.43–45 As a result of such animal model work, a similar activitybased therapy approach is now followed in human SCI. This activity-based therapy can focus on massed practice, task specificity, or challenging the system to build in robustness. For example, transfer training can be performed on the therapy mat with massed practice of hip hinge or sit to stand. These skills will next be used in task specific practice to transfer from a chair/couch to the commode. Chunking is performed during massed practice, which is the breakdown of the components of a functional task, repeated with high volume to improve the movement toward normal physiologic parameters. Increasing activity to and engaging spinal circuitry is a common goal in neural recovery in SCI, for example in locomotor training. There is significant evidence describing the existence of central pattern generator neural circuitry for locomotion in animal models, located in the lumbar spinal cord. This circuitry has also been demonstrated in humans following clinically and physiologically complete SCI.46 This neural circuitry normally receives input from peripheral sensory afferents as well as descending supraspinal (and likely propriospinal) pathways, but those latter pathways are damaged to varying degrees in SCI. The idea behind locomotor training is that providing repetitive, physiologically appropriate (limb loading, joint movement, muscle lengthening, and shortening) afferent input from stepping should activate, with progressively greater ease over time, the spinal neural circuitry for stepping. The translation of locomotor training from animal models to humans has revealed, however, that the extent to which afferent input alone can activate stepping is greater in animal models than in humans (locomotor training effects in humans are readily seen in incomplete injury, but are not of functional consequence in complete injury).47 In humans with incomplete SCI, there is evidence that locomotor training can impact supraspinal neural circuit plasticity.48 Locomotor training can be delivered in the water, on a treadmill, or over ground. Limb loading in any of these settings needs to be sufficient to provide important afferent feedback, but cannot be so much as to compromise mechanical function of the legs. Hydrotherapy, or aquatherapy, for gait training has the advantage of decreasing body weight and allowing weak muscles to move the extremity with kinematic parameters more similar to non-SCI controls.49 Out of the water, locomotor training utilizes body weight support (BWS) systems, either over a treadmill or over ground. Most centers begin locomotor training with therapists performing manual assistance/guidance or using robotics (e.g., Lokomat, Hocoma, Seminars in Neurology

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Inc., Norwell, MA) on a treadmill. The advantage of robotic body weight supported treadmill training (BWSTT) is the consistency of the stepping, the number of steps possible per session (no therapist fatigue or injury), the precise control the therapist has over joint angles and stepping speeds, and the ability to start therapy very early in the very weak. Manual training allows for more step-to-step variability and instantaneous feedback to the patient from the therapist. Both methods can use an “assist as needed” process, thereby encouraging patient effort while guiding kinematically appropriate stepping. Both have their advantages and training often progresses from the former to the latter. Training can then progress to BWS overground training (e.g., ZeroG, Aretech, LLC, Ashburn, VA) or even eventually to patient selfsupported ambulation if there is sufficient recovery of strength. In the last few years, overground robotic exoskeletons (e.g., Indego, Parker Hannifin Corp., Cleveland, OH; ReWalk, ReWalk Robotics, Yokneam, Israel; and Ekso, Ekso Bionics, Richmond, CA) have been developed, but their place in training locomotion and generating neural recovery after SCI is yet to be determined. They are currently being used as neural prosthetics for complete SCI or cauda equina injuries where little recovery is expected. To date, locomotor training in SCI has shown a wide range of efficacy,13 but improvements have been reported in gait parameters, spasticity, and motor strength, with no significant difference in outcome measures between the methods of delivery.50,51 Locomotor training has also been shown to benefit lipid profiles, cardiorespiratory fitness, autonomic regulation of heart rate and blood pressure, muscle composition and mass, balance, and psychological well-being and health-related quality of life.52 Although outcomes have not demonstrated a significant difference between the delivery of various locomotor training options, there are logistical differences including time with setup, skilled staff assistance requirements and education, and overall cost and maintenance of the equipment. Current research in animal models and humans is seeking to augment the locomotor training effect by a variety of means, including pharmacology and with electrical stimulation of sensory afferents either peripherally or as they enter the spinal cord. A variety of substances including glutamate agonists and monoamines have been shown to augment locomotor training and recovery in cat models of SCI,53 and now SSRIs have been tested in humans.54 Selective serotonin reuptake inhibitors increase both motor strength and spasticity so gait is not improved with medication alone, but pilot work has begun to show some added benefit of medication and training together. Using electrical stimulation for neuromodulation has a long history in SCI, and ranges from activating peripheral nerves at the right time in the gait cycle to augment function (increased leg flexion during swing initiation following common peroneal stimulation at terminal stance) to more recent advances with tonic spinal cord stimulation (most probably at the level of the dorsal roots). Dimitirijevic and colleagues began using epidural lumbar spinal cord stimulation in the 1980s to modulate spinal motor control,46,55–66 and others

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have now used the method to augment locomotion and voluntary motor control.67,68 It has been shown that the effects of epidural stimulation can be reproduced using transcutaneous stimulation,69–72 and benefits with this noninvasive stimulation include improvements in stepping, voluntary motor control, and spasticity. This work will require additional research and testing before it can be safely and efficaciously applied in broad clinical practice, but clinicians eagerly await the results of these studies. More traditional forms of neuromodulation have also been used in SCI. Neuromuscular functional electrical stimulation on its own (Empi Continuum, DJO, LLC, Vista, CA), as a neuroprosthesis (Bioness L300/H200, Bioness, Inc., Valencia, CA; Walk Aide, Ability Prosthetics and Orthotics, Exton, PA), or used in conjunction with upper/lower extremity cycle ergometry (RT300SL (SA), Motomed, RECK-Technik GmbH & Co. KG, Betzenweiler, Germany), has shown benefit in the SCI population in several ways, including neurogenic bowel and bladder sensation and control, bone density, spasticity, and motor strength,73 if not locomotor recovery itself. Rehabilitation efforts in areas other than locomotion are developing and it is anticipated that UE rehabilitation will follow in the footsteps of gait training. This will be more difficult for several reasons, including a mix of UMN and LMN injuries, more complex tasks performed by the UE and the degrees of freedom or different strategies that can be used to accomplish these tasks. Nevertheless, UE robotics (Armeo, for instance) are now being used for mass practice in a video gaming environment to improve UE function in incomplete tetraplegia. Currently, acute inpatient rehabilitation varies to some degree at each institution, even among CARF-accredited SCI programs. Many of these facilities provide advanced neural restorative therapies intertwined with conventional, functional rehab, in the form of FES and gait training. Functional electric stimulation devices are currently being used in the acute inpatient settings. The applications are broad, including electrode application to paretic muscles to assist with functional tasks and abdominal electric stimulation to improve bowel programs. Multiple small studies have been performed using FES in the acute SCI setting, highlighting prevention of muscle atrophy, increasing muscle mass and bone mineral density, and increasing blood pressure in the setting of orthostatic hypotension.74–77 Although a direct safety and outcome study has not been performed, no significant adverse events have been reported when using FES on SCI patients in the acute inpatient setting in these small studies. There are many other avenues of research being pursued in human SCI; there are multiple SCI clinical trials currently listed on clinicaltrials.gov. We have had a handful of trials with drugs, transplanted cells, and other reparative strategies, but to date none have shown marked efficacy or have completed phase 3 studies. In summary, the state of the science in SCI neurorehabilitation has taken tremendous leaps forward over the past few decades, directly reflected by the various types of rehabilitation equipment and the method of their delivery for people with SCI, specifically for the purposes of neural restoration.

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However, there continues to be barriers in providing neurorehabilitation for SCI. Proximity to SCI centers, where skilled therapists, physicians, and the equipment necessary to supply neural restoration are located, is a major barrier. The expense of the equipment is another barrier. In best case scenarios, people with SCI who travel a great distance to receive therapy at SCI centers receive exercise programs which they can perform, or direct their caregivers to perform, at home or in a therapy gym. Most health care insurance companies do not cover this durable medical equipment, viewing it as exercise equipment rather than neurorestorative equipment. Not only must there be an effort to decrease the footprint of this equipment to make it available for home use, but the cost must decrease to make it affordable for an SCI population, the majority of whom report incomes below the national poverty line. To effectively make these changes, including improving the technology for home use, decreasing the costs, and justifying the expense of neural restoration to health insurance companies, continued high-quality research must be performed. Outcome measures must not only include functional improvements in SCI, but also sensitive measures that demonstrate neural restoration. All of the scientific knowledge indicates that neural restoration is possible, but it will require more skilled therapy and education, home exercise, and equipment that insurance currently does not cover due to the lack of evidence to justify the expense. In the field of SCI neurorehabilitation, we know that this is true. The burden of proof must come from the experts in the field.

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