Neural repair and rehabilitation an introduction

Dorn Spinal Therapy

Spine Healing Therapy

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Michael E. Selzer1, Stephanie Clarke2, Leonardo G. Cohen3, Pamela

W. Duncan4 and Fred H. Gage5

1 University of Pennsylvania, Philadelphia, PA, USA;2 University of Lausanne, Lausanne, Switzerland; 3National Institutes of Health, Bethesda, MD, USA;4University of Florida, Gainesville, FL, USA; 5The Salk Institute, La Jolla, CA, USA

Among medical specialties, rehabilitation has been one of the slowest to develop a basic science framework and to establish evidence-based practices as its norms. The reasons for this relate in part to the urgent need for clinical service and the dearth of experienced practitioners in the field during its formative years. It is imperative now, that the perceived lack of a scientific basis be reversed in order for rehabilitation medicine to achieve its full academic recognition and fulfill its great potential for relieving human suffering. This book represents an attempt to place the practice of neurorehabilitation in a rigorous scientific framework. Precisely because the need and the potential are so great, the editors have devoted equal space and emphasis to the clinical practice of neurorehabilitation and to its basic science underpinnings. In particular, two areas of basic science are highlighted - neuroplasticity and neural repair. In this respect, the book differs from most clinical textbooks. However, the professional neurorehabilitation community has been especially supportive of this direction and has taken very active steps to further the development of a basic scientific underpinning for its field. Similarly, the field of rehabilitation medicine, and in particular neurorehabilitation, has begun to put great emphasis on the development of evidence-based medical practices (DeLisa et al., 1999; Ottenbacher and Maas, 1999; Practice PPoE-B, 2001). The chapters in the clinical sections of this book stress those therapies for which evidence exists based on controlled clinical trials.

1 Definitions

Neurorehabilitation

Neurorehabilitation is the clinical subspecialty that is devoted to the restoration and maximization of functions that have been lost due to impairments caused by injury or disease of the nervous system. According to the social model of disability adopted by the World Health Organization (WHO), "'impairment' refers to an individual's biological condition ...," whereas "... 'disability' denotes the collective economic, political, cultural, and social disadvantage encountered by people with impairments" (Barnes, 2001). These definitions have collapsed older distinctions of the WHOs 1980 International Classification of Impairments, Disabilities and Handicap (ICIDH) (Thuriaux, 1995). In that classification, "impairment" referred to a biological condition: for example, spinal cord injury; "disability" referred to the loss of a specific function: for example, loss of locomotor ability consequent to the impairment; and "handicap" referred to the loss of functioning in society: for example, inability to work as a postman, consequent to the disability. In order to improve healthcare data reporting by the nations of the world, the WHO replaced ICIDH with an International Classification of Functioning, Disability and Health (ICF) in 2001. ICF has two parts, each with two components:

• Part 1: Functioning and disability:

(a) body functions and structures,

(b) activities and participation.

• Part 2: Contextual factors:

(c) environmental factors,

(d) personal factors.

It is not possible to review the entire classification here, but because of its widespread use, including some of the chapters in this book, a brief summary is presented in Chapter 32 of volume II. The complete version can be found at http://www3.who.int/ icf/icftemplate. cfm. By focusing on components of health, ICF can be used to describe both healthy and disabled populations, whereas the ICIDH focused on consequences of disease and thus had a narrower usefulness. However, the older classification is more useful in understanding the level of interventions and research performed by the rehabilitation community. Traditionally, rehabilitation medicine has concerned itself with disabilities and handicaps but very little with the level of impairment and even less with the molecular and cellular mechanisms that underlie impairments. In recent years, this state of affairs has begun to change as rehabilitation professionals have come to recognize the continuity that exists from molecular pathophys-iology to impairments to disabilities and handicaps. Neurorehabilitation has come to represent the application of this continuum to neurologically impaired individuals.

Over the last 30 years, interest in understanding the mechanisms underlying recovery of function has increased. An expression of this interest has been the substantial increment in basic science and translational studies geared to characterize the extent to which the central nervous system (CNS) can reorganize to sustain clinical rehabilitation.

Neuroplasticity

The term "neuroplasticity" is used to describe the ability of neurons and neuron aggregates to adjust their activity and even their morphology to alterations in their environment or patterns of use. The term encompasses diverse processes, as from learning and memory in the execution of normal activities of life, to dendritic pruning and axonal sprouting in response to injury. Once considered overused and trite, the term "neuroplasticity" has regained currency in the neurorehabilitation community as a concise way to refer to hypothetical mechanisms that may underlie spontaneous or coaxed functional recovery after neural injury and can now be studied in humans through such techniques as functional imaging (including positronemission tomography (PET) and functional magnetic resonance imaging (fMRI)), electrical and magnetic event-related potentials (including electroencephalogram (EEG), evoked potentials (Eps), and magneto-encephalography (MEG)) and non-invasive brain stimulation in the form of transcra-nial magnetic or electrical stimulation (TMS and trancranial direct current stimulation, tDCS).

Neural repair

The term "neural repair" has been introduced in the past several years to describe the range of interventions by which neuronal circuits lost to injury or disease can be restored. Included in this term are means to enhance axonal regeneration, the transplantation of a variety of tissues and cells to replace lost neurons, and the use of prosthetic neuronal circuits to bridge parts of the nervous system that have become functionally separated by injury or disease. Although there is overlap with aspects of "neuro-plasticity," the term "neural repair" generally refers to processes that do not occur spontaneously in humans to a degree sufficient to result in functional recovery. Thus therapeutic intervention is necessary to promote repair. The term is useful as part of the basic science of neurorehabilitation because it encompasses more than "regeneration" or "transplantation" alone. In recent years, concepts of neural plasticity have been accepted as important elements in the scientific understanding of functional recovery. The rehabilitation community has been slower to embrace repair as a relevant therapeutic goal. "Neural repair" has been used in the title of this textbook in order to convey the breadth of subject matter that it covers and is now considered relevant to neurorehabilitation.

2 History of neurorehabilitation as a medical subspecialty

Origins of rehabilitation medicine

In late 19 th century America, interest developed in the possibility that then exotic forms of energy, that is, electricity, could help to heal patients with diseases and disabilities. In particular, high-frequency electrical stimuli were applied to generate deep heat in tissues (diathermy) and some physicians adopted this treatment modality as a specialty. In the early days, X-ray treatments and radiology were closely linked to electrotherapy (Nelson, 1973) and in 1923, the American College of Radiology and Physiotherapy was formed, changing its name to the American Congress of Physical Therapy in 1925. This organization merged with the American Physical Therapy Association in 1933 and in 1945, it adopted the name American Congress of Physical Medicine, then American Congress of Physical Medicine and Rehabilitation, and finally in 1966, the American Congress of Rehabilitation Medicine (ACRM). This is a multidisciplinary organization with membership open to physicians from many specialties and to non-physician rehabilitation specialists. With the large number of injuries to soldiers in World War I, the need for therapists to attend to their retraining and reintroduction to productive life created a new specialty that was based on physical modalities of treatment, including physical and occupational therapy, diathermy, electro-stimulation, heat and massage. These modalities were expanded during World War II. Training programs for physical therapy technicians were started in the 1920s and an American Medical Association (AMA) Council on Physical Therapy (later the Council on Physical Medicine) was started in 1926. By 1938, a medical specialty organization, the American Academy of Physical Medicine and Rehabilitation (AAPM&R) was formed and in 1947, the Academy sponsored a specialty board with a residency requirement and qualifying examination (Krusen, 1969). Gradually, the focus of rehabilitation has broadened to include the social and psychological adjustment to disability, treatment of medical complications such as bedsores, autonomic instability and urinary tract infections, management of pain syndromes and other medical aspects of the treatment of chronically ill patients. As with the name of the ACRM, the term "Rehabilitation Medicine" has replaced "Physical Medicine and Rehabilitation" in the naming of some hospital and university departments, since the latter term is associated with limitations to specific therapeutic modalities, such as physical therapy, rather than to a target patient population or therapeutic goal, i.e., restoration of function. With variations, parallel developments have occurred in many countries throughout the world.

A concomitant of the broadening of the focus of rehabilitation has been a trend toward specialization, including organ system-specific specialization. Previously, the tendency was to approach disabilities generically, based on their symptoms (e.g., gait disorder) and signs (e.g., spasticity), regardless of the cause. But with a growing conviction that the rehabilitation of patients requires knowledge of the pathophysiolog-ical basis of their disorders, medical specialists outside of physical medicine and rehabilitation (PM&R) became more interested in the rehabilitation of patients whom they might have treated during the acute phase of their illness. This was especially true among neurologists. The American Academy of Neurology formed a section on rehabilitation and in 1990, members of that section formed the American Society for Neurorehabilitation. National societies of neurorehabilitation were also formed in Europe and more recently in other parts of the world. In 2003, these national societies confederated officially as the World Federation of Neurorehabilitation, designating Neurorehabilitation and Neural Repair as its official journal.

Epidemiology of neurological disabilities

For many years, and especially during the two world wars, the practice of rehabilitation medicine was dominated by orthopedic problems, such as bone fractures and limb amputations. More recently, progress in keeping severely neurologically injured patients alive has shifted the emphasis toward rehabilitation of patients with developmental neurological disorders, stroke, traumatic injuries of the brain and spinal cord, and other chronic disabling diseases. It is estimated that in the USA, chronic health conditions cause activity limitations 61,047,000 times each year (Kraus et al., 1996). The five conditions causing the most limitations are: heart disease (7,932,000); back problems (7,672,000); arthritis (5,721,000); asthma (2,592,000); and diabetes (2,569,000). However, the conditions causing people to have major activity limitations most often are: mental retardation (87.5% of people with the condition have a limitation); multiple sclerosis (69.4%); malignant neoplasm of the stomach, intestine, colon, and rectum (62.1%); complete and partial paralysis of extremities (60.7%); malignant neoplasm of the lung, bronchus, and other respiratory sites (60.6%); and blindness in both eyes (60.3%). The WHO estimates that more than 300 million people worldwide are physically disabled, of whom over 70% live in the developing countries. In the USA, approximately 300,000 people are admitted to inpatient rehabilitation facilities each year. In a recent survey, orthopedic conditions (hip and limb fractures, amputations, hip replacements) accounted for 20% of rehabilitation admissions, while neurological conditions (stroke, traumatic brain injury, spinal cord injury, polyneuropathy, and other neurological conditions) accounted for 80% (Deutsch et al., 2000). The survey excluded Guillain-Barré syndrome, so the prevalence of neurological disabilities may have been underestimated. Thus disorders of the nervous system are those most often requiring intensive rehabilitation interventions.

3 Outcomes measurement in rehabilitation medicine

The complex medical, emotional, and social problems of the medically disabled patient population, and the complexity of the treatment regimens, has made assessing outcomes difficult. As practiced in most countries, rehabilitation is a multidisciplinary process, involving combinations of treatment modalities administered by multiple therapists. Moreover, the most important outcome of the rehabilitation process is the degree of reintegration of the patient in society, in terms of roles in work, family, and community. This also was difficult to assess with the limited instruments available only one generation ago. In order to catch up to other fields in the practice of evidence-based medicine, the rehabilitation field has been forced to become extremely resourceful in designing outcomes measures to evaluate the efficacy of its treatments (Stineman, 2001). The resulting sophistication of outcomes measurement has had an important impact on all of medicine, which now routinely considers quality of life in the evaluation of effectiveness in clinical trials.

4 Impact of evidence-based medicine on neurorehabilitation

Ironically, while outcomes measurement has begun to have an important impact on the evaluation of systems of rehabilitation, and on complex aspects of rehabilitation outcomes, the evaluation of outcomes for specific physical therapy treatments has lagged. A consensus conference was held in 2002, which developed a structured and rigorous methodology to improve formulation of evidence-based clinical practice guidelines (EBCPGs; Practice PPoE-B, 2001). This was used to develop EBCPGs based on the literature for selected rehabilitation interventions in the management of low back, neck, knee, and shoulder pain, and to make recommendations for randomized clinical trials. To date, only two large-scale, prospective, multicenter, randomized clinical trials have been carried out to test-specific physical therapy treatments. These are the trial of body weight-supported treadmill training for spinal cord injury (Dobkin et al., 2003; see Chapter 3 of volume II) and the trial of constraint-induced movement therapy for upper extremity dysfunction after stroke (Winstein et al., 2003; see Chapter 18 Volume II). Evidence that amphetamines combined with physical therapy can enhance recovery in several animal models of stroke and traumatic brain injury has led to several small-scale randomized clinical trials. These have suggested a tendency toward effect in human patients with ischemic stroke (Long and Young, 2003). A larger clinical trial is underway.

5 Impact of the revolution in the science of neuroplasticity and regeneration on neurorehabilitation

Between 1980 and 2003, there was a relatively constant 3.8-fold increase in annual publications in the field of rehabilitation medicine (best searched on Medline using the term "physical rehabilitation"). A Medline search using the terms "neuroplasticity" or "nerve regeneration" showed a steady or slightly accelerating 7.8-fold increase during the same time (Fig. 1). However, the combination of "rehab ilita-tion" and either "neuroplasticity" or "regeneration" did not appear until after the term "neurorehabilita-tion" became current.

As indicated in Fig. 2, the term "neurorehabilita-tion" was used less than 10 times/year in Medline-indexed articles until 1994. From then until 2003, the annual number of articles on "neurorehabilitation" increased 9.4-fold. During that same period, the number of articles on ("neuroplasticity" or "regeneration") and "physical rehabilitation" increased 7.6-fold. Similarly, the terms "rehabilitation" and "evidence-based medicine" did not appear in the same article until 1994. From then until 2003, their coincidence increased 25.5-fold. Thus there is a correlation between the use of the term "neurorehabilitation" and acceleration in the application of basic science and evidence-based medicine to rehabilitation research. This can be ascribed to the accelerated interest in organ-specific rehabilitation, and in particular, to interest in the rehabilitation of patients disabled by neurological disorders. As in other fields of medicine, the trend toward specialization in the field of rehabilitation medicine carried with it recognition of the need to develop a basic science research underpinning and to become more rigorous in the evaluation of its therapies and clinical practices.

Year

Figure 1. Parallel growth of research in medical rehabilitation and in neural plasticity and repair over the past 25 years. In order to estimate research in medical rehabilitation, a PubMed search was conducted using the term "physical rehabilitation," which yielded the highest combination of sensitivity and specificity among such terms as "medical rehabilitation," "rehabilitation," and "rehabilitation medicine." In order to estimate research on neuroplasticity, the term "neuroplasticity" was sufficient. In order to estimate research on regeneration in the nervous system, the best combination of specificity and sensitivity was achieved by searching for the term "nerve regeneration."

Year

Figure 1. Parallel growth of research in medical rehabilitation and in neural plasticity and repair over the past 25 years. In order to estimate research in medical rehabilitation, a PubMed search was conducted using the term "physical rehabilitation," which yielded the highest combination of sensitivity and specificity among such terms as "medical rehabilitation," "rehabilitation," and "rehabilitation medicine." In order to estimate research on neuroplasticity, the term "neuroplasticity" was sufficient. In order to estimate research on regeneration in the nervous system, the best combination of specificity and sensitivity was achieved by searching for the term "nerve regeneration."

From the above, it can be seen that the maturation of neurorehabilitation as a clinical specialty has experienced two phases, which replicates the pattern seen in other specialties. In the first phase, the enormous need for clinical service was met by reliance on the experience and a priori reasoning of medical clinicians and therapists in devising methods to maximize function. In the second phase, scientific exploration in animal models was used to buttress the rationale for these therapies, while the rigors of prospective, controlled clinical trials were applied to test the effectiveness of those treatments in patients. This second phase is still very active, but we are already witnessing the beginning of a third phase, in which therapy is directed not only at maximizing function based on the post-injury residual anatomical substrate, but incorporates attempts at repairing that substrate. As with clinical trials of neuroprotective agents in human stroke and trauma, early results of cell and gene therapies for

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