In the past, Research Status Reports on the Prevention of Cerebral Palsy and on the Diagnosis of Cerebral Palsy have been prepared and distributed by the Foundation. This Research Status Report on the Treatment of Cerebral Palsy is the most recent report in the series.

THE TARGETS OF THE FOUNDATION’S RESEARCH PROGRAM ON TREATMENT ARE:

REPAIR OF THE INJURED BRAIN

• Replacing the injured or dead cells of the brain.
• Repairing the injured or poorly developed fibers of cells of the brain.
• Improving the transmission between nerve cells of the brain.
• Stimulating the development of alternative pathways in the brain to better control muscle coordination and movement.

MANAGEMENT OF IMPAIRMENT AND FUNCTIONAL LOSS IN THE NEURO-MUSCULAR SYSTEM

• Interventions addressing:
  • impaired functioning of the brain and/or spinal cord.
  • weak, hypertonic and spastic muscles.
  • poor muscle coordination.
  • the control of involuntary movements.
  • “thin” and injured bones and poorly aligned joints.
• Interventions to improve function, performance and quality of life.

IMPROVED PUBLIC INFORMATION

• In collaboration with UCP and its affiliates, tailoring the UCP-Foundation joint public information programs so they are relevant, timely, user friendly, easily available and widely disseminated.

The “treatment of cerebral palsy” involves two issues: (1) treatment of the injured areas of the developing brain that control muscle coordination and movement and (2) management of the impairments of muscle coordination and of the resulting disabilities that are the consequences of cerebral palsy; these latter include (a) impairments such as muscle spasticity, muscle weakness, and uncontrolled muscle movements and (b) disabilities such as impaired mobility, inability to feed oneself, and difficulty with speech. It must also be remembered that the muscle control dysfunctions that characterize cerebral palsy are often accompanied by one or more other nervous system dysfunctions (co-morbidities); these include visual difficulties, hearing loss, convulsive disorders, bone fragility, learning disabilities, cognitive deficits, behavioral problems and the impact of aging. Research addressing co-morbidities will not be included in this Cerebral Palsy Research Status Report on Treatment, but information about them and special problems such as drooling, swallowing and the effects of aging can be found in Foundation’s Research Fact Sheets.

STUDIES OF THE REPAIR OF THE INJURED BRAIN

There are three major directions of research on repairing the injured brain: (1) replacing the several types of brain cells that have been injured and have either died or are functioning poorly, (2) repairing injured nerve cell processes such as cell axons and (3) stimulating the development and use of alternative pathways in the brain to better control muscle coordination and movement.

At this time, there are no clinically meaningful interventions that are able to successfully repair the existing damage to the areas of the brain that control muscle coordination and movement. For several years, experimental procedures have been utilized in animals and in humans to replace injured brain cells. The clinical model that has been usually used is that of Parkinson’s disease, a brain degenerative disorder in which cells in a specific region of the brain (basal ganglia) have died and the chemical they produce, dopamine, is no longer available. This pathology leads to the abnormal movements and lack of motor control that are characteristic of the disease. Several years ago, a number of animal and clinical experiments were done in which embryonic nerve cells (not undifferentiated stem cells, but rather embryonic cells that are more mature and are already primitive nerve cells) were injected into the area of the brain that had been injured. The result was a modest return of function for a limited period of time. From a clinical viewpoint, the result did not support the use of this methodology as a treatment for Parkinson’s disease. In recent years, more primitive cells (undifferentiated stem cells) have been injected into the injured area. Stem cells have the advantage of being able to multiply and differentiate in the brain. However, the clinical results using injections of stem cells again did not support the use of this methodology for treatment. Similar experiments with injection of stem cells following stroke (cerebral infarction) also appear to have limited beneficial results.

There are no reports at this time of the use of embryonic or of stem cells in either animal models or in humans with cerebral palsy. However, the theoretical concept of the use of stem cells is scientifically a very appealing hypothesis. Studies of their potential use in developmental brain damage are needed, particularly since the immature brain may be more amenable to their functional incorporation then is the mature brain. However, at this time, the repair of the injured brain by replacing injured or dead cells with embryonic or stem cells must be considered experimental, with guarded expectation of its clinical usefulness at any time in the near future. Nevertheless, the possibility does exist that the injured human brain can be repaired or restructured with a resulting improvement in function.

One type of cerebral palsy is due to a lack of myelination (insulation) of brain nerve cell processes (e.g. axons) and the resulting poor transmission of nerve impulses. The specialized brain cells responsible for myelination (oligodendricytes) fail to mature and become functional. At a basic science level, experiments are in progress that introduce cell growth factors into the environment of these cells to learn if their development can be stimulated and their myelination function restored. There are initial reports of success in cell maturation, but as yet no evidence of restored function.

Another treatment approach is the development and use of other brain pathways to assume the function of the damaged areas of brain. This is referred to as brain plasticity. The functional anatomy of the brain at the nerve cell level and at its connections with other cells (synapses) is constantly changing in response to alterations in the cell’s environment such as stimulation from the sensory systems (e.g. touch). These changes are a biological basis of learning during development and maturity. As a result, the brain is able to acquire new or improved skills in controlling motor coordination. Studies are in progress to target these changes to specific brain functions in order to correct the muscle coordination impairments and functional loss associated with cerebral palsy.

Programmed repetition such as is provided by physiotherapy, occupational therapy and speech therapy is one means of “teaching” the brain to improve motor performance skills. There are several “schools of therapy” in each of these disciplines which claim to do this more effectively than others (e.g. neurodevelopmental therapy; conductive education); however, meaningful evidence that these differences in approach are of major importance remains to be demonstrated. In the several trials of therapy, it appears that patient motivation and the intensity and the duration of therapy may be more important than the details of the specific therapy per se. It is now recognized that sensory input linked to motor performance is a critical factor in bringing about the desired motor control learning. One example of this is the recent application of “partial constraint therapy” as part of a program of physiotherapy; other examples are the controlled use of training devices (e.g. stationery bicycles and treadmills linked to sensory stimulation) for providing input into the brain; another is the use of the "Adeli Suit" to strengthen muscles by increasing resistance at joints and heighten proprioception (joint sense). The resulting improvements in motor control initially are often of relatively short duration, but with repetition they often become longer lasting. In animal models, it has been reported that certain stimulatory drugs can assist in improving motor performance; this added stimulus is presently also under study in humans.

People with disabilities and their caregivers sometimes turn to unconventional approaches to the repair of the injured brain because of dissatisfaction with the results of conventional therapies and their impatience with the time it often requires to develop and carefully evaluate new methods of treatment. These unconventional approaches are referred to as complimentary and alternative medicine (CAM). Some of the CAM approaches that have been attempted to improve brain function are dietary supplements, herbal extracts, electrical and magnetic brain stimulation, acupuncture, patterning, cranio-sacral manipulation, force field therapy and hyperbaric oxygen therapy. Reports of the success of CAM interventions are nearly always anecdotal in character (reports of individual experience) that lack the necessary information which would come from organized clinical trials. Clinical experience and testimonials are usually the sole evidence offered in support of CAM therapies. Also, the biologic principle that would explain the reason for success of a CAM intervention (proof of principle) is generally hypothetical and often contrary to known biologic information. To date, there are no CAM therapies that have been demonstrated scientifically to improve brain function for the control of muscle spasticity or improvement in motor coordination.

This lack of scientific evidence includes the anecdotal reports claiming the usefulness of hyperbaric oxygen therapy (HBOT) in restoring lost brain function. The results of one clinical trial dispute those claims; the trial demonstrated no differences in the results of HBOT when compared to air administered at low increased atmospheric pressure. More recently, there are reports that HBOT is being tried in brain injury threatened newborns with the hope of protecting the infant’s brain. It is difficult to evaluate the reported success of these individual case reports. However, a word of caution. There is documented evidence that a result of excess oxygen administration to the newborn, particularly the premature infant, is serious visual loss including blindness (retrolental fibroplasia). In clinical research or innovative medicine, the expectation of important beneficial results of an experimental therapy must be weighed against its potential for doing harm.

It is important to recognize that unproven CAM therapies demand attention utilizing modern methods of scientific evaluation. In the interim, at a substantial personal cost in time and money, small groups continue to use a variety and often a combination of CAM therapies in hopes of repairing developmental brain damage in persons with cerebral palsy.

Despite all of the exciting possibilities being studied, there is a fundamental problem with the concept of any single method of intervention being able to repair the injured brain of all persons with disabilities due to cerebral palsy. It must be recognized that cerebral palsy is not a single disorder. It is a clinical syndrome that includes a number of different types of injury to a variety of areas of the developing brain. These include: (1) failure of a variety of developing brain cells to migrate during development from their site of origin to appropriate functional locations in the brain; (2) failure of specialized cells of the brain (oligodendricytes) to deposit myelin on cell fibers resulting in the poor transmission of nerve impulses; (3) the death of brain cells such as “grey matter” cells; and (4) poor function at the connections between brain cells (synapses) resulting in faulty or no transmission of nerve impulses between cells. An effective treatment will have to be specific to the pathology to be successful. However, at a functional level increased plasticity by recruitment of other nerve tract pathways may be useful in several of the pathological situations depending on the magnitude and site(s) of brain injury.

Studying approaches to the repair of specific injuries in the developing brain is an exciting area of active research which has captured the attention of scientists in both basic neurobiology and in clinical neuroscience. Specific questions have been identified and are being explored. Their answers will provide the basis both for clinical experiments addressing the repair of the specific pathology in the injured brain and for the information necessary for developing methods to improve function in persons with disabilities due to cerebral palsy.

STUDIES OF THE MANAGEMENT OF IMPAIRMENT AND FUNCTIONAL LOSS IN THE NEURO-MUSCULAR SYSTEM

Increased or decreased muscle tone, spasticity, muscle weakness, involuntary movement and loss of control of muscle coordination are the hallmarks of damage to the motor system of the developing brain. Although the muscles and peripheral nerves are not damaged initially (with time, there are changes), the brain is unable to provide the delicate control that is necessary to permit the multitude of coordinated small muscle and large muscle movements necessary for the common activities of daily living (e.g. using a fork, walking, swallowing, speech). In technical terms, the damage to the brain is called “an upper motor neuron” lesion. The characteristics of this poor control by the brain of the neuro-muscular system in persons with cerebral palsy are a variety of impairments such as muscle spasticity, increased reflexes and involuntary movements. At this time, there are a number of treatments available that diminish the degree of impairment (e.g. muscle spasticity) and increase participation in activities of daily living (e.g. independent mobility).

The specific characteristics of the impairment due to an upper motor neuron lesion are a clue as to which focal area(s) of the brain have been damaged. Therapeutic interventions have been developed to lessen resulting impairments of the neuro-muscular system, but which do not always lead to improved function. Thus, although spasticity of a limb muscle has been decreased (a lessening of the impairment), it is not necessarily true that the limb can be used more efficiently. An improvement in function often requires additional procedures to improve muscle strength and coordination.

The research and clinical approaches to diminish impairment and the associated disability can be considered from the viewpoint of the sites in the neuromuscular system that are being approached:

The Brain and/or Spinal Cord: A variety of oral medications have been used to diminish the “sensitivity” of local nerves and muscles in order to control their reactions to environmental stimuli which result in muscle spasticity and/or involuntary movements. These medications are of modest benefit because of their undesirable side effects. The therapeutic levels needed to have a desirable effect on muscles and peripheral nerves have unacceptable negative effects on brain function (e.g. awareness, alertness, personality) and on muscle strength. The only exception to this are preliminary reports on the use of a drug, L Dopa, to successfully treat the muscle incoordination and involuntary movements associated with what is called “dopamine deficient cerebral palsy”.

Several neurosurgical procedures on brain structures controlling muscle movement have been studied. Their therapeutic effects for control of spasticity have been found to be minimal and their side effects undesirable. Neurosurgical procedures on brain areas are still being evaluated for control of the athetotic form of cerebral palsy characterized by uncontrolled involuntary movements. Areas of the brain are sometimes destroyed or electronic stimulators implanted to control these movements. Reports of individual case successes using brain electronic stimulation devices for improvement in patients with abnormal movements are sometimes spectacular. However, there are no systematic studies available at this time to be able to judge the indications for or appropriateness of this intervention.

A neurosurgical procedure cutting selected sensory nerves entering the lower spinal cord, dorsal rhizotomy, has been evaluated in at least three controlled clinical trials in North America. The procedure clearly decreases spasticity in the muscles associated with these severed nerves. In some cases, there are undesirable effects such as poor control of bowel and urinary function. In all cases, in order to have a beneficial functional effect on lower limb function, the person must also then participate in an intense program of physiotherapy. The controversial issue continues to be: for whom are the beneficial results of dorsal rhizotomy worth its undesirable side effects, particularly when other less intrusive therapies may also provide beneficial results? At this time, the consensus of expert opinion is that dorsal rhizotomy should be considered as one of several possible interventions, but used only for persons with severe muscle spasticity in the lower extremities and for whom other therapies have been unsuccessful.

Intrathecal Baclofen has been evaluated in several trials as a treatment for muscle spasticity in the lower limbs; also, recently in the upper limbs. Baclofen is a drug that diminishes nerve cell sensitivity (a GABA agonist). When its concentration is increased in the cerebrospinal fluid bathing the nerve cells in the lower spinal cord, the nerves to the spastic muscles of the legs become less sensitive and the degree of muscle spasticity decreases. The drug can be administered by means of a relatively small pump implant under the skin of the abdomen with a tube leading from it to the spinal canal. The pump has a reservoir that stores the chemical and the rate of release is programmed electronically. When performed by physicians skilled in the procedure, there are relatively few undesirable side effects or dangers associated with it. Baclofen clearly diminishes muscle spasticity. However the drug decreases muscle tone in all of the muscles whose nerves it baths. It addresses the impairment: muscle spasticity. It has no direct effect on improving function but does set the stage for other interventions to improve function (e.g. physiotherapy). There are initial reports of its usefulness also in the control of involuntary limb movements.

Bone and Muscle: Orthopedic procedures, medical and surgical, are used to repair injured bones, strengthen weakened bone, align poorly positioned bone(s), lengthen shortened muscles and move tendons. These procedures are aimed at providing stability to a poorly aligned skeletal structure and to redirect forces at joints to provide for improved function. Until relatively recently, the success of innovations and variations in orthopedic procedures were based nearly exclusively upon the skill of the individual physician and on his/her subjective analysis of a series of cases. In recent times, the availability of both structured evaluations and of electronic means for the analysis of gait, motion and performance before and after a procedure has lent quantification and objectivity to the evaluation of the results of orthopedic interventions. In addition, more attention is now being given to the long term consequences of these interventions as they impact on the quality of life of persons who have had these procedures done in earlier years. However, the technique of the controlled clinical trial is still not often used in the study of “established” or innovate orthopedic procedures; thus, it continues to be difficult to evaluate the effectiveness of many of these interventions.

Botulinum toxin is a very powerful drug (“Botox”; “Mycobloc”) which when injected into the neuro-muscular junction of a hypertonic or spastic muscle will cause that muscle to relax for a period of 4-6 months. Limited amounts of drug can be used at one time thus restricting the number of muscles that can be injected. Several clinical trials have demonstrated its effectiveness in the treatment of the spasticity associated with cerebral palsy. During the extended period of muscle relaxation, other interventions are used (e.g. physiotherapy) to improve muscle strength and coordination. Several courses of botulinum therapy are usually needed to obtain the performance results desired. Other medical injection techniques to cause a nerve block resulting in muscle relaxation have been used; these include alcohol or phenol injection into the nerve to the spastic muscle. These nerve injections have relatively long lasting effects, can be painful and permanent damage to the nerve can result. At this time, nerve block injections are reserved for use only in very special circumstances.

Therapists in the disciplines of physiotherapy, occupational therapy and speech therapy utilize a number of physical and behavioral approaches to improve function, diminish disability, and maintain performance. These approaches are used alone, but also are often incorporated as an integral part of other intervention strategies (e.g. post-surgical; following botulinum toxin injection; etc). The methods used are aimed at lengthening contracted muscles, improving the strength of weakened muscles, increasing the range of motion at restricted joints, improving movement coordination and developing compensatory strategies to accomplish tasks.

As indicated earlier, there are a number of “schools of physiotherapy” that favor one therapeutic regimen over others. Several clinical trials over the past decade indicate that the success of a particular technical (and sometimes philosophical) approach is probably dependent more on the motivation of the patient, the type and degree of impairment, the impact of the therapist-patient interaction, the intensity of therapy, the duration of therapy and sometimes the environment in which the therapy is conducted than it is on the specifics of the particular methodology being used. It is generally accepted that these interventions are important either as primary “treatments” or as adjuncts to other interventions (e.g. botulinum therapy). Experience demonstrates that they serve both to improve function and to maintain existing function. However, the important questions that remain to be answered about the use of these therapies are: for whom? when? how much? and for how long?

A number of devices and approaches have been developed to add to the techniques used by physicians, therapists and other clinicians to decrease impairments and improve function. These include biofeedback and therapeutic electrical stimulation (TES). There have been limited evaluations of these technologies and the significance of their role in the treatment of cerebral palsy has not been established. On the other hand, orthotic devices and casts are used regularly by clinicians, particularly for the appropriate alignment of bone and adjusting the range of motion at joints. These devices have often not been evaluated as such, but have usually been included as part of the treatment protocol of other interventions that are being evaluated. Their value is rarely questioned, but the actual evidence from well constructed trials of the usefulness of a specific type of orthosis is limited. In addition, there are now a host of assistive technology devices available to assist persons in their activities of daily living. This continuingly evolving area ranges from simple mechanical devices to assist in eating—to motorized wheel chairs—to highly sophisticated electronic devices important to communication. In recent years, adapting computer programs to the tasks important to education and to employment has broadened the opportunities for persons with disabilities for participation in family and community activities.

However, as these devices become more sophisticated, their availability has become a problem, their cost has increased greatly, and special training for their use has become essential. The issues of availability, cost and special training are major problems requiring additional attention by clinical care and community service organizations.

There are a number of exercise and sport-related regimens presently being used to strengthen weak muscles and improve coordination; among these are water exercises, tai chi and horse back riding. These are undoubtedly pleasurable and increase motivation of the participants to build muscle strength and coordination as well as to maintain general health. There are a number of observational reports about their usefulness, but more information about the specificity of their impact is needed.

CONCLUSION

As presented above, there are now a number of interventions targeting the central nervous system and the neuro-muscular system that have been developed and are being explored to “treat” both the injured brain and the impairments and disabilities associated with cerebral palsy. Since there are few animal models that replicate the developmental brain damage characteristic of cerebral palsy, most clinical studies are done in humans. These studies are directed at lessening impairments such as an increase in muscle tone and spasticity; a few have addressed the involuntary movements associated with cerebral palsy. Increased research attention is now being given also to develop better methods for the lessening of disability and improvement in quality of life. However, there is a paucity of attention to research on the impact of aging on persons with impairments and disabilities due to cerebral palsy and other developmental brain injuries. Controlled clinical trials for studies of clinical interventions are now steadily replacing the prior method of the case observation or clinical case series. This change in research methodology is having an important impact on the quality and significance of studies to evaluate the usefulness of interventions that can impact on the quality of life of persons with disabilities due to cerebral palsy and on their families. Data is replacing clinical observation as the basis for treatment. Important research questions are being identified; methods are becoming available to answer those questions; a targeted effort on the search for answers is in progress.

The research program of the UCP Research and Educational Foundation has contributed to these advances in treatment and is actively encouraging and supporting the development and evaluation of the new approaches needed to make treatment even more timely and effective.

UCP RESEARCH AND EDUCATIONAL FOUNDATION
GOALS AND STRATEGY

The goals of the UCP Research and Educational Foundation are the prevention of cerebral palsy and improving the quality of life of persons with disabilities due to cerebral palsy. In order to achieve these goals, it sponsors a research and educational program on the basic science and clinical research aspects of prevention, diagnosis and treatment of cerebral palsy. The Foundation program strategy includes:

STIMULATING NEEDED RESEARCH

• seeking the continuing advice and assistance of research leaders in the field, particularly the Foundation’s Scientific Advisory Council.
• interacting with and sometimes being part of the research advisory structure of other organizations such as government research agencies (e.g. NIH, CDC, NIDRR), academic institutions, research institutes (e.g. Burke, Kessler, Salk, Kennedy Krieger), foundations (e.g. Hearst Foundation, Kirby Foundation, Dana Foundation), industry and other organizations.
• developing research workshops in which scientific leaders address a critical research question, share findings and problems, and agree to cooperate in answering the question.

SUPPORTING RESEARCH AND CAREER DEVELOPMENT; PROVIDING PUBLIC INFORMATION

• providing risk venture financial support for pilot research projects exploring new approaches to the answer of important basic science and clinical research questions.
• funding the training and career development of young clinician-scientists to become the future leaders in cerebral palsy research, teaching and patient service.
• informing the public of the status of and continuing advances in research and clinical care relevant to cerebral palsy and the disabilities associated with it.

We want to thank several authors and publishers for permission to use their pictures and illustrations. The references are on file and information about them is available.