Cerebral Palsy International Research Foundation comments on FDA Public Notification concerning adverse events reported in child

Concerns about the safety of Botox injections to treat spasticity in individuals with CP have recently been raised. It has not been established whether these adverse events are causally related to Botox treatment. Serious adverse events have been reported in children with cerebral palsy. The FDA is currently reviewing safety data from clinical studies submitted by the drug’s manufacturers, as well as post-marketing adverse event reports and medical literature. The FDA is not advising health care professionals to discontinue prescribing these products.

After completing a review of the data, the FDA will communicate to the public its conclusions, resulting recommendations and any regulatory actions. In the interim, the FDA is not advising health care professionals to discontinue prescribing these products. CPIRF is closely monitoring this situation and will alert the CP community of any new developments.

Background

The severe adverse events resulting in death reported in the United States occurred in three children with CP. All involved some degree of aspiration, respiratory infections, and other breathing complications; all 3 children had a history of respiratory compromise and dysphagia prior to treatment with Botox. It is unknown if treatment with Botox was causal in their deaths.

Botox use has been approved for the treatment of limb spasticity in individuals with CP in approximately 60 countries since 1995. While not approved in the US by the FDA for this use, highly trained physicians have been effectively treating spasticity (severe arm and leg muscle spasms) with Botox over the last 15 years.

The FDA is aware of the body of literature describing the use of botulinum toxins to treat limb spasticity in children and adults with CP.

Comments

Botox has been a very helpful and effective method for treating children and adults with disabling spasticity and dystonia for many years. Those being treated by a qualified and experienced physician should discuss their concerns with their physician, but there is no indication that treatment should be discontinued, and the product is not being “recalled”.

It is critical that Botox only be administered by highly trained physicians who understand and fully explain the risks to patients and their care-givers. It is also important that physicians make patients and care-givers fully aware of the signs and symptoms of botulism. The symptoms include difficulty in swallowing, weakness, difficulty in breathing, difficulty in speaking. Patients and care-givers should also understand that these side effects can occur as early as one day and as late as several weeks after a Botox injection and that if they have any of these symptoms they should seek medical attention immediately.

Serious adverse events should be reported to FDA’s MedWatch reporting system by completing a form on line at http://www.fda.gov/medwatch/report/hcp.htm, by faxing (1-800-FDA-0178), by mail using the postage-paid address form provided online (5600 Fishers Lane, Rockville, MD 20853-9787), or by telephone (1-800-FDA-1088).

By Dr. Mindy Aisen

The field of stem cell research offers enormous promise for the treatment of human disease. Stem cells are “undifferentiated” cells; they have the potential to develop into virtually any specialized type of cell in the body. So theoretically, stem cells might be used to regenerate human tissue or organs damaged by disease. There is hope that some day stem cells may provide effective restorative therapy for many human conditions, including those caused by damage the nervous system such as stroke, Parkinson’s Disease, spinal cord injury and cerebral palsy. At the present time, however, the field of stem cell research is in its infancy, and there are few effective uses of this type of therapy.

Stem cells can be derived in several ways. Embryonic stem cells (removed from early stage embryos) can be maintained in the laboratory and coaxed into differentiating into various cell types. Fetal cord blood contains human stem cells that can also be grown in the laboratory or frozen for later use. A recent technique for generating human stem cells involves obtaining cells from skin biopsies and “deprogramming” them into stem cells that can then be differentiated into various human cell types. The adult human brain contains viable neural stem cells; it may be possible to use medications to stimulate these natural stem cells into regenerating damaged brain tissue.

Stem cell scientists are currently working on the optimal conditions to maintain stem cells in the laboratory, the precise methods necessary to convert stem cells into the specific cells that might reconstitute damaged human tissues, and the techniques required to direct such cells to function effectively together. At the present time, much work remains to be done before the practical application of stem cells to the treatment of human disease becomes feasible.

In cerebral palsy, brain tissue is damaged at a very early stage of development: in utero, at or around the time of birth, or up until the age of 2 years. The brain is, of course, the most incredibly complex of all human organs. The brain consists of many different cell types interacting in a precisely organized fashion to produce the different aspects of thought and behavior in different brain regions. Before stem cells can be used to repair damaged brain tissue in cerebral palsy or any other brain disorder, scientists will have to discover how to turn stem cells into various specific types of brain cells, and induce them to form the precise connections and organization necessary for meaningful brain function. It is likely that stem cells converted into brain cells will have to be implanted in the precise areas that they are needed in order to provide effective treatment.

Specific Types of Approaches: Cord Blood Infusions

It is extremely unlikely that the administration of stem cells by peripheral infusion of cord blood can effectively treat cerebral palsy. Such cells have not been “taught” to form the necessary types of brain cells, and they will not be able to enter the brain, because there is an anatomic and physiological barrier which prevents certain medications and cells from reaching the brain, known as the blood brain barrier.

How can one explain the reports of improvements in the symptoms of cerebral palsy (CP) following cord blood infusions? Medicine is filled with such “anecdotal” reports of improvements when novel treatments are applied to chronic conditions. The symptoms of all chronic conditions fluctuate, and subjective factors, including the optimistic expectations that accompany novel therapies, often seem to alleviate disease manifestations. But in almost all cases, the underlying disease remains unchanged, and there is no meaningful long-term benefit. Indeed, in most cases, the risk of harm outweighs the chance of benefit when unproven novel therapies are used.

CPIRF strongly supports research into the use of stem cells to treat CP. But at present, CPIRF, in consultation with leading stem cell scientists, has reached the firm conclusion that use of cord blood or other forms of stem cell treatments for CP is inadvisable. Basic and applied research into various approaches to stem cell neural regeneration therapy must be vigorously pursued, and CPIRF will continue to fund such efforts. But at present, administration of cord blood to people with CP offers no meaningful chance of benefit.

Furthermore, the long term risks of cord blood infusions have not been studied, receiving infusions in other countries from donated cord blood may have significant risk and certainly present substantial financial strain for the families of those being treated.

We strongly endorse an organized scientifically rigorous initiative focused on rapidly identifying the most effective methods for using stem cell treatments to help repair the damaged brains of children and adults with developmental brain conditions.

There have been many research studies that have tried to answer this question.A variety of treatments have been studied, including orthopedic surgery (tendon transfer, muscle lengthening, etc.), spasticity control (rhizotomy, BTX, or phenol blocks, etc.), orthotic prescription (some type of ankle–foot orthosis, etc), and others (e.g. serial casting, muscle strengthening exercise, biofeedback, etc).

When clinicians are considering potential treatments for an individual, they are often faced with a multitude of previous research studies. There might be conflicting results among the many studies, often making it difficult to draw some conclusion as to whether a particular treatment is effective. One of the techniques that is sometimes used in an attempt to evaluate a large number of research studies is called “meta-analysis.” Meta-analysis is a statistical technique for combining the results of many studies. By combining the results of many studies, a meta-analysis can often produce a more accurate estimate of the efficacy of a treatment than is possible with a single study. Such an estimate may be more broadly generalized to the larger population than just one estimate from a single study.

Performing a meta-analysis can also sometimes give a rough estimate of the overall quality of research that has been performed.

Researchers almost always publish the results of their studies in professional scientific, medical, and engineering journals. The largest freely available database of the articles in these journals is maintained by the National Library of Medicine (it is referred to as Medline or PubMed). Each article in this database is assigned some appropriate indexing terms, called Medical Subject Headings. In Medline, there are over 11,000 articles under the Medical Subject Heading “Cerebral Palsy,” and over 12,000 articles under the Medical Subject Heading “Gait” and its various subheadings (Gait is a term used interchangeably with walking). At the time we did our meta-analysis, there were approximately 650 citations that have both “Cerebral Palsy” and “Gait” as Medical Subject Headings. We reviewed the abstracts of all of these 650 articles, and found that the speed of walking was the most frequently measured quantity to describe how well individuals walked. It is generally assumed among most researchers and clinicians that any treatment that increases walking speed means that the treatment improved walking.

One of the problems in conducting a meta-analysis is that researchers often measure things in different ways. This is true of studies of human walking. Walking has been described using measures of speed, stride length, number of steps per unit of time or distance, the angles of the segments of the leg and foot, the forces between the feet and the ground, and the activities of muscles in the leg, among others. However, how fast someone walks seems to be the most common measure among the studies we reviewed.

On the basis of our literature review, we decided to conduct our meta-analysis by asking the question “Do treatments intended to improve walking in CP result in an increase in walking speed?”

There were 41 of these 650 articles that reported the effect of a treatment on gait velocity. Of these 41 articles, many reported more than one intervention, so the total number of studies in our meta-analysis was 63.

We chose to do the type of meta-analysis that based on a quantity called the “effect size.” In our meta-analysis, effect size was a measurement of how much the speed of walking changed as a result of the treatment. An effect size of zero means that the treatment had no effect. The larger the effects size, the better the treatment worked. Effect sizes of 0.2 are considered small (but still significant) effects, while effect sizes of 0.8 are considered large effects. The effect size is sometimes negative, which means the treatment actually made things worse.

The majority of the 63 studies were small sample prospective studies using samples of convenience. The number of studies in the four categories of treatments were orthopedic surgery (17), spasticity control (15), orthotic prescription (26), and other (5). The number of people participating in a particular study ranged from four to 115. The elapsed time between the pre-treatment and post-treatment testing varied between hours and years. Statistical tests (if used) included parametric tests, most commonly t-tests and analysis of variance (ANOVA). All studies appeared to include participants of both sexes, typically combining results for both sexes; a few studies did not explicitly report gender. Results for participants of different ages were also combined, although some studies differentiated between two age groups. Patients with hemiplegia and diplegia were also analyzed together in most studies, although some studies used only patients with diplegia. No study appeared to differentiate participants by ethnic background. Most studies did not explicitly specify whether patients were receiving other interventions concurrently.

This meta-analysis showed that taken as a whole, treatments intended to improve walking in individuals with CP do have a statistically significant effect on walking speed. The overall effect size for all 63 studies was 0.17, which would be considered small. There were differences in effect size between the different types of interventions. However, we do not believe our meta-analysis results are sufficient to warrant clinical recommendations regarding efficacy of various treatment modalities. This is because we believe additional research is needed.

This meta-analysis led us to suggest some important considerations for future research in this field that are addressed primarily to researchers. There were six recommendations.

(1) Studies trying to determine if interventions actually result in improved walking need to be sufficiently powered to detect improvements. Larger sample sizes are needed, and this suggests researchers need to cooperate in multicenter studies to increase sample size (“power” in a statistical sense means that if an improvement has been made, the study will be able to detect the improvement). Of the 63 studies in our meta-analysis, few were adequately powered.

(2) When quantitative data about walking are reported by researchers, both raw and scaled/normalized data need to be reported to allow for easier comparison and use in future meta-analyses that will be undertaken. We had to exclude 14 studies from our meta-analysis because only normalized data were reported.

(3) In addition to describing the treatment that is being studied to improve walking, researchers need to describe any other interventions which their research subjects might also have received or be receiving which might influence their walking ability.

(4) Future studies are needed to determine if some treatments might be more effective in different subgroups (such as hemiplegia versus diplegia) or different age groups.

(5) Future studies are also needed to determine if there is an optimum time or age at which to provide the treatment, and the time it takes for the treatment to become effective.

(6) Finally, studies need to be performed to determine what level of improvement in the various measures of walking constitute improvements that are not only reported by the patient, but also recognized as clinically meaningful rather than just statistically significant results. While the major focus in this meta-analysis was speed of walking, we realize that there are other measures that may also need to be considered.

In conclusion, our meta-analysis shows that treatments to improve walking ability in CP do work – overall, they do increase the speed of walking. Future research in this field needs to attend primarily to concerns regarding sample size, statistical power, and subject inclusion criteria.

Note: This fact sheet is based on an article “Evaluating interventions to improve gait in cerebral palsy: a meta-analysis of spatiotemporal measures” by Paul, et. al, which appeared in Developmental Medicine & Child Neurology 2007, 49: 542–549.

Studying and Restoring Neurological Function in Children and Adults with Developmental Disabilities using Robotics, Virtual Reality, Neuro-imaging and other Technologies to Establish Best Care Practices

Cerebral Palsy (CP) is by definition damage to the brain before the age of two years resulting in some degree of impaired movement. The degree of impairment can be as minor as a limp or so severe it causes the person to be unable to move or communicate. Some with CP have completely normal intellect and psychosocial development, and some have severe intellectual impairment, features of autism and numerous other “brain related signs and symptoms”. Recent discoveries suggest that intensive intervention and access to appropriate technologies can change the outcomes for those with CP and other developmental disorders. Translational research is needed to ascertain whether such interventions can indeed make a substantial difference in physical and cognitive abnormalities commonly seen not only in CP but in other developmental disorders, such as autism.

CPIRF recently sponsored a workshop with the Rehabilitation Institute of Chicago to explore new ways in which 21st Century Technologies can be combined with new developments in neuro-imaging and new concepts in brain plasticity. By sharing knowledge across disciplines and studying ways to use these technologies to provide appropriate and focused therapy, we can change the future for hundreds of thousands of people disabled by motor impairments caused by brain injury sustained early in childhood.

Typical therapy for children with CP uses purposeful activity and task-specific training to improve motor function and independence. (1, 2). Motor learning approaches combining repetition and practice in functional context are commonly used in physical therapy. No one form of intervention, to date, has proven more effective than others in improving motor abilities in the paretic arm. (3). Diane Damiano has emphasized that massed practice, cognitive engagement, and functional relevance are common features of successful therapy for movement disorders related to CP (4). Many believe that it is necessary for therapists to provide a far more intense and meaningful therapy experience, than is generally possible in conventional therapy programs. Highly intensive approaches, such as constraint induced movement therapy (CIMT), have produced positive results in children with CP and upper limb impairments. (5)

There is now preliminary, but statistically meaningful data that robotic therapy can provide new opportunities for improving upper limb coordination and function in children with moderate to severe impairments due to cerebral palsy or stroke, and Dr. Krebs who has authored a number of these papers spoke on this topic. Combining elements of mass practice, robotics, virtual reality, patterned neuro-muscular stimulation, priming with transcranial magnetic stimulation and other advanced technologies, may well be the way to a future which revolutionizes the neurologic rehabilitation of children and adults with developmental disabilities.

1. Valvano J. (2004) Activity-focused motor interventions for children with
neurological disorders. Phys Occup Ther Pediatr 24:79-107.

2. Volman MJ, Wijnroks A, Vermeer A. (2002) Effect of task context on reaching performance in children with spastic hemiparesis. Clin Rehabil 16:684-692.

3. Law M, Russell D, Pollock N, Rosenbaum P, Walter S, King G. (1997). A
comparison of intensive neurodevelopmental therapy plus casting and a regular occupational therapy program for children with cerebral palsy. Dev Med Child
Neurol 39:664-670.

4. Damiano, D. (2006). Activity, activity, activity: Rethinking our physical therapy
approach to cerebral palsy. Physical Therapy, 86: 1534-1540.

5. Charles, J.R., Wolf, S.L., Schneider, J.A., & Gordon, A.M. (2006). Efficacy of a child-friendly form of constraint-induced movement therapy in hemiplegic cerebral palsy: a randomized control trial. Dev Med Child Neurol, 48: 635-642.

Muscle weakness, often seen in children with cerebral palsy, may be due to a variety of factors including: decreased central nervous system motor unit recruitment and discharge rates; increased antagonist coactivation during agonist contractions; or changes in muscle morphology, including atrophy. Until recently, clinicians would not advise muscle strength training in children with CP, due to the unsubstantiated belief that high effort voluntary contractions may promote increased muscle spasticity and tone. Recent studies have demonstrated that strength training in children with CP can improve gait speed, stride length, amount of knee flexion at foot strike and gross motor function. Furthermore, a systematic review of the literature concluded that strength training can improve muscle force production in children with CP without increasing spasticity.

Because children with CP are unable to fully activate their voluntary muscles as compared to typically developing children, the use of voluntary contractions for strength training may not produce sufficient force to induce muscle growth. Neuromuscular electrical stimulation (NMES), an alternative strength training technique, has been used successfully to treat adults with deficits in voluntary muscle activation. A recent study compared NMES to volitional strength training in a cohort of children aged 8 to 12 with spastic diplegic cerebral palsy to determine which group would experience greater gains in isometric force production, muscle cross sectional area (CSA) and walking speed after a 12 week program. Results indicated that NMES produced a significantly greater normalized force production for the both the quadriceps femoris and triceps surae muscles as well as a greater post training walking speed. The study also found that NMES produced greater changes in quadriceps CSA than the volitional group, but no significant difference was found between the two groups in the CSA of the triceps surae muscles.

These researchers are currently funded by NIH to conduct a randomized, controlled clinical trial comparing NMES to volitional strength training in a cohort of children with CP. Their specific aims are to compare the force generating, volitional activation, contractile and fatigue characteristics of leg muscles in typically developing children and children with CP; 2) to assess the ability of NMES strength training to increase leg muscle force-generating ability as compared to volitional strength training and a no-exercise control group in children with CP; 3) to assess the mechanisms underlying improvements in force-generating ability of the leg muscles after strength training in children with CP; and 4) to assess the ability of strength training to improve gross motor function and gait in children with CP. This work will help clinicians design rehabilitation strategies based on the physiologic differences in skeletal muscle and mechanisms for force production between children with CP and children of typical development. These researchers believe that there is great potential for NMES to be used in conjunction with volitional strength training and other motor learning therapies to help increase motor function in children with CP.

* Stackhouse SK, Binder-Macleod SA, Stackhouse CA, McCarthy JJ, Prosser LA, Lee SCK. Neuromuscular electrical stimulation versus volitional isometric strength training in children with spastic diplegic cerebral palsy: a preliminary study. Neurorehabil Neural Repair 2007;21:475-485.

Precise studies of the brain white matter tracts yield insight into structural and functional differences among children with cerebral palsy.

Cerebral palsy (CP) is the most common motor disability of childhood. Risk factors, causal pathways, clinical manifestations and response to treatments vary widely among children with this broad diagnosis. Conventional brain magnetic resonance imaging (MRI) provides pictures of white and gray brain matter injury in these children. Diffusion tensor imaging (DTI) is a novel technique that allows a more detailed observation of specific brain white matter tracts (WMT). In our research, we identified 26 white matter tracts and established criteria for evaluation of these tracts on a 3 point ordinal scale (normal, abnormal, severely abnormal-absent) in children born preterm with cerebral palsy. Our results indicate variable patterns of brain injury to central sensory and motor pathways in these children. Practical application of this advanced imaging and WMT grading classification within clinical and research situations will help us learn more about inter-individual differences among children with cerebral palsy. Our long-term goal is to use this information to improve the classification of cerebral palsy. We believe that improved diagnostic techniques will contribute to the development and assessment of effective rehabilitative therapies tailored to individual children.

*Nagae LM, Hoon Jr AH, Stashinko E, Lin D, Zhang W, Levey E, Wakana S, Jiang H, Leite CC, Lucato LT, van Zijl PCM., Johnston MV, and Mori S. (2007).American Journal Neuroradiology, 28: 1213-1222.

This work was supported by the United Cerebral Palsy Research and Educational Foundation, the National Institute of Health (NIH) grant R01 AG20012, P41 R15241, the Dana Foundation Clinical Hypothesis Program in Imaging, the National Center for Research Resources (NCRR), and the Johns Hopkins University School of Medicine General Clinical Research Center, Grant #M01-RR00052 from the NCRR/NIH.

By Mindy Aisen, MD

Last month Dr. Paolo Bonato of Spaulding Rehabilitation Hospital reported on his study of using robotic assisted body weight supported treadmill training (BWSTT) to improve walking ability in children with CP. I want to expand on this topic by reporting on the recently published results of three different groups of investigators who are also evaluating the effectiveness of this treatment modality in CP kids. In addition, I want to discuss the use of neuromuscular stimulation used in combination with BWSTT as a potential rehabilitation technique for impaired gait, and finally, I want to re-emphasize the great need for more rigorous, well-controlled clinical trials to provide definitive scientific evidence for the widespread use of this promising intervention for the improvement of gait and ambulatory skills in children with CP.

As Dr. Bonato previously stated, there is growing evidence that the human central nervous system is capable of significant recovery after insult or injury when prescribed an effective treatment modality at the proper dose. In particular, the use of task-specific training such as BWSTT, has shown great promise in helping stroke and motor incomplete spinal cord injured patients regain some walking ability. In addition, BWSTT has shown promise in helping to correct the gait and improve functional ambulation in children with CP. In a non-randomized study of 10 children with CP, some of who were non ambulatory, Schindl et al reported significant improvement in functional ambulation of all 10 children after 3 months of BWSTT ¹. In 2004, Day et al reported a case study in which a 9 year old child with spastic tetraplegic CP who could not support his own weight and had never experienced walking began to walk short distances with a rolling walker after 44 sessions of locomotor training that included BWSTT ².

More recently, Provost et al reported improvement in four out of six ambulatory children with CP after only 2 weeks of BWSTT in twice daily therapy sessions lasting 30 minutes each ³. Four of these children showed improvement in endurance and a functional gait measure. Begnoche et al combined intensive physical therapy with BWSTT in a study of 5 children with spastic CP. The training sessions consisted of 4 weeks of training, three to four sessions per week for 2 hours each. All five children showed significant improvements in motor and ambulatory skills ⁴. Finally, Dodd and Foley conducted a small, controlled clinical trial of 14 children who were matched according to type of CP (spastic, athetoid), age, sex and gross motor functional classification system level. The experimental group underwent BWSTT twice a week for 6 weeks in a school-based program. The experimental group showed significant improvements over the control group in walking speed and a trend towards increased endurance over the range of moderate to severe disability ⁵.

CP may lead to profound muscle weakness in the affected extremities. Stackhouse et al demonstrated that children with CP have large deficits in voluntary muscle activation as compared to a group of age-matched unaffected children ⁶. This inability to produce sufficient force using voluntary contractions may not induce muscle growth during training exercises prescribed for CP kids. Recently, this same group conducted a study using neuromuscular electrical stimulation (NMES) in conjunction with a 12 week isometric strength training program in a group of children with spastic diplegic CP ⁷. The control group participated in the strength training program without the NMES. The investigators found that the NMES group had greater normalized force production for the quadriceps (muscle strength) and greater walking speed post training than did the control group. While to date, NMES in conjunction with BWSTT has not been reported in CP children, it has been shown to be more effective in restoring gait in stroke patients than BWSTT alone ⁸. NMES may enhance the benefits of BWSTT already demonstrated in CP children by recruiting and strengthening muscles that are needed to complete normal gait cycles.

There is limited scientific evidence that supports the use of BWSTT, NMES and many other treatment modalities to improve strength, endurance and functional mobility in children with CP. Unfortunately, none of these modalities have been clearly established as effective in scientifically rigorous, well-controlled clinical trials. Until there is well-established evidence for the use of these interventions they will never come into widespread use for the treatment of gait abnormalities in children with CP because of third-party reimbursement issues. I urge investigators interested in the neurorehabilitation of CP to begin to collaborate on issues of dose, frequency of therapy and different combinations of treatment modalities so that the much needed large clinical trials can begin to take place. Without these studies, treatment advances that are taking place in the treatment of stroke, spinal cord injury and other nervous system disorders will not be realized in the treatment of CP.

       1. Schindl MR. Forstner, C, Kern H, and Hesse S. Treadmill training with partial body weight support in nonambulatory patients with cerebral palsy. Arch Phys Med Rehabil. 2000:81(3) 301-6

       2. Day JA, Fox EJ, Lowe J, Swales HB and Behrman AL. Locomotor training with Partial Body Weight Support on a Treadmill in a non-ambulatory Child with Spastic Tetraplegia Cerebral Palsy: A Case Report. Pediatr Phys Ther 2004: 16(2):106-113.

       3. Provost B, Dieruf K, Burtner PA, Phillips JP, Bernitsky-Beddingfield A, Sullivan KJ, Bowen CA, Toser L. Endurance and gait in children with cerebral palsy after intensive body weight-supported treadmill training. Pediatr. Phys Ther 2007: 19(1)2-10.

       4. Begnoche DM and Pitetti KH. Effects of traditional treatment and partial body weight treadmill training on the motor skills of children with spastic cerebral palsy. A pilot study. Pediatr Phys Ther. 2007 19(1): 11-19.

       5. Dodd KJ and Foley S. Partial body-weight supported treadmill training can improve walking in children with cerebral palsy: a clinical controlled trial. Dev Med Child Neurol. 2007 49(2):101-105.

       6. Stackhouse SK, Binder-Macleod SA, and Lee SC. Voluntary muscle activation, contractile properties and fatigability in children with and without cerebral palsy. Muscle Nerve 2005 31(5):594-601.

       7. Stackhouse SK, Binder-Macleod SA, Stackhouse CA, McCarthy JJ, Prosser LA and Lee SC. Neuromuscular Electrical Stimulation versus Volitional Isometric Strength Training in Children with Spastic Diplegic Cerebral Palsy: A Preliminary Study. Neurorehabil Neural Repair. 2007. Mar 16

       8. Daly JJ, Roenigk KL, Rogers JM, Butler K, Gansen J, McCabe J, Fredrickson E, Holcomb J, Ruff RL: A Randomized Controlled Trial of FNS in Chronic Stroke Subjects. Stroke 2006, 37:172-178.

By Paolo Bonato, PhD

A decrease in walking proficiency and economy is a major cause of physical disability in children with CP. High lower limb agonist-antagonist muscle coactivations, increased tone, tightness of Achilles tendon, and knee and hip musculature cause abnormal gait and high energy expenditure while walking. As a result, a high precentage of children with CP have a gait that is characterized by slow speed and disturbed motor control.

Training interventions to improve gait outcomes in CP usually include strength training, balance control and weight bearing activities. Recent studies have demonstrated beneficial effects of intensive task-specific gait training on motor recovery in children with CP 1-2 as well as adults with paraparesis and hemiparesis.

Recent developments in the neuro-rehabilitation field have been stimulated by information on neuronal recovery processes and their modulation by various physical and pharmacological interventions. There is a growing body of evidence demonstrating that the human brain is capable of significant recovery providing that the amount and frequency of treatments are applied appropriately. In addition to quantity, the quality of the intervention is equally important with task specific interventions enhancing neural reorganization and behavioral recovery.3-5

Task oriented rehabilitative gait techniques include Body Weight Supported Treadmill Training (BWSTT). BWSTT enables severely affected individuals to follow principles of motor learning and to train while walking. Treadmill training has been often cited as task-specific training because it allows for complete gait cycles with multiple repetitions facilitated by the treadmill’s consistent rate of movement. Several studies have shown the potential of this technique in patients after stroke, spinal cord injuries and children with CP.1,2,6

Despite the potential benefits of BWSTT, its application in the clinical setting is physically demanding and limited by personnel time and labor requirements. At least two therapists are involved in a gait training session. They manually guide the lower extremities of the patient to facilitate movement of the limbs during ambulation. Often a third individual is involved to stabilize the pelvis. Recently, robotic devices referred to as driven gait orthoses (DGOs) have been developed to assist in the delivery of BWSTT. A DGO is a computer-controlled exoskeleton that is secured to a person’s legs while he/she is supported over a motorized treadmill using an unloading system. A DGO replaces the manual assistance provided by therapists with guided lower extremity trajectories that are consistent with physiological gait patterns.

Led by Paolo Bonato, PhD and Donna Nimec, MD and supported by UCP Research and Educational Foundation, a group of researchers at Spaulding Rehabilitation Hospital in Boston MA (which is home to the Harvard Medical School Department of Physical Medicine and Rehabilitation) is conducting a study on the use of a DGO (Lokomat, Hocoma AG, Switzerland) to enhance gait retraining in children with CP. The robotic components of the device drive the knee and hip joints, which enables movement through symmetric, coordinated trajectories that mimic physiological walking patterns. Although studies with this robotic-assisted BWSTT have been performed and are underway in the adult spinal cord injured and post-stroke populations, to date there is no published literature on the use a DGO in the pediatric population. Therefore, there is a great deal of excitement about this ongoing study in children with CP at Harvard Medical School.

The research team (including Anat Mirelman, PT and Ben Patritti, PhD, who are responsible for carrying out the training and evaluation sessions) anticipates that the use of a DGO will maximize locomotor function in children with CP by increasing the duration, intensity and specificity of training while overcoming the limitations of the labor intensive interventions provided by therapists during traditional BWSTT. The research is a pilot study to investigate the suitability of the DGO for training children with CP, and to develop protocols that will allow clinicians to achieve in children with CP the encouraging results already attained in other adult patient populations.

Schindl MR, Forstner C, Kern H, Hesse S. (2000) Treadmill training with partial body weight support in nonambulatory patients with cerebral palsy. Arch Phys Med Rehabil 81:301-306

Maltais D, Bar-Or O, Pierrynowski M, Galea V. (2003) Repeated treadmill walks affect physiologic responses in children with cerebral palsy. Med Sci Sports Exerc. 35(10):1653-1661

Nudo RJ, Wise BM, SiFuentes F, Milliken GW. (1996) Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 272:1791-1794

Liepert J, Bauder H, Miltner WHR, Taub E, Weiller C. (2000) Treatment- induced cortical reorganization after stroke in humans. Stroke. 31:1210-1216

Barbeau H. (2003) Locomotor training in neurorehabilitation: emerging rehabilitation concepts. Neurorehabilitation & Neural Repair 17(1):3-11
McNevin NH, Coraci L, Schafer J. (2000) Gait in adolescent cerebral palsy: the effect of partial unweighting. Arch Phys Med Rehabil 81:525-528

Increasing attention is being given to intensive functional training as a means of increasing motor function in the disabled. One form of intensive training is constraint-induced movement therapy (CIMT), which aims to increase the amount and quality of upper extremity movement in children with hemiplegic cerebral palsy (CP). A number of studies have suggested that CIMT is beneficial for many individuals with CP (see CIMT fact sheet, March 2007). However, CIMT has a number of limitations, including the fact that it is potentially invasive, and it focuses exclusively on one hand impairments, which does not greatly impact functional independence and quality of life. Given recent work showing impaired coordination of both hands, a better goal of upper extremity rehabilitation would be to increase functional independence and quality of life by improving use of both hands in cooperation.

Bilateral (or bimanual training) is a new class of interventions aimed at increasing the efficiency of movement in the context of using both hands together. The brain and spinal cord underlying human dexterity are capable of considerable reorganization after damage, likely responsible for recovery of function. Pathways on the same (ipsilateral) side of the impaired upper extremity have been implicated in the control of the affected hand in CP as well as the recovery of function after stroke in adults. Thus, task recruitment of these ipsilateral pathways, such as symmetrical bilateral movements, may be beneficial. Bilateral practice may result in changes in cortical representations and excitability in the undamaged hemisphere. This reasoning has provided the basis for bilateral training protocols in adults with stroke (e.g., 1). The efficacy of bilateral training in the stroke population is not clear, although several studies report positive outcomes. However, it should be noted that most of these training protocols involve non-functional, repetitive symmetrical movements (e.g., upper extremity cycling). Such tasks are unlikely to sustain interest for sufficient periods of time in children. Thus, protocols need to be created that are child friendly.

To date, there is limited work on bilateral training in the pediatric population. One protocol, Hand-Arm Bimanual Intensive Training (HABIT) has recently been developed and tested with support from the United Cerebral Palsy Research and Education Foundation (2). HABIT takes advantage of the key element of CIMT, intensive practice, but does not involve restraint of the less affected upper extremity. Instead, it utilizes structured (part and whole) task practice embedded in bimanual play and functional activities. Task difficulty is increased by progressing the more affected hand from a passive stabilizer to an active manipulator. HABIT is performed in a day-camp setting and is based on understanding of the mechanisms of underlying hand impairments in CP, recognized benefit of treatment intensity, principles of motor learning and neuroplasticity using prototypical behaviors, goal orientation, knowledge of results, motivation and rewards.

In a small randomized trial, researchers at Teachers College, Columbia University have presented the results of a preliminary study of HABIT (3). A single-blinded randomized control study was performed to examine its efficacy in 20 children (3.5-15.5 yrs). Children were engaged in play and functional activities that provided structured bimanual practice six-hours per day for 10 days. Children who received HABIT demonstrated improved scores on the Assisting Hand Assessment and bimanual items of the Bruininks-Oseretsky Test of Motor Proficiency, increased involved extremity use measured using accelerometry and a caregiver survey, and better coordination completing a draw-opening task with two hands measured kinematically. Thus, the results from this report were encouraging.

Comment:

Bimanual training is based on sound scientific principles, and in theory, should address some of the limitations of CIMT. Despite its promise, a more complete understanding of the neurological basis of hemiplegia and mechanisms of recovery are needed to fine-tune such protocols. Larger studies across a more diverse subject population with long-term follow-up are required. The appropriate age and impairment levels need to be identified and factors such as side and location of brain damage, attention span, optimal dosage and identification of key ingredients need to be considered to ultimately define the most efficacious rehabilitation strategy. Finally, the extent to which it may compliment CIMT will be of interest.

(1) Cauraugh JH, Summers JJ (2005) Neural plasticity and bilateral movements: A rehabilitation approach for chronic stroke. Prog Neurobiol:75:309-320

(2) Charles J, Gordon AM (2006) Development of Hand-Arm Bimanual Intensive Therapy (HABIT) for Improving Bimanual Coordination in Children with Hemiplegic Cerebral Palsy.

Dev Med Child Neurol 48:931-936.

(3) Charles J, Gordon AM (2006) Efficacy of Hand-Arm Intensive Bimanual Training (HABIT) on upper extremity movement in children with hemiplegic cerebral palsy. Dev Med Child Neurol 48: 24 (Supplement No. 106)

Constraint-induced movement therapy (CIMT) is a physical rehabilitation technique that has been receiving increasing attention in the pediatric rehabilitation community. CIMT was developed based on animal models of sensory deprivation from 1960’s and 70’s. The adaptation of the general procedures (using a restraint to encourage contralateral limb use) to humans initially occurred in adults with hemiparetic stroke, where the majority of published research reports have been focused to date. These initial studies, conducted in the 1980’s, involved “forced use,” or encouraging use of the involved extremity by restraining the non-involved extremity alone or along with conventional physical/occupational therapy. Subsequently, CIMT was conceptualized, which involves intensive targeted practice with the involved extremity along with the restraint (typically 2-3 weeks in duration). Thus, CIMT is an active, task-driven, treatment administered by a trained practitioner, combining principles from the fields of behavioral psychology and motor learning. The results of a recent, randomized, multi-site trial of CIMT indicate CIMT produced clinically relevant improvement in involved upper extremity function in stroke patients (1).

Despite the success of CIMT in adults with stroke to date, there is considerably less evidence of its efficacy in children with hemiplegia. Until recently much of the evidence has been in the form of case studies or small ABA design studies. In the last several years, however, there have been a number of small randomized control trials of CI therapy in children (2). All of these studies to date have suggested efficacy in improving quality and quantity of affected limb use in children with hemiplegia. The research to date has focused on a variety of age groups spanning from ~ nine months to adolescence. Theoretically, the increased plasticity in the developing brain would suggest that efficacy would be greater the earlier CIMT is administered. However, the evidence to date does not support this notion, as efficacy has been shown across all ages. One study even suggests increasing efficacy up until the age of ~4-5 years is likely due to increasing ability of children to stay on task as they mature (and thus increase intensity of treatment) (3). Furthermore, recent evidence suggests that efficacy may be related to severity of hand impairments, with very mild or severe impairments may not be amenable to treatment (4).

Comment:

While the evidence to date is promising, considerably more work is required, including large-scale, multi-site randomized control trials. Most of the studies to date have used differing outcome measures, the types of practice and restraints (e.g., casts, slings, mitts) and varying treatment durations. Since it is not the restraint that induces change, rather it is the environment that is used to solicit intensive practice, there is no evidence supporting the use of more invasive devices such as bi-valved casts. Furthermore, studies of spinal cord tract development in the kitten indicate that restriction of limb use at an early “critical” age may even permanently damage development (5). In light of recent studies suggesting efficacy with modest restraint (using a mitt) for just two hours per day in very young children, long-periods of restraint should not be used until these risks in young children have been determined. Dosing effects need to be determined as well. Both modified (i.e., reduced) schedules and more passive “forced use” paradigms have been shown to be effective in younger children, but the extent to which more intensive and active treatment is required with increasing age is unknown. Furthermore, restraining the unaffected limb without structuring the environment and providing tasks graded to provide success likely leads to frustration as a child attempts to negotiate activities within their normal routine. Left unsupervised, there would be increased risk of injury in the event of loss of balance since the child’s normal protective response would be inhibited.

CIMT should complement, rather than replace, other treatments throughout the child’s long-term pediatric care since it only occurs during a short period. Recent evidence suggests that repeating it may result in cumulative improvements. CIMT was developed to overcome learned non-use in adults with hemiplegia while children with hemiplegia may have never effectively learned to use their involved extremity. Thus CIMT must be modified to be developmentally focused (6). Trained therapists need to understand the concept of CIMT before starting treatment and have theoretical and practical knowledge of motor-learning principles of skill acquisition and motor development, as well as a pedagogical framework regarding how to teach children to learn. One key issue is to start with the end goal in mind. CIMT is a unimanual intervention, and increased functional independence in the child’s environment requires use of both hands in cooperation. Principles of motor learning would suggest that this might be best accomplished by skipping the restraint and practicing bimanual skills directly. The efficacy of such bimanual training remains a promising area for future exploration.

Wolf S, Winstein C, Miller J, Taub E, Uswatte G, Morris D, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke” The EXCITE Randomized Clinical Trial. JAMA 2006;296:2095-2104.

Charles J, Gordon AM. A critical review of constraint-induced movement therapy and forced-use in children with hemiplegia. Neural Plasticity 2005;12:245-262.

Eliasson AC, Krumlinde-sundholm L, Shaw K, Wang C. Effects of constraint-induced movement therapy in young children with hemiplegic cerebral palsy: an adapted model. Dev Med Child Neurol 2005;47(4):266-75.Charles et al. 2006

Charles JR, Wolf SL, Schneider JA, Gordon AM. Efficacy of a child-friendly form of constraint-induced movement therapy in hemiplegic cerebral palsy: a randomized control trial. Dev Med Child Neurol 2006;48(8):635-42.

Friel KM, Martin JH. Role of sensory-motor cortex activity in postnatal development of corticospinal axon terminals in the cat. J Comp Neurol. 2005 Apr 25;485(1):43-56.

Gordon AM, Charles J, Wolf SL. Methods of constraint-induced movement therapy for children with hemiplegic cerebral palsy: development of a child-friendly intervention for improving upper-extremity function. Arch Phys Med Rehabil 2005;86(4):837-44.