Most treatments for cerebral palsy (CP) are initially directed toward children. What is not clearly established is the long- term effects of such treatments. Many appear helpful in the short term but prove to be disadvantageous in the long run. Selective dorsal rhizotomy (SDR) is a permanent, irreversible neurosurgical procedure for reducing spasticity in cerebral palsy.  Parents contemplating SDR for their child would like assurance that that there will not be harmful complications from it as the child ages into adolescence and adulthood. We now have new evidence to address this concern.

SDR was first described in the medical literature more than 100 years ago but was largely forgotten until the 1960’s when it was modified and popularized, first in France, Italy, and South Africa, then subsequently in North America.

Normally, when a muscle is stretched, sensors in that muscle detect this change and inform a pool of nerve cells in the spinal cord via sensory nerve fibers. An immediate reflexive response is sent back to the muscle causing it to contract. This is a safety mechanism to prevent overstretching of the muscle, much like the rapid withdrawing of a hand when a hot stove is touched. The brain dampens this reflex so that the muscles are not overly sensitive to changes in movement. However, in the spastic type of cerebral palsy, the inhibitory input from the brain to the spinal cord is reduced resulting in high muscle tone and muscles that are overly reactive to stretch and movement. This leads to difficulties with walking, reaching, and self-care as well as joint contractures.  SDR interrupts the excessive flow of nerve impulses to the muscles that causes stiffness and over-reaction to stimulation and position changes.

In SDR, the neurosurgeon gains access to the sensory fibers going into the dorsal (back) side of the spinal column. About 50-70% of the nerve roots are cut, often guided by response of certain nerve roots to electrical stimulation. By cutting these nerve roots, the amount of sensory stimulation coming from the muscles into the spinal cord is reduced, thereby reducing the degree of reactive muscle contraction and, therefore, spasticity.

There is marked variability with SDR across surgical centers and among neurosurgeons in patient selection, operative procedures, complications, and in immediate and long term follow-up care. While most agree that the best candidates for SDR are individuals with spastic diplegia (predominantly high tone in the lower extremities), some surgeons have expanded the procedure to include those with quadriplegia (high tone in upper as well as lower extremities). Individuals with the dystonic type of CP (sustained muscle contractions with twisting and repetitive movements) are not candidates for SDR.

Determination of which and how many nerve roots to cut, how to gain access to the nerve roots and at what spinal cord levels, can vary markedly from medical center to medical center. These decisions can affect the type and degree of post-operative discomfort and complications that occur. Some patients go home very quickly after the procedure; others remain hospitalized for several weeks. Weeks of recuperative physical therapy are required to overcome weakness and to regain (and hopefully attain new) mobility capabilities.

Studies of SDR, though limited because of the variability of surgical techniques and outcome measures, have generally been positive. The procedure clearly reduces spasticity and improves range of movement in the lower extremities. For most individuals, there is better sitting and walking ability, improvements in self-care and performance of activities of daily living, some improvement in upper limb use, and sometimes a reduced need for orthopedic surgery.

Fortunately, serious complications from SDR have been rare. Because the operation requires disruption of sections of the spinal column, there appears to be a possible increased risk of spinal deformity (such as scoliosis or twisting of the spine) resulting from SDR in a population already at high risk for this problem, especially among those with spastic quadriplegia.

Dr. Hurwitz at the University of Michigan evaluated medical outcomes, interventions, satisfaction with life and subjective impressions about SDR in older adolescents and adults who underwent the procedure as children. He found that the majority of adults would recommend SDR to others. Very few reported negative impressions of the procedure. Levels of satisfaction with life were generally high. However, despite the SDR, additional surgical and nonsurgical interventions were necessary in the majority of patients.

Although SDR has typically been performed on children with CP, there is some experience with the procedure in adults. Dr. Matthew Reynolds at the St. Louis Children’s Hospital published a report on adults with spastic diplegia. In a short term follow-up, patients reported less spasticity and improved ambulatory ability, coordination, joint range of motion, and independence.

The following are recommendations for those considering SDR for their child with spastic CP or for themselves.

• Once SDR is mentioned as a possible option for yourself or your child, prepare for a discussion of SDR by reading about its rationale, selection process, operative procedures, complications, and outcomes from outside sources so that you are ready to ask detailed questions about a particular center’s methods.
• Consider a center with an experienced, interdisciplinary diagnostic and management team that might include: neurosurgeon, orthopedic surgeon, physical and occupational therapists, orthotist, developmental pediatrician, pediatric neurologist, and physiatrist.
• Ask about details of the procedure at this center and how they might differ from other centers, expected post-operative course, length of hospitalization, and type and extent of physical and occupational therapies, cost and insurance coverage.
• Ask whether and why you or your child fit the candidate criteria for SDR.
• Ask about other treatment options and why SDR is indicated at this time. What are the expected outcomes specifically for you or your child? Take time to consider alternative options.

Sources

1. Hurvitz EA, Marciniak CM, Daunter AK, et al. Functional outcomes of childhood dorsal rhizotomy in adults and adolescents with cerebral palsy. J Neurosurg Pediatr. Published online February 8. 2013.
2. McLaughlin J, Bjornson K, Temkin N. Selective dorsal rhizotomy: Meta-analysis of three randomized controlled trials. Dev Med Child Neurol 2002;44:17-25.
3. Nordmark E, Josenby AL, Lagergren J, et al. Long-term outcomes five years after selective dorsal rhizotomy. BMC Pediatr 2008;8:54-69.
4. Reynolds MR, Ray WZ, Strom RG. Clinical outcomes after selective dorsal rhizotomy in an adult population. World Neurosurg 2011;75(1):138-144.
5. Steinbok, P. Selective dorsal rhizotomy for spastic cerebral palsy: A review. Childs Nerv Syst 2007;23:981-990.
6. Tedroff K, Lowing K, Jacobson DNO, et al. Does loss of spasticity matter? A 10-year follow-up after selective dorsal rhizotomy in cerebral palsy. Dev Med Child Neurol 2011;53:724-729.

Each stage of human development is characterized by a unique set of behaviors and emotional challenges: the terrible twos and temper tantrums, adolescence and rebellion, middle age and discontentment, the later years and loneliness. When these “normal” stages of development are coupled with individual temperamental differences and the occasional but inevitable environmental stressors, a range of dysfunctional responses – transient or chronic, inconsequential or debilitating – may result. This is baseline for everyone.

A motor impairment such as cerebral palsy — alone or in combination with associated intellectual, sensory, or other health impairments — may exacerbate life’s stressors and the challenges they pose to a person’s mental well-being. Early recognition and appropriate intervention may prevent or mitigate the possibility of a transient or inconsequential behavioral or emotional problem turning into something chronic and debilitating. Health professionals need to be attuned to the fact that for patients with disabilities — as for all of their patients — discussing/determining existing barriers to psychological well-being is a crucial component of a health examination.

Some time ago, as part of my clinical research as a developmental pediatrician, I surveyed parents of infants and toddlers with developmental disabilities, including cerebral palsy, to determine the frequency and level of parental concern about common behavioral problems (such as sleep difficulties, temper tantrums, and excessive crying). Parents of children with disabilities reported a larger number of problems during the first year of life, that the problems persisted longer, and that the parents were more concerned about these occurrences than were parents of very young children without disabilities. (1)

From infancy onward, aspects of the mental well-being picture for some people with cerebral palsy is significant. Recently, a researcher in Iceland studied the behavioral and emotional symptoms of preschool children with cerebral palsy. She found elevated rates of problems with attention, withdrawal, aggressiveness, anxiety, and depression compared to a group of similar-aged children who did not have cerebral palsy. (2)

In a cross-sectional study of school-aged children with cerebral palsy in several European countries Parkes and colleagues found a significant proportion of the children displayed psychological symptoms or social impairments severe enough to warrant referral to specialist mental health services. (3)

In a Canadian national study conducted by Stevens and others, adolescents (aged 11-16) with physical disabilities were compared to their non-physically-disabled peers on a set of life-satisfaction criteria. The teens with disabilities reported good self-esteem, strong family relationships, and as many close friends as the other adolescents in the national sample. However, study results indicated that adolescents with physical disabilities participated in fewer social activities and had fewer close relationships with their friends, but that they had more positive attitudes toward school, teachers, and their fellow classmates. (4)

The transition to adulthood is challenging for all adolescents. Navigating transitions to independent living, post-secondary education or training, employment, and the acquisition of social relationships beyond the school setting are inherently stressful. Restricted gross motor functioning that may limit daily activities and social participation can impose additional challenges for young adults with cerebral palsy. (5)

In middle schoolers and adolescents, one of the biggest threats to self-esteem and happiness is “bullying.” Michael Kutcher, twin brother of actor Ashton, recently received a prestigious award from the American Academy for Cerebral Palsy and Developmental Medicine in recognition for his advocacy (on Capitol Hill) for more funding for cerebral palsy research. In his acceptance speech, Michael spoke about growing up with cerebral palsy. He identified bullying (mostly verbal) as a major unpleasantness in his life as an adolescent. Fortunately, his brother often came to his rescue — many children are not so fortunate. School personnel and parents may not be aware of this common but often subtle agony. Bullying is, by no means, limited to the physically disabled, but it does occur regularly and can cause great anguish. It is a factor that should be assessed as part of a health examination for all in this age group.

In a review of the health and well-being research literature concerning adults with cerebral palsy, Dr. Gregory Liptak reported that they have a lower rate of participation than the overall population in areas such as social interactions, employment, marriage, and independent living. (6) He stated that this may result in high levels of loneliness and resultant depression. Very few studies have identified interventions that will help physically disabled adults achieve optimal health and well-being, although perhaps several are self-evident: maintaining mobility, community access, and adult support services. More studies concerning physically disabled adults and mental well-being are needed.

Finally, apart from the challenges to sound mental health among individuals with cerebral palsy, there is an impact on family function as well. Parents of a child with cerebral palsy face a range of stressors depending on their child’s age, development, and functioning. At the time of initial diagnosis, parents typically grieve when confronted with the fact that their child is not developing normally and life will present ongoing struggles for them and their child. In the second phase, parents experience the desire to help their child function as normally as possible. They seek appropriate support services as the child’s needs change, including the transition from home to independent adult-living settings. (7) The trend towards family-focused, rather than simply technical or short-term rehabilitation and interventions focused only on the child, have improved outcomes and reduced family stress. (8)

At each stage of life for an individual with cerebral palsy (as for everyone) there are challenges to mental well-being. Awareness of these challenges and sensitivity to the signs of anxiety and depression, including: externalizing behaviors (e.g. aggressiveness, hyperactivity, non-compliance), and/or their opposite, internalizing behaviors (e.g. social withdrawal, passivity, fearfulness) provide opportunity for early intervention and remediation. Comprehensive care must include mental health surveillance and support in addition to traditional medical, physical, and educational care.

References
1. Blackman JA, Cobb LS. A comparison of parents’ perceptions of common behavior problems in developmentally at-risk and normal children. Children’s Health Care 1989;18(2):108-113.

2. Sigurdardottir S, Indredavik MS, Eiriksdottir A, et al. Behavioural and emotional symptoms of preschool children with cerebral palsy: A population study. Developmental Medicine and Child Neurology 2012;52:1056-1061.

3. Parkes J, White-Koning M, O Dickinson H, et al. Psychological problems in children with cerebral palsy: A cross-sectional European study. Journal of Child Psychology and Psychiatry 2008;49(4):405-413.

4. Stevens SE, Steele CA, Jutai JW, et al. Adolescents with physical disabilities: Some aspects of health. Journal of Adolescent Health 1996;19(2):157-164.

5. Donkervoort M, Roebroeck M, Wiegerink D, et al. Determinants of functioning of adolescents and young adults with cerebral palsy. Disability and Rehabilitation 2007;29(6):453-463.

6. Liptak GS. Health and well being of adults with cerebral palsy. Current Opinion in Neurology 2008;21:136-142.

7. Rentinck ICM, Ketelaar M, Jongmans MJ, et al. Parents of children with cerebral pasly: A review of factors related to the process of adaptation. Child: Care, Health and Development 2006;33(2):161-169.

8. Raina P, O’Donnell M, Rosenbaum P, et al. The health and well-being of caregivers of children with cerebral palsy. Pediatrics 2005;115(6):e626-e636.

Sensory integration dysfunction is characterized by difficulties in receiving, registering, modulating, interpreting, and acting on information that comes to the brain through various sensory receptors. Ever since Occupational Therapist and Developmental Psychologist Dr. Jean Ayres first described this condition in the 1960s, the diagnosis and treatments have been controversial.

Recently, the Council on Children with Disabilities of the American Academy of Pediatrics (AAP) released a statement entitled “Sensory integration therapies for children with developmental and behavioral disorders” (AAP, 2012).  The Council acknowledged that there is no universally- accepted framework for the diagnosis of sensory processing disorder and that evidence for the efficacy of sensory-based therapies is limited; but it advised that occupational therapy with the use of sensory-based therapies may be acceptable as one component of a comprehensive treatment plan.

The aim of any therapy, including sensory, is to enhance function and participation, either by remediating (i.e. curing) the underlying impairment or by accommodation and adaptation. Traditional sensory integration therapy, as developed by Ayres, provides a child with various sensory experiences through the use of big rolls and balls, trampolines, and suspended equipment that provide intense proprioceptive  (movement detection), vestibular (balance), and tactile (touch) experiences. These experiences are intended to remediate the child’s sensory processing ability and thus enable the child to better organize sensory input and respond appropriately.

There are differing opinions regarding the proven efficacy of sensory integration therapy, even within the Occupational Therapy field. In a thoughtful response to the AAP statement, Dr. Lucy Miller, Executive Director of the Sensory Processing Disorder Foundation, pointed out that the Council failed to cite significant research demonstrating the effectiveness of sensory processing disorder treatment (Miller, 2012).

In contrast, Nancy Pollock, an Occupational Therapist at the Canchild Centre for Childhood Disability Center at McMaster University in Hamilton, Ontario, says that, while there has been more effectiveness research conducted on sensory integration therapy than on any other intervention in the field of occupational therapy, to date the evidence of its effectiveness is weak at best (Pollock, 2009).

Most of the efficacy research on sensory treatments has been conducted on children with autism spectrum disorder, learning problems, attention deficit hyperactivity disorder, or isolated sensory processing problems. In contrast, there has been little research on children with cerebral palsy, probably because formal sensory processing disorder testing is difficult in individuals with motor impairments and it may be difficult to isolate central sensory processing problems from the complex motor, sensory, and cognitive issues that may be involved in cerebral palsy.

No experienced clinician doubts that there are children with developmental disabilities, including cerebral palsy, who have difficulty utilizing sensory information effectively. The challenge is to determine the best ways to address such difficulty.

Although the primary problem in cerebral palsy is motor, the condition is often accompanied by disturbances of sensation and perception as well.  In addition to input from the major senses of vision and balance mechanisms in the inner ear, a necessary element of successful motor function is sensory feedback from muscles and tendons. In order to coordinate purposeful movements, the brain needs to know which muscles are contracting and what position a limb is in at any given time. This is accomplished by sensory receptors and nerves that carry this information to the spinal cord and from there to the brain’s sensory cortex.

From the sensory cortex this information travels to various areas of the brain where it is integrated with other sensory information (e.g. visual and vestibular), with memory (What happened the last time the arm moved in this way?), and with intellect (What needs to be accomplished with this movement?).  Some motor responses to incoming sensory information from the skin, muscles, and tendons are instantaneous and occur without the brain’s involvement, such as pulling a finger away from a hot stove. Other motor responses need the brain’s input to modulate the response: that is, to continue, dampen, or correct an errant response.  Much of the brain research on cerebral palsy has focused on the motor function alone. With the use of advanced brain imaging techniques it has become clear that the sensory network in the brain can also be impaired (Hoon, 2002).

As noted above, the emphasis on sensory therapy has been on children with autism, attention and learning problems, or isolated sensory processing problems.  In these disorders, the primary sensory organs and their ascending sensory tracts to the brain (e.g. visual, vestibular, tactile, proprioceptive) are intact and working normally. Likewise, motor output is intact. That is, if appropriate motor commands are issued from the brain, the descending motor tracts and muscles should execute these commands just fine. The problem in these conditions occurs between the reception of sensory signals and the execution of motor commands. When various sensory signals reach the brain, they must be integrated with all of the other information stored in the brain and organized into meaningful thought and purposeful responses. This function is known as “sensory processing.” However, in cerebral palsy all or parts of the system can break down, not only at the sensory processing level in the brain, but equally likely at the incoming sensory and/or outgoing motor levels.

Dr. Miller asserts that, in some geographic locations, the treatment for sensory dysfunction may be limited to specific protocols that use techniques such as brushing, spinning, or wearing weighted vests, (not necessarily tailored to the individual or based on clinical reasoning). In contrast, she says that advanced Occupational Therapy clinicians focus on social participation, self-regulation, self-esteem/confidence and participation in everyday activities, and sometimes employ sensory therapies as part of a treatment program.

Incorporating the Ayres’ concepts of sensory processing and integration into an individually tailored program that focuses on function and participation through accommodation and adaptation makes good intuitive sense and, perhaps, will have growing research support.

Drawing from the AAP’s statement on sensory integration therapies as well as commentaries by Miller and Pollock, there are common conclusions and recommendations that can guide parents, therapists, and program administrators on best practice:

1. Whether sensory processing disorder is a distinct diagnosis or simply accompanies other disorders remains in dispute. Treating the symptoms (whatever the condition is labeled) is much more important than the diagnostic label. The goal should be to determine how impairments in sensory inputs impact function, how these impairments can be remediated (e.g. corrective lenses for far-sightedness, amplification for hearing impairment , baclofen medication for spasticity) or, if irremediable, how they can be accommodated or adapted to.
2. Multiple reasons why a child may be having functional difficulty should be considered. Sensory processing difficulties may be part of the problem, but it is important to keep an open mind and work with other professionals to develop a comprehensive, individually-tailored treatment plan.
3. Set specific and measurable goals, in collaboration with parents and other caregivers, that target restricted activities and participation. Set specific time intervals to evaluate the effectiveness of a specific treatment. As an individual family’s therapy resources (covered by insurance) may be limited, it is important that treatments be prioritized on the basis of positive effects on sensory problems.
4. As with all interventions, be they medicinal, nutritional, or therapeutic, parents should be be appraised of the evidence (of lack thereof) for use of sensory-based therapies in cerebral palsy.

References

Ayres, A. J. (1972).Types of sensory integrative dysfunction among disabled learners. American Journal of Occupational Therapy, 26, 13-18

Section on Complementary and Integrative Medicine and Council on Children with Disabilities, American Academy of Pediatrics. (2012). Pediatrics, 129, 1186-1189.

Miller, L.J. (2012). Letter to the Editor Re: Sensory Integration Therapies for Children with Developmental and Behavioral Disorders. Pediatrics, published online May 31, 2012.

Hoon, A.H. (2002)Diffusion tensor imaging of periventricular leukomalacia shows affected sensory cortex white matter pathways. Neurology, 59, 752-756

Pollock, N.(2009). Sensory integration: A review of the current state of the evidence. Occupational Therapy Now, 11(5), 6-10.

Given limited funding resources, differences of opinion often arise over whether research priorities should focus on prevention and cure or on applications that enhance function and quality of life for those with cerebral palsy.

An excellent example of a current basic science approach to prevention and cure (or at least to reduction of the severity of motor impairment in cerebral palsy) is a research project funded by the Cerebral Palsy International Research Foundation (CPIRF) and conducted by Dr. Vittorio Gallo, Director of the Neuroscience Research Program at Children’s National Medical Center in Washington, DC.  Under Dr. Gallo’s direction, postdoctoral fellow Dr. Matthew Raymond is conducting a study entitled “The Role of Astrocytes in Cerebral Palsy.”  Here is a summary of their ongoing work.

     Besides actual neurons (nerve cells) in the brain, there are two other essential cells that sometimes do not get much attention. One is called an oligodendrocyte (oh-lee-go-den-dro-site) whose function is to create the outer, insulating layer (myelin) of the long projecting arms (axons) of neurons. Because myelin is mostly whitish fat, it constitutes the brain’s so-called “white matter.” The main purpose of myelin is to speed up nerve impulses that travel along its fibers, thereby increasing the efficiency of motor, cognitive, and language commands. When white matter fails to develop or is injured during a crucial developmental time period during the third trimester of pregnancy, these functions, especially motor, can be impaired, resulting in spastic-type cerebral palsy.

     Star-shaped astrocytes (a-stro-sites) are the most abundant cells in the brain. They also play an important supporting role to the neurons. Their many tasks include provision of nutrients to neurons, maintaining chemical balance in surrounding fluid, and repair after injury.

     Lack of oxygen to the brain (hypoxia) is a major factor responsible for white matter damage that can lead to cerebral palsy. The immature lungs of very premature infants make them particularly vulnerable to the effects of hypoxia. Oligodendrocytes, the producers of white matter, are known to be very susceptible to hypoxic injury. However, much less is known about the effects of hypoxia on astrocytes.

     Drs. Gallo and Raymond are studying how astrocytes can be encouraged to remove excessive amounts of a normally present stimulative chemical in the brain called glutamate. Too much glutamate can kill oligodendrocytes. In this way, white-matter damage associated with cerebral palsy might be preventable. Furthermore, astrocytes have stem-cell potential, meaning they could actually turn into oligodendrocytes that would produce and replace essential white matter.

            Studies such as the one described above have important implications for the development of therapies that prevent or cure cerebral palsy. Certain chemical pathways in the brain and specific cell populations are attractive targets for early medical intervention. Modification of these targets can potentially prevent or reverse white matter damage in the premature infant susceptible to cerebral palsy.

In contrast, Dr. Peter Rosenbaum, Professor of Pediatrics and Chair of the CPIRF Scientific Advisory Council states, “We have very few opportunities, at the present time, to prevent or cure conditions [like cerebral palsy].  In an article entitled, “The ‘F-words’ in Childhood Disability: I swear this is how we should think!” (Child: Care, Health and Development, preprint publication online 1 Nov, 2011), he describes the expansion of the World Health Organization’s 2001 International Classification of Functioning, Health and Disabilities (ICF). The new classification includes aspects of disabling conditions that go beyond the limits of traditional medical interventions to such areas as enhanced quality of life and full participation in family and community activities.

Dr. Rosenbaum does not dismiss the importance of basic science research to promote or cure cerebral palsy or other disabling conditions nor clinical research to develop new treatments that reduce unwanted symptoms of cerebral palsy, such as drug therapies for spasticity or robotics for enhanced mobility.  Rather, he encourages readers to expand (not reject) traditional biomedical concepts by considering more dynamic, empowering notions of clinical service, research and advocacy that incorporate ICF concepts of full participation in family life, recreational activities, and meaningful education and employment. To this end, Professor Rosenbaum’s proposes six guiding “F” words: function, family, fitness, fun, friends and future.

Prevention and cure, on the one hand, and optimization of function, participation, and quality of life, on the other hand, should not be viewed as separate or competing research goals but rather as a continuum. Surely, no person with a disability would argue against research aimed at prevention of cerebral palsy; yet, for thousands of individuals living with cerebral palsy (and their families) achieving the “F” words to the fullest extent deserves equal emphasis.

Increasingly, proposals for research at the most basic laboratory level must clearly identify how the results of their discoveries will yield positive results for the lives of people, if not in complete prevention, then in improving potential for achieving the highest quality of life.

The Cerebral Palsy International Research Foundation is committed to fostering high quality research along the continuum from basic to applied. Your interest in and questions about our efforts are always welcome.

Thus, we have two differing opinions on the role of genetics in cerebral palsy, given the current state of knowledge.  Both the authors of the article and the experts from Australia agree that genetics is a factor in some, perhaps many, cases of cerebral palsy.  The disagreement is in how certain we can be about the percentage of those cases at this time and whether there is sufficient knowledge about this relationship to warrant extensive and expensive genetic testing in every case, especially when there is confidence about the cause. This may be yet another instance where technology has advanced faster than the ability of a clinician to interpret the results of very  sophisticated genetic tests. It is often difficult to interpret various abnormalities that may be revealed – that is, do they have anything to do with the condition being tested for?  Until we know what such abnormalities mean, they may serve only to frighten and worry parents or individuals with cerebral palsy.  This would clearly be the case if such testing were done as part of prenatal counseling. The Moreno-De-Luca article serves to call attention to a possibly more prominent role of genetics in cerebral palsy than previously appreciated. However, a call for universal genetics testing of all individuals with cerebral palsy may be premature at this time. Rather,  individualizing such recommendations as part of a comprehensive care plan would seem sensible. Persons with or parents of children with cerebral palsy interested in a possible genetic cause should discuss this question with an expert in cerebral palsy, such as a developmental pediatrician, neurologist, or physiatrist.  Additional consultation with a genetics expert might be warranted in some cases.

Reference:
Moreno-De-Luca A, Ledbetter DH, Martin CL. Genetic insights into the causes and classification of the cerebral palsies.
Lancet
Neurology 2012

Stem cell therapy is promising yet there is misunderstanding regarding the current state of its readiness for treatment of cerebral palsy. There are only two institutions in the United States conducting carefully designed research trials of stem cells in cerebral palsy but there are a number of clinics outside the US offering this therapy.

Recently Dr. Luigi Titomanlio and colleagues published an excellent review of stem cell therapy for neonatal brain injury, one cause of cerebral palsy Titomanlio L, Kavelaars A, Mani S, et al. Stem cell therapy for neonatal brain injury: Perspectives and challenges.

Annals of Neurology 2011;70(5):698-712.

As this review was intended for a medical audience, it is somewhat technical. However, it does explain the many aspects of stem cell therapy and summarizes the current state of knowledge regarding their use. I asked Drs. Gordon Worley and Jessica Sun from Duke University to comment on this article. Afterwards, I will provide less technical comments on stem cell treatment in cerebral palsy and list several excellent on-line sources of dependable information.

This European review of stem cell therapy for neonatal brain injury is written for physicians interested in learning about where we stand now. Background about the five different types of stem cells that are used in animal experiments to treat neonatal injury is provided. These types are neural stem cells, induced pluripotent stem cells, mesenchymal stem cells harvested from bone marrow, and umbilical cord blood stem cells. Each has
some advantages and some problems for cell therapy, as discussed in the paper.

Strategies for use of stem cells in newborns are presented. Obstacles that need to be studied are cell dose, timing of transplantation, route of administration (directly into the brain or other), and assessment of mechanism of action. An issue that needs to be determined by animal studies is whether stem cells after injury improve outcome (when they have been shown to) by “paracrine” effects, that is, by secretion of growth and differentiation factors that stimulate endogenous regeneration, or by engraftment (the stem cells themselves forming the neural cell elements). Potential complications of engraftment of some kinds of stem cells are neuroblastoma (with human neural stem cell transplantation), teratoma (with embryonic stem cell transplantation), and acute and chronic rejection (with
neural stem cell transplantation).

Clinical trials of stem cell therapy in neonates with brain injury were reviewed. All studies are preliminary. The authors conclude that “based on animal models of hypoxic ischemicencephalopathy, human cord blood cells and mesenchymal stem cells (MCS) may be the most promising stem cells, as they are effective and potentially available for human studies. Human cord blood stem cells have advantages over MCS that may support their use for neonatal insults.”

We at Duke are conducting a clinical trial to evaluate the effectiveness of an intravenous infusion of a child’s own umbilical cord blood in young children with cerebral palsy, ages 12 to 72 months. The safety and feasibility of an intravenous infusion of autologous cord blood in children with acquired brain injuries was demonstrated in a “lead up study” to the clinical trial. The trial is a double-blind placebo controlled study, with crossover at one year. The placebo infusion looks and even smells like the cord blood infusion. Three challenges we have faced in designing a robust trial are: parents willingness to have their children randomized to placebo treatment; defining eligibility criteria that allow assessment of endpoints without unduly limiting enrollment and assessing change due to cellular therapy above what is expected in the development trajectories of children with CP. Gross motor, fine motor, cognitive, and speech and language capabilities are assessed objectively with accepted measures. MRI with DTI and tractography provide objective measures of neuroplasticity. Quality of life is also assessed.

We are actively recruiting subjects to participate in what we consider to be an important study. Interested parents or physicians with potential referrals are encouraged to e-mail Dr. Jessica Sun at jessica.sun@duke.edu the Study Coordinator, or Dr. Joanne Kurtzberg at joanne.kurtzberg@duke.edu for more information.

─ Gordon Worley, MD, Program in Neurodevelopmental Disability and Jessica Sun, MD, Pediatric Hematology and Oncology (Bone Marrow Transplant Service) Duke University

Dr. Michael Fehlings and colleagues at the Universityof Toronto have published an online newsletter, aimed at a non-scientific or health professional audience, on stem cell treatments for cerebral palsy (http://www.childhooddisability.ca/cdc_en/newsletter.php).

More detail can be obtained at that website. Here are some of the key points:

• Transplanting stem cells into the brain could support and/or replace deteriorating brain tissue during the process of white matter damage in cerebral palsy.
• Animal models used in research on cerebral palsy have shown that many types of stem cells can be used to reduce damage and return motor function after brain injury.
• New technological improvements make it possible for skin cells to be taken from a patient and turned into the exact cell needed to repair injured tissue, getting rid of the need for tissue donor waiting lists and anti-rejection drugs.
• Once stem cells are put in, they can never be removed.
• There are no proven stem cell treatments available for patients with cerebral palsy right now, and it will take a number of years for safe and effective therapies to make it to the clinic.
• Unregulated clinics outside of North America are offering stem cell transplants; however, these clinics have shown no scientific proof that their
  procedures offer any effect beyond placebo effects and/or normal development.
• Stem cell transplantation would probably have to be performed within the window of time between the first appearance of injury and irreparable loss of neurons.

Here are some excellent websites for information on stem cell treatments that you can trust.

International Society for Stem Cell Research
(ISSCR)

A world leader for stem cell research. A very authoritative and helpful source of practical information. http://www.isscr.org/public

U.S. National Institutes of Health

A government-sponsored initiative providing upt-to-date information on stems cells in regenerative medicine. http://stemcells.nih.gov/

Childhood Disability Link

A bilingual (French and English) website linking information and new knowledge on childhood disability to service providers and families. http://www.childhooddisability.ca/cdc_en/newsletter.php

Current North American Clinical Trials on stem cells for cerebral palsy

Duke University http://clinicaltrials.gov/ct2/show/NCT01147653

GeorgiaHealth Sciences
University http://clinicaltrials.gov/ct2/show/NCT01072370

According to the Children’s Hemiplegia and Stroke Association (www.chasa.org) constraint-induced movement therapy (CIMT), sometimes called “forced use therapy”, has been used in the adult stroke population for years. Recently, this type of therapy has gained the attention of therapists who work with children who have hemiplegia (weakness on one side of the body due to an injury to the brain on the opposite side).

CIMT focuses on regaining movement on the affected side of the body by restraining the non-affected arm, thus forcing the child to learn to move the affected arm more efficiently and effectively. There is increasing evidence that this therapy may result in positive structural changes in the brain, prompting Brady and Garcia, in an excellent review of CIMT (Dev Disabil Res Rev 2009;15:102-111), to comment that CIMT is an example of an emerging “paradigm shift” in rehabilitation of CNS injury, from an emphasis on compensatory skills to a hope for partial restoration.

Accumulating research reports have generally shown a favorable response to CIMT, although questions remain about what is the critical level of intensity of therapy necessary for a positive effect (how much? how frequently?).  As with any new therapy, another important question is whether it is superior to what is already available and being implemented, perhaps at less expense.

A recent article by Wallen and colleagues from Sydney, Australia compared a modified form of CIMT with intensive occupational therapy on activities of daily living and upper limb outcomes in children with hemiplegic cerebral palsy. They concluded from their study that modified constraint-induced therapy is no more effective than intensive occupational therapy.(Dev Med Child Neurol 2011;53:1091-1099)

In a Letter to the Editor (accepted but not yet published by Developmental Medicine and Child Neurology)  Dr. Stephanie DeLuca (University of Alabama at Birmingham) and colleagues long involved in CIMT research raise some interesting questions about the Wallen study. An excerpt follows:

We raise many serious issues about the {Wallen et al.} study as well as present directly comparative data from a multisite trial of CIMT that we recently completed (and is forthcoming as a manuscript in the  Am J Occup Ther, January, 2012). The purpose of the comparative data is to help readers better interpret the magnitude of changes reported among children in the two Wallen et al treatment groups – for an objective outcome (the Assisting Hand Assessment) and a subjective one (parental ratings on the Pediatric Motor Activity Log).

What concerns us most is that when clinical trials are conducted in a way that fails to clearly specify the intervention treatment and to document its fidelity of implementation, then readers are at a loss as to how to use the findings. Rigorous clinical trials have clearly agreed upon standards about what constitutes adequate, objective outcome data. Based on the published article, the Wallen et al. study did not meet criteria of a rigorous clinical trial with appropriate primary outcomes.

The field is eager to resolve critical questions about whether Constraint-Induced Movement Therapy (CIMT) works, and for whom it works best, and what format (dosage, constraint) yields the best results. The Wallen et al study is described as though it answers some of these questions. In fact, we judge the form of administration (parent delivered almost exclusively) and the dosage (below 1.5 hr/day) and constraint (a mitt worn less than 1.5 hr/day) of the so-called “modified” Constraint-Induced Therapy to be insufficient to know if it really WAS CIT.

We think the field needs to develop clear and agreed upon definitions for different therapy approaches, with operational definitions and measures of the delivery of the components of a specified form of therapy. Otherwise, we fear that CIMT – which thus far is one of the most promising evidence-based therapies available for children with unilateral cerebral palsy  –  may go the way of earlier “popular” therapies that became so ill-defined (such as Neurodevelopmental Therapy – NDT) that it becomes a “discounted” or disrespected therapy, because no one can describe exactly what it is. In our view, use of a short-term form of constraint and only slightly more than a one hour therapy session per week cannot qualify as CIMT!

Children need evidence-based treatments. The field needs a solid, trustworthy database to inform treatment recommendations and the training for therapists who deliver treatments. Wallen et al, unfortunately, failed to clarify or advance the role of CIMT per se. It did, however, perhaps show low dosages of CIMT fail to produce large and statistically significant improvements in function (despite parents liking the intervention and being satisfied with their children’s progress).

This kind of interplay between researchers is very healthy and will lead to a better understanding of the most cost-effective approaches to therapy for cerebral palsy. I encourage parents, therapists, physicians and all others interested in cerebral palsy treatment and research to read the Wallen et al. article and the more complete Letter to the Editor by DiLuca et al that is to follow in Dev Med Child Neurol.

We asked Dr. Wallen to
respond to this critique and she kindly furnished the following:

Our trial evaluated a
modified form of CIMT (modCIT), devised in response to families requesting CIMT
which was less intensive than pre-existing models, and therapists who proposed
that these models were not clinically feasible within the Australian health
services context. We compared modCIT with an intensive block of occupational
therapy, arguing that a constraint-based intervention needed to be
substantially more effective than the best available service currently offered,
in order to justify its additional intensity and intrusiveness.

The statement that modCIT
“cannot qualify as CIMT” is disingenuous. What is CIMT?  Case-Smith, DeLuca and colleagues¹
employed a cast worn 24 hours per day for 18 days during which time children
participated in an intervention protocol of either 3 or 6 hours per day. This
was followed by a period in which children participated in bimanual
intervention.   How do we delineate the
effects of CIMT from those of the bimanual therapy or an interaction between
the two in this protocol?  Diverse CIMT
protocols are reported in the literature variously using casts, splints,
slings, mitts and even holding to achieve constraint for 1 to 24 hours per day
over periods from 9 days to 8 weeks. Which of these options is CIMT?  Case-Smith, DeLuca and colleagues very
accurately stated that “consensus has not been reached on the differential
effects of dosage (or intensity) of therapy or a minimum threshold to produce
significant effects” (p.16).  Each study
adds its own unique contribution to the ever-increasing and complex knowledge
base.  

Dr DeLuca stated that our
trial “did not meet criteria of a rigorous clinical trial with appropriate
primary outcomes.”  In our response to
the Letter to the Editor of DMCN we provide evidence that the Canadian
Occupational Performance Measure is valid for use with young children with
cerebral palsy and reiterate that we specifically chose to use this measure as
it individualizes and prioritizes outcomes.
Furthermore, it is consistent with family-centred care, a fundamental
philosophy of contemporary practice. We take this opportunity to further
highlight the aspects of our study which demonstrate methodological rigor:  randomisation with allocation concealment,
blinding of raters and data analysis, adequate sample size determined by sample
size calculation, a priori selection of primary and secondary outcome measures
and endpoints, data analysis completed according to principles of intention to
treat and so on.

In our response to the
Letter to the Editor of DMCN we expressed strong concerns about the integrity
of comparing results from Case-Smith’s trial with our trial.  There was no consideration of the
heterogeneity of the trials (e.g., age group of participants), and information
from Case-Smith’s report (e.g., variability of data, severity of disability)
which would facilitate an informed and responsible comparison, was not
provided. Furthermore it is erroneous to compare data from different versions
of one of the measures, the Pediatric Motor Activity Log.

We concur with Professor
Blackman’s observation that scholarly dialogue is healthy and contributes to
the evidence-base informing stakeholders about intervention for children with
cerebral palsy.  We also urge
stakeholders to read our article, the aforementioned Letter to the Editor of
DMCN and our response to this letter in DMCN.

1. Case-Smith J, deLuca
S, Stevenson R, Landesman Ramey
S. Multicenter randomized controlled
trial of pediatric constraint-induced movement therapy: 6-month follow up. The
American Journal of Occupational Therapy. 2012;66:15-23.