Updating Research Priorities for Cerebral Palsy by Mindy Aisen, MD

1. Updating Research Priorities for Cerebral Palsy by Mindy Aisen, MD Medical Director Cerebral Palsy International Research Foundation Washington, DC

2. CPIRF - Mission • The Cerebral Palsy International Research Foundation (CPIRF) is a not for profit 501(c)3 organization dedicated to funding research and educational activities directly relevant to discovering the cause, cure and evidence-based care for those with cerebral palsy and related developmental disabilities. • CPIRF was founded in 1955, and its 55 year history has been the nation’s principal non-government agency sponsoring research and education for cerebral palsy.

3. Today’s Talk: Updating CP Research Priorities (where we are and where we need to go) • Changing Picture of Cerebral Palsy • Research Opportunities • Epidemiology • Early Identification (imaging, electrophysiology) • Early Interventions • Neuro-protection • Neural Regeneration • Neuro-plasticity • Neuro-rehabilitation • Adults with Cerebral Palsy

4. CHANGING PICTURE OF CEREBRAL PALSY • In the developed world, the major risk factor for CP is prematurity/low birth weight • In the US, pre-term birth rates have risen 30% over the last two decades, now 12.7 % • Periventricular White Matter Injury (PWMI) is the most common pathology associated with the subsequent diagnosis of CP in premature infants • Based on recent CDC surveillance data, the prevalence of CP in the US is 3.6 per 1000 8-year old children • There are significant racial and SES disparities in the prevalence of CP • The prevalence of CP is 30% higher in blacks than non-Hispanic whites; the prevalence of CP is 70% higher in low/middle income families than high income families • Most individuals with CP are now living well in adulthood • Adults with CP experience a premature ‘aging’, with chronic pain, extreme fatigue, osteoporosis, and osteoarthritis – resulting in an early loss of ambulation and independence • It is estimated that there are now one million children and adults with CP in the US

5. EPIDEMIOLOGY • Develop a National Registry for CP • Natural history of impairments associated with CP subgroups through-out the lifespan • Age- Specific Prevalence of Secondary Conditions • How is the development of secondary conditions influenced by an individual’s sex, GMFCS level, cognition level, type of interventions, etc? • Trends in Incidence; Etiology • Clinical Trials

6. Early Identification and Timing of Injury • Serial electroencephalography (Kidokoro et al 2009): EEG within 48 hours of birth to detect acute stage abnormalities (ASAs) and in the second week of life to detect chronic stage abnormalities (CSAs) in premature infants (gestational age < 33 weeks) • Severity of ASAs and CSAs correlated with severity of PVL diagnosed by MRI and clinical findings at two years of age • Data suggest that the timing of the initial insult resulting in severe PVL and subsequent CP occurs near the time of birth or very early after birth which has implications for the timing and length of time for administration of neuroprotective agents

7. NEUROIMAGING METHODS FOR EARLY DIAGNOSIS; ETIOLOGY • Structural MRI • Physical shape and form of the brain and its structures • Subcortical volumes and cortical surface thicknesses • CPIRF is funding a study using serial 3-D Spoiled Gradient Recalled Activation (SPGR) MRIs (Emily Tam, UCSF) to understand the mechanisms of brain damage in intraventricular hemorrhage • Preliminary data demonstrate that severe IVH alters the microstructural development of the cerebellum

8. NEUROIMAGING FOR ETIOLOGY; PLASTICITY/MOTOR FUNCTION • Functional magnetic resonance imaging (fMRI) • Utilizes the paramagnetic effect of deoxyhemoglobin to study brain organization and biochemistry of functional pathways in both movement and speech • May be used to study neuroplasticity and the effects of rehabilitation on brain re-organization • Difficult to use in children with movement disorders

9. NEUROIMAGING FOR ETIOLOGY; PLASTICITY/MOTOR FUNCTION • Functional Near Infrared Spectroscopy • fNIRS, unlike fMRI, is not as susceptible to artifacts due to uncontrolled movements • Measures changes hemoglobin concentrations in the cerebral cortex providing an indirect measure of changes in cerebral neuronal activity • CPIRF is currently funding a project using fNIRS as a tool to detect flow changes sensorimotor brain activity during motor tasks in children with CP (Mauricio Delgado , Scottish Rite Hospital – Dallas, TX)

10. NEUROPHYSIOLOGICAL METHODS FOR MAPPING BRAIN MOTOR FUNCTION • Transcranial magnetic stimulation • A non-invasive technique that activates the primary motor cortex and can be used to map a muscle's representation in the motor cortex • Goal is to develop a non-invasive measure that maps brain motor function (George Wittenberg, University of Maryland) • For predicting responses to interventions • For identifying “plastic” changes before and after rehabilitation

11. PREVENTION: MECHANISMS OF NEUROLOGICAL DAMAGE • Periventricular white matter injury (PWMI) is the predominant brain abnormality seen in CP of prematurity • Is the mechanism inflammatory? Is it Hypoxia/Ischemia? • Chorioamnionitis – seen in 70% of premature newborns (<30 wks) • Fetal Inflammatory Response may be involved, may contribute to organ damage • Hypoxia/Ischemia • Researchers funded by NIH are studying mechanisms by which acute degeneration of late oligodendrocyte progenitors (preOLs) occurs. • Is disrupted myelination after H-I is related to the acute degeneration of preOLs that triggers chronic reactive astrocytosis?

12. MECHANISMS OF BRAIN DAMAGE and HOW TO PREVENT IT • Animal Model Studies funded by CPIRF • Role of pentraxin in the cascade of neuronal death program in neonatal brain injury triggered by hypoxia-ischemia • Use of Cardiotrophin-1 (gp130 ligand) as a Neuroprotective Agent against HI-Reperfusion Injury • How brain insults (HI, inflammation) affect oligodendrite and oligo-progenitor cell processes • Protection and Differentiation of OL’s • Rivkees (Yale) is studying the effectiveness of a sulfonylurea agonists (diazoxide) to prevent white matter damage by causing hyperpolarization of OL’s and Pre-OL’s in an animal model • Role of mitochondria and free radicals following pre-natal HI in reperfusion injury • Restoring Excitatory Neuronal Input • Kanold (University of Maryland )is studying GABAergic transmission for enhancing maturation of thalomo-cortical and inhibitory circuits in model with ablated subplate neurons

13. Neuroprotective Agents/Treatments Research needs • CPIRF funded studies (cont.) • Effect of electrical stimulation on inactivated corticospinal (CS) terminations • In hemiplegic CP, ipsilateral as well as contralateral corticospinal terminations are present in the damaged hemisphere (bilateral motor control) • It is hypothesized that this is due to unbalanced competition between CS systems on each hemisphere as a result of brain injury • The researchers propose to use ES to reactivate dormant CS axon terminals in a post-natal animal model to reestablish competition between CS systems in each hemisphere • Use of Cardiotrophin-1 (gp130 ligand) as a Neuroprotective Agent against HI-Reperfusion Injury • Previous studies have demonstrated that CT-1 acts as a neuroprotectant for motor, sensory and sympathetic neurons in the PNS • It is hypothesized that the neuroprotective effects of CT-1 are mediated by anti-apoptotic mechanisms

14. NEUROPROTECTIVE AGENTS • Yale University: trial to assess the efficacy of N-acetylcysteine (a potent free radical scavenger) to prevent adverse neonatal outcomes in preterm deliveries complicated by infection associated with preterm labor or preterm premature rupture of membranes (PPROM). • Working hypothesis: N-acetylcysteine protects the fetus by preventing the development, or decreasing the intensity and/or progression of the fetal inflammatory syndrome. • Magnesium Sulfate • Meta-analysis of randomized, controlled clinical trials of antenatal administration of Mag Sulfate to pregnant women at risk of premature labor (before 34 wks gestation) revealed a significant reduction in the occurrence of CP and/or substantial motor dysfunction • Six trials involving 4796 women and 5357 infants were included in the analysis

15. NEURAL REGENERATION • Cell-Based Therapies – How they may help • Restore tissue by becoming neurons or glial cells and integrate into the neuronal network • Restore tissue by promoting activation of endogenous stem cells • Preventing tissue damage by changing bodies immune response • PVL • Neural stem cells Oligodendrocytes Repair/Replace Myelin on Axons

16. NEURAL REGENERATION • Cell-Based Therapies: Endogenous sources • Neural Stem Cells (adult stem cells) • Give rise to neurons; astrocytes; oligodendrocytes • NIH-funded studies are examining the role of neural stem cells derived from the subventricular zone (SVZ) of the brain in response to neo-natal HI • The researchers hypothesize that SVZ neuroblasts and glioblasts redirect their migration toward brain areas injured by H/I; that SVZ NSCs expand lineage restrictions following H/I; and that Doublecortin is necessary for SVZ neuronal migration in response to H/I. • Vascular Endothelial Growth Factor (VEGF) • Although the SVZ expands in size after H/l injury, there is a shift in the production of astrocytes and oligodendrocytes. • VEGF, a key mediator of tissue repair after ischemia, is rapidly induced after H/l injury and increases the specification of astrocytes from bipotential glial progenitors in vitro • VEGF isoforms may cause an aberrant shift in the proliferation and differentiation of SVZ progenitors towards astrocytic phenotypes instead of a more appropriate oligodendrocyte lineage after H/l injury. • A particular isoform of VEGF may stimulate mainly oligodendrocyte production in response to a perinatal H/I injury

17. NEURAL REGENERATION • Delayed Cord Clamping • The current obstetrical practice at birth in the United States is that the umbilical cord of the very low birth weight (VLBW) infant is clamped immediately; this can result in up to 25% of the fetal-placental blood volume being left in the placenta acutely increasing vulnerability to hypovolemia. • Hypovolemia can precipitate a cascade of physiologic events including poor tissue perfusion, ischemia, and initiation of the fetal/neonatal inflammatory responses • NIH-funded trial is evaluating health outcomes (reduction in intraventricular hemorrhage) in a cohort of VLBW infants randomized to either immediate clamping of the umbilical cord versus a 45 second delay in the clamping of the umbilical cord • Exogenous Sources • NIH-funded study evaluating exogenous adult stem cells implanted into the subventricular zones of a developing brain after HI. • Adult neural stem cells will be implanted into the injured animal in either the lateral ventricle or injured cortex at 24 hours and 7 days post injury • 7-14 days post transplant, the location, cell type, and degree of differentiation of the transplanted stem cells will be analyzed.

18. NEURAL REGENERATION • Genetic Engineering • Researchers funded by NIH are investigating whether administration of genetically engineered oligodendrocyte precursors into a mouse model of congenital leukodystrophy leads to more robust myelination and improved survival. • Previous work has demonstrated that Dlx homeobox transcription factors act as repressors of oligodendrocyte formation and maturation during embryogenesis • Cells will be generating by using conditional Dlx2 knockout mice with loss of Dlx2 function in postnatal SVZ progenitors • Cord Blood • Umbilical cord blood has a 2 – 5 % fraction of stem cells, mostly hematopoietic stem cells, but also other cells including CD133+ stem cells which can be differentiated into various CNS cells; also has neuronal growth factors, vascular growth factors and cells that modulate immune and inflammatory responses • UCB’s relative cellular immaturity compared to adult sources suggests a potentially unrivaled degree of plasticity. • Umbilical cord blood transplantation has been widely used in cancer patients and has shown beneficial effects in a number of neurologic conditions such as Infantile Krabbe's Disease

19. NEURAL REGENERATION • Currently 2,719 clinical trials involving stem cell therapy registered in clinicaltrials.gov • Most are for treatment of hematological disorders • There are 9 active or completed clinical trials using stem cells to treat motor dysfunction resulting from stroke, 1 to treat TBI and 1 to treat MS • Currently, there are no registered clinical trials for the treatment of CP with stem cell therapy

20. NEUROREHABILITATION RESEARCH FOR CHILDREN WITH CP • Is there a role for neurorehabilitation modalities such as mass practice/robotics, transcranial magnetic stimulation, virtual reality, neuromuscular stimulation and focal antispasticity agents that have shown benefits in patients with stroke and/or spinal cord injury in the treatment of children and adolescents with CP? • Can they help develop new locomotion and functional skills? • Will this lead to reduced muscle atrophy and increased muscle strength? • Will they be effective in preventing future contractures, pain, and lessening fatigue and spasticity? • Will they prevent the future metabolic repercussions of inactivity such as metabolic syndrome, depression, cognitive decline and loss of cardiovascular fitness?

21. CLINICAL RESEARCH FOR CHILDREN WITH CP • Mass Practice/Robotics • 2 studies funded by CPIRF of Upper Extremity Robot-assisted Therapy • Evaluation of the effectiveness of upper extremity robots (MIT-MANUS) in improving function in children with hemiplegic CP • Preliminary results show increased upper extremity function as assessed by Fugl-Meyer and decreased spasticity as assessed by the Modified Ashworth. • Visual feedback and patient intent appear to be key factors in motor learning using robot-assisted therapy. • 1 study funded by CPIRF of Lower Extremity Robot-assisted Therapy • Evaluation of robot-assisted BWST training in children with diplegic CP • Results indicated that after 6 weeks of therapy showed improved gait kinetics and kinematics as well as a decrease in the severity of the crouch gait • 1 European sponsored - randomized, controlled clinical trial of the Pediatric Lokomat • 15 sessions within 5 weeks will be examined in a sample of 24 children with cerebral palsy. Children will be randomly assigned to an intervention or waiting list group. Outcomes will be assessed using 3-D Gait Analysis

22. CLINICAL RESEARCH FOR CHILDREN WITH CP • Electrical stimulation • Children with CP have reduced muscle strength which affects functional abilities in children with CP. • Volitional strength training in children with CP can produce substantial gains in force production with concomitant gains in function. Volitional strength training, however, may not be optimal for producing strength gains in this population due to reduced voluntary muscle activation. • Neuromuscular electrical stimulation (NMES) activates a greater number of motor units and produces higher firing rates of the active motor units than can be obtained volitionally. • Researchers funded by NIH are assessing the effectiveness of a 12-week NMES program to increase quadriceps femoris and triceps surae muscle force-generating ability in children with diplegic CP

23. CLINICAL RESEARCH FOR CHILDREN WITH CP • Virtual Reality • Virtual reality environments (VRE) are being increasingly used as adjunctive therapies for rehabilitation of trunk and limb motor control • The added value of VREs is the ability to incorporate attributes important for motor learning • Exercise intensity • Feedback on specificity of movement • Motivation/Engagement • There are few published studies of VR and CP, however they have consistently shown improvement in motor skills; some other findings include:

24. CLINICAL RESEARCH FOR CHILDREN WITH CP • VR cont • Neuroplastic change documented by fMRI in a child with hemiplegic CP after VR was associated with enhanced functional motor skills including reaching, self-feeding, and dressing. • Better outcomes generally seen in children with higher cognitive skills • Only one study is currently in the NIH CRISP Database for CP and VR: ankle strengthening using virtual reality and robotic dynamometer for CP patients • Future directions in VR: Error augmentation- VR: the subject sees something unexpected that is perceived as an error. Errors induce learning, and judicious error augmentation (through forces or visual distortions) can lead to lasting desired changes.

25. CLINICAL RESEARCH FOR CHILDREN WITH CP • Chaotic Perturbation – Funded by CPIRF • Researchers are conducting a randomized clinical trial to evaluate the effectiveness of shoes that employ chaotic perturbation (random changes in slope during the swing phase) in adolescents with diplegic CP; health outcomes include balance and walking endurance • Focal pharmacological treatment of spasticity- Funded by CPIRF • Studies of the neuromuscular plasticity of children with CP after a botulinum toxin A injection • Significant changes occur in muscle activity (gastrocnemius activity becomes more normal during swing and stance phase), at the spinal level (decreased H reflex latency), and in cortical reorganization (as reflected by fMRI) in response to botulinum toxin injections • These effects persist even during the wash out period when gait kinematics and kinetics return to pre-injection values.

26. CLINICAL RESEARCH FOR CHILDREN WITH CP • Constraint-Induced MovementTherapy • A systematic review of studies evaluating Constraint-Induced Movement Therapy (CIMT) in children with Cerebral Palsy supports improved arm and hand use, however • Studies varied widely in type and rigor of design; subject, constraint, and intervention characteristics and outcome measures

27. CIMT FOR CP (cont) • The critical threshold for intensity that constitutes an adequate dose cannot be determined from the available research. • Further research should include a priori power calculations, more-rigorous designs and comparisons of different components of CIMT in relation to specific children, and measures of potential impacts on the developing brain • Currently one active clinical trial for CIMT registered ClinicalTrials.Gov • Randomized, active control, blind outcomes assessment using CIMT in 52 children 30 months to 14 y.o. with hemiplegic CP • Dose – 90 hours of wearing constraint for 2 weeks in a camp setting

28. CLINICAL RESEARCH FOR CHILDREN WITH CP • Strength Training • Some have suggested that these muscle changes in CP may be irreversible; however, it is now known that muscles are one of the most 'plastic' tissues in the body. • It is unknown how effectively muscles in CP can adapt to training stimuli that target specific muscle architectural parameters, such as fascicle length and cross-sectional area. These parameters have been observed to be decreased in CP, suggesting loss of sarcomeres in-series (fiber shortening) and in-parallel (muscle atrophy).

29. CLINICAL RESEARCH FOR CHILDREN WITH CP • Strength Training cont. • A clinical trial funded by MUSC proposes to the determine whether and how muscle architecture of the quadriceps muscles in cerebral palsy (CP) adapts to two separate training programs: traditional strength training (ST) vs. velocity-enhanced training (VT). • For the ST group, it is hypothesized that muscle size will increase in conjunction with strength. For the VT group, in addition to the above, it is hypothesized that fiber length will increase with measures of muscle power. It is hypothesized that walking velocity will improve in both groups but that knee motion and step length will improve only in the VT group.

30. CLINICAL RESEARCH FOR CHILDREN WITH CP • Hippotherapy • Physical therapy derived from movement of a horse • Studies have shown improvement in muscle symmetry in children with CP • Shurtleff et al demonstrated significant changes with large effect sizes in head/trunk stability and reaching/targeting after a 12 week intervention in a study of 11 children with spastic diplegic CP. These improvements were maintained after a 12 week wash-out period.

31. ADULTS WITH CEREBRAL PALSY • Health Outcomes • Which treatment and intervention strategies have been most successfully used to prevent secondary conditions and age-related problems. How is this influenced by level of impairment, CP subgroup, education, employment history, SES? • Evaluate the long-term outcomes of early interventions including exercise therapies, splinting/bracing, Botox, spine surgeries, etc • CPIRF is currently funding a study looking at long term health outcomes of Intrathecal Baclofen to treat spasticity • Health Services • Who is providing care to children, adolescents and adults with CP? • How is this care being provided? What is the quality and comprehensiveness of this care? How accessible is the care? How many individuals with CP are receiving inadequate or no care? How is care being financed for children, adolescents, adults? • How can care for these groups be improved? • What type of medical specialties are needed? • How can we better inform parents, caregivers ?

32. ADULTS WITH CEREBRAL PALSY • Mechanisms of Secondary Complications • Muscle Weakness, Fatigue • The combination of specific muscular deficits in childhood coupled with the natural history of sarcopenia and atrophy in adulthood may contribute to early loss of strength, endurance, and mobility in cerebral palsy • What sort of interventions can prevent/mitigate early loss of muscle strength? • Osteoarthritis • Weight-bearing activity, repetitive movements and/or inappropriate therapies on malaligned, poorly functioning joints may lead to early arthritis • CPIRF is currently funding “The Relationship between Running, Lower Extremity Alignment and Participation in Important and Meaningful Physical Activities in Children with Cerebral Palsy” • The goal of this project is to develop intervention programs that prevent injury and the long term problems that can arise from faulty lower extremity alignment and biomechanics

33. ADULTS WITH CEREBRAL PALSY • Metabolic Syndrome • Decreased muscle mass from lack of exercise may lead to an increased incidence of metabolic syndrome and cardiovascular complications in CP similar to the increased incidence seen in immobilized individuals such as those with spinal cord injury • Osteoporeosis • Muscle weakness and administration of anti-epileptic medications may increase risk of osteoporosis and fractures in CP • When should a patient with cerebral palsy be screened for osteoporosis? By what technique and how often should this occur? How should it be treated if found? • What is the long term impact of immobility caused by surgery, casting, and/or splinting? • Do the exercise, nutrition, and pharmacotherapy regimens used to treat osteoporeosis in the general population work for adults with cerebral palsy? • CPIRF is currently funding a study to assess bone growth and structure in pre-pubertal and adolescent children with cerebral palsy.

34. CLINICAL RESEARCH FOR ADULTS WITH CP • Promote research on methods to conserve, protect and restore musculoskeletal and neurologic function. • What is the effectiveness of current interventions, such as exercise, muscle strengthening, nutrition, weightbearing, gait training, and other modalities in promoting health and wellness and preventing musculoskeletal and neuromuscular impairments, loss of ambulation and resulting secondary medical conditions in adults with cerebral palsy? • Dr. Deborah Thorpe is studying the effectiveness of aquatic therapy in diminishing the severity of select secondary impairments associated with adults who have CP • Can we apply the same principles established for experience dependent neural plasticity in stroke rehabilitation to cerebral palsy?

35. BETTER DESIGNED CLINICAL TRIALS FOR CP INTERVENTIONS • Most current treatments for CP are not evidence-based • Most clinical studies assessing interventions in CP do not have adequate sample size to achieve significance • In a recently published meta-analysis of 63 studies assessing interventions to improve gait, few were adequately powered. • Most studies have not controlled for other interventions such as botox administration or surgeries • Most have heterogeneous patient groups, i.e., children with spastic diplegia are grouped with patients that have spastic hemiplegia; neuroimaging and TMS have shown these subgroups have different pathologies • Most studies have used outcome measures that are not necessarily clinically meaningful

36. IMPORTANT CLINICAL QUESTIONS TO BE ANSWERED • 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. • Future studies are also needed to determine if there is an optimum time or age at which to provide interventions, and the time it takes for the treatment to become effective. • Future studies need to determine if the effect is lasting and relevant to secondary outcomes • Future studies are needed to optimize the intervention strategy (e.g., dose, duration, frequency of dosing).  • Future studies are needed to select the best of two or more potential interventions; dosing regimens; and/or combination therapies to evaluate in a subsequent definitive trial, based on tolerability or evidence of biological activity.

37. Thank You for Your Attention !