Updating Research Priorities for Cerebral Palsy by Mindy Aisen, MD

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Updating Research Priorities for Cerebral
Palsy by Mindy Aisen, MD

• Medical Director
• Cerebral Palsy International Research Foundation
• Washington, DC

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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 nations principal
  non-government agency sponsoring research and
  education for cerebral palsy.

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Todays 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

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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

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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 individuals sex, GMFCS level,
  cognition level, type of interventions, etc?
• Trends in Incidence Etiology
• Clinical Trials

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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 lt 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

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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

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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

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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)

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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

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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 (lt30 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?

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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 OLs
• Rivkees (Yale) is studying the effectiveness of a
  sulfonylurea agonists (diazoxide) to prevent
  white matter damage by causing hyperpolarization
  of OLs and Pre-OLs 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

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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

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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

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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

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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

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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.

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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
• UCBs 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

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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

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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?

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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

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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

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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

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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.

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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.

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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

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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

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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).

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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.

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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.

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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 ?

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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

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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.

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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?

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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

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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.

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Thank You for Your Attention !