Download Updating a Research Agenda for Cerebral Palsy Drs. Laura

UPDATING RESEARCH
PRIORITIES FOR
CEREBRAL PALSY
BY
MINDY AISEN, MD
Medical Director
Cerebral Palsy International Research
Foundation
Washington, DC
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 nongovernment agency sponsoring research and
education for cerebral palsy.
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Today’s Talk: Updating CP Research Priorities
(where we are and where we need to go)
Changing Picture of Cerebral Palsy
 Research Opportunities
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Epidemiology
Early Identification (imaging, electrophysiology)
Early Interventions
Neuro-protection
Neural Regeneration
Neuro-plasticity
Neuro-rehabilitation
Adults with Cerebral Palsy
CHANGING PICTURE OF
CEREBRAL PALSY
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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
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Most individuals with CP are now living well in adulthood
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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
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
EPIDEMIOLOGY
 Develop
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Natural history of impairments associated
with CP subgroups through-out the lifespan
Age- Specific Prevalence of Secondary
Conditions
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a National Registry for CP
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
Early Identification and Timing of
Injury
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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
NEUROIMAGING METHODS FOR
EARLY DIAGNOSIS; ETIOLOGY
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Structural MRI
Physical shape and form of the brain and its structures
 Subcortical volumes and cortical surface thicknesses
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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
NEUROIMAGING FOR ETIOLOGY;
PLASTICITY/MOTOR FUNCTION
 Functional
magnetic resonance imaging
(fMRI)
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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
NEUROIMAGING FOR ETIOLOGY;
PLASTICITY/MOTOR FUNCTION
 Functional
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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)
NEUROPHYSIOLOGICAL METHODS
FOR MAPPING BRAIN MOTOR
FUNCTION
 Transcranial
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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
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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
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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
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Animal Model Studies funded by CPIRF
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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 oligoprogenitor 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
NEUROPROTECTIVE AGENTS/TREATMENTS
RESEARCH NEEDS
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CPIRF funded studies (cont.)
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Effect of electrical stimulation on inactivated corticospinal
(CS) terminations
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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
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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
NEUROPROTECTIVE AGENTS
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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
NEURAL REGENERATION
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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
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PVL
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Neural stem cells
Oligodendrocytes
Repair/Replace Myelin on Axons
NEURAL REGENERATION
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Cell-Based Therapies: Endogenous sources
 Neural Stem Cells (adult stem cells)
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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)
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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
NEURAL REGENERATION
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Delayed Cord Clamping
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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
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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.
NEURAL REGENERATION
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Genetic Engineering
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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
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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
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
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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
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Mass Practice/Robotics
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2 studies funded by CPIRF of Upper Extremity Robot-assisted
Therapy
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1 study funded by CPIRF of Lower Extremity Robot-assisted Therapy
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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.
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
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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
CLINICAL RESEARCH FOR CHILDREN
WITH CP
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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 12week 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
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Virtual Reality
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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:
CLINICAL RESEARCH FOR
CHILDREN WITH CP
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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
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Chaotic Perturbation – Funded by CPIRF
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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
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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.
CLINICAL RESEARCH FOR
CHILDREN WITH CP
 Constraint-Induced
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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
CIMT FOR CP (cont)
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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
CLINICAL RESEARCH FOR
CHILDREN WITH CP
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Strength Training
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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).
CLINICAL RESEARCH FOR
CHILDREN WITH CP
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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.
CLINICAL RESEARCH FOR
CHILDREN WITH CP
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Hippotherapy
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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 washout period.
ADULTS WITH CEREBRAL PALSY
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Health Outcomes
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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
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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 ?
ADULTS WITH CEREBRAL PALSY
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Mechanisms of Secondary Complications
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Muscle Weakness, Fatigue
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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
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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
ADULTS WITH CEREBRAL PALSY
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Metabolic Syndrome
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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
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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?
BETTER DESIGNED CLINICAL TRIALS
FOR CP INTERVENTIONS
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Most current treatments for CP are not evidencebased
Most clinical studies assessing interventions in CP do
not have adequate sample size to achieve significance
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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
IMPORTANT CLINICAL QUESTIONS
TO BE ANSWERED
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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.
THANK YOU FOR YOUR ATTENTION !