Download Evaluation and Management of Severe Brain Injury: Mission

Interventions to Enhance Motor Neurorecovery: Lessons
Learned and Opportunities
AAPMR 2015
Boston, MA
Ross Zafonte,DO.
Earle P. and Ida S. Charlton Chair and Professor Department
of Physical Medicine and Rehabilitation
Harvard Medical School
Vice President Medical Affairs
The Spaulding Rehabilitation Hospital Network
Chief Physical Medicine and Rehabilitation
Massachusetts General Hospital
Brigham and Women’s Hospital
RED SOX foundation/MGH Homebase Program
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
1
Disclosures
• None related to this presentation
• NIH, NIDRR, DOD, CIMIT, NFLPA
• Caveats!!!
• My thanks!!!!
– Randi Black Schaffer
• Comments welcome
2
Objectives
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•
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Describe recent post acute trials
Discuss limitations in recent post acute studies
List potential next steps in post acute clinical trials
One day better every day !***Caveats!
– TBI
– Stroke
– SCI
3
CNS system is the most complicated
organ
4
Brain Trauma is a process, not
an event.
minutes
hours
days
Department of Physical Medicine & Rehabilitation
Harvard Medical School
minutes
hours
days
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
5
Every brain injury is unique
6
Genetics link: TRACK+ COBRIT+UW
Yue et al
Neurogenetics 2015
7
Post acute: what if behavior is the
target?
Perhaps targeting what we are dealing
with might work!
8
Where
Citicoline Acts
Terminal
Glutamate
NMDA-R
AMPA/KA-R
Spine
V-gated
mGluR
Ca2+ Ch
Na+
DAG
IP3
Depolarization
PKC
Ca2+
mobilization
Ca2+
NOS
Proteases
PLA2
Arachidonic
acid
Altered
cytoskeleton
Xanthine
oxidase
Death Proteins
Endonucleases
NO
Dendrite
FREE RADICALS
DNA damage
CELL DEATH
9
Baseline
Acute Stroke: Diffusion Weighted MRI
Lesion Volume = 62 cc
Treatment: citicoline 2000 mg per day for 6 weeks
Week 12
Chronic Stroke: T2-Weighted MRI
10
Lesion Volume = 17 cc
DATA POOLING ANALYSIS
Total Recovery
30
25
20
% 15
10
5
0
25.2
Citicoline (Total)
20.2
Placebo
OR 1.33 [1.10;1.62]; p = 0.0034
Stroke, 33 (2002)
11
Citicoline Brain Injury Treatment Trial (COBRIT)
Effect of Citicoline on Cognitive Status Among Patients with
Traumatic Brain Injury. Published in JAMA 2012;308;19:1-8
Author’s Affiliations:
1Harvard
9University
2Mount
10Moss
Medical School, Department of Physical Medicine and
Rehabilitation, Boston, MA
Sinai School of Medicine, Department of Health Evidence and
Policy, New York, NY
3National
Institutes of Health, The Eunice Kennedy Shriver National
Institute of Child Health and Human Development, Bethesda, MD.
4University
of Alabama at Birmingham, Rehabilitation Medicine,
Birmingham, AL
5Columbia
6
University, Department of Biostatistics, New York, NY
Columbia University, Department of Epidemiology, New York, NY
7Geisinger
8Thomas
PA.
Medical Center, Neurosurgery, Danville, PA
Jefferson University, Neurosurgical Critical Care, Philadelphia,
Department of Physical Medicine & Rehabilitation
Harvard Medical School
of Maryland School of Medicine, Department of Neurosurgery,
Baltimore, MD;
Rehabilitation Research Institute, Philadelphia, PA
11University
of Pittsburgh at Pittsburgh, Department of Physical Medicine
and Rehabilitation, Pittsburgh, PA
12Uniformed
Services University of the Health Sciences, Center of
Neuroscience and Regenerative Medicine, Rockville, MD
13Virginia
VA
Commonwealth University, Division of Neurosurgery, Richmond,
14University
WA.
of Washington, Department of Neurological Surgery, Seattle,
15University
of Washington, Department of Rehabilitation Medicine,
Seattle, WA.
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
13
Kaplan Meier Survival Curves Stratified by
Treatment
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
90-day Global Test Results
Analysis
Global OR
Overall
0.98
0.83 – 1.14
0.71
Moderate and Severe
1.05
0.79 – 1.40
0.74
Complicated Mild
0.91
0.75 – 1.10
0.33
Department of Physical Medicine & Rehabilitation
Harvard Medical School
95% Confidence Interval
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
p-value
TBI-180 day results
16
ICTUS: European Stroke study
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Moderate and severe stroke
Germany(11) Portugal(11) and Spain(37)
2298 subjects
1000mg bid-IV x 4 weeks then enteral therapy- 6
weeks
• Global recovery- 1.03 odds ratio
• Adverse events similar between groups
Davalos et al,Lancet 2012
17
Benefit analysis- Caution
Davalos et al,Lancet 2012
18
Translational concerns: avoiding the
sirens song!!
• The quick jump from animals to humans
• Concerns with Phase 2 studies with out biotargets
– perceptions of benefit
• Phase 2 outcomes – hearing the siren!!
Schwamm et al NEJM 2015
19
Drugs that may positively
influence recovery
• Noradrenergic agonists
• Serotonergic agonists
• Dopamine agonists
Potential mechanisms of drug influence on
recovery
• Resolution of inflammatory response (SSRIs)
• Enhanced activation of primary cortices (adrenergic
agonists, SSRIs)
• Cortical remapping
– Axonal, dendritic sprouting
• adrenergic agonists, SSRIs
– Neurogenesis
• adrenergic agonists, SSRIs
Dextroamphetamine - effects in animal
studies
• Increases release of norepinephrine
• Promotes behavioral recovery when given days to
weeks after injury
• Accelerates neurite growth
• Promotes synaptogenesis
• Dosing 1-2mg/kg
Dextroamphetamine for stroke motor
recovery in humans
Author
N
Dose
Measure
Results
Walker-Batson D, et
al 1995
10
10 mg 2x/wk x 10 doses of
drug or placebo
paired with PT
Fugl-Meyer
Motor Scale
(FMMS)
p=.047 at
conclusion
and 12 mo.
10 mg 2x/wk x 10 doses of
drug or placebo
paired with PT
FMMS, Barthel
Index
No signif.
Differences
at conclusion
10 mg 2x/wk x 10 doses
of drug or placebo
paired with PT-NDT
Rivermead,
Barthel Index
No signif.
Differences at
3 mo.
10 mg 2x/wk x 10 doses of
drug or placebo
paired with PT-NDT
FMMS
FIM
ChedokeMcMaster
No signif.
Differences
At 6 wks, 3
mo.
2-4 wks
post infarct
Sonde L, et al. 2001
39
<4 wks
post infarct
Trieg T, et al
2003
24
Gladstone DJ, et al
2006
71
<6 wks post
infarct
5-10 days
post infarct
Why little positive effect in humans?
• Dose – 1-2 mg/kg in rats = 60-120 mg in humans
• PT dose low – 2x/wk for 60 min
• PT intervention heterogeneous
– not focused on one motor variable
– not standardized across patients
• Outcomes scales – broad measures of mobility and
ADLs
• Strokes – diverse locations
Serotonergic agents
(SSRIs) - CNS effects
• Inhibit inflammatory
cytokines
• Increase axonal sprouting
• Promote synaptogenesis
• Upregulate BDNF
• Induce VEGF expression
Fluoxetine
• Stimulate pyramidal cells in
motor cortex
• Reduces contralatesional
hemisphere cortical
excitability
• Increase hippocampal
neurogenesis
Chollet, F, et al. Fluoxetine for motor recovery after acute
ischaemic stroke (FLAME): a randomised placebo-controlled
trial. Lancet Neurol 2011.
Trial design
N
Multi-center (9 57
sites), Double
blind
56
First infarct,
hemiparesis
NIHSS<21
5-10 days after
stroke
Drug/dose
Fluoxetine
20 mg
vs.
Placebo
Results
At 90 Days:
Fluoxetine +34 pts
Placebo +24 pts
p = .003
FMMS
Daily x 90 days
mRS 0-2
Plus usual
inpatient
rehabilitation
care
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Outcome
Measures
Fluoxetine 34%
Placebo 11%
p = .021
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
SSRIs for stroke Recovery: Review and
Meta-analysis
Mead, GE, et al. Stroke 2013. Cochrane Library
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•
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52 RCTs, 4059 patients
0-12 months after stroke
Chinese language trials included
SSRI vs placebo or usual care
Effect of SSRI on measures of
dependence/disability
• Pts given SSRI less likely to be
dependent, disabled,
neurologically impaired,
depressed, anxious at end of
study
• Greater effect in those who
were depressed at
randomization
• Treatment effects smaller in
high quality trials
DA Tissue Levels in the Frontal Cortex
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Dixon et al
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Dopamine- defining responders
• Genetic risk- opportunity
– Humans who carry the D2R polymorphism TAQ-IA
express lower dopamine receptor density, lower
dopaminergic tone and cannot learn from errors as
efficiently as controls.
• Metrics of Dopamine functional status
– Cremer S et al
29
Persons with Stroke
Dopamine
Deficient
Stroke Lesion
PET Imaging
Stroop Color-Word Test
Symbol Digit Modalities
Moderately
Dopamine
Deficient
Dopaminergic
Treatment
Halstead Finger Tapping
CSF dihydroxyphenylalanine
CSF dihydroxyphenylacetate
Minimally
Dopamine
Responsive
Genetic Risk Score
TMS
Adequate
Dopaminergic
Signaling
Patients who Qualify
for Robotic Therapy
Fugl-Meyer
Non-Dopaminergic
Neurotransmitter
Treatment
Combination
Therapy
Robotic
Therapy
Modified Ashworth
Tran et al in press
Command Following
Minimal Limb Pain
Conventional Therapy
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Patients Not
Qualified for
Robotic Therapy
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Effect of levodopa in combination with physiotherapy on
functional motor recovery after stroke.
Scheidtmann K, Fries W, Muller F, Koenig E. Lancet 2001.
Trial Design
N
Drug/Dose
Outcome Measures
Results
Prospective
Double blind, RCT
47
Levodopa 100 mg
or placebo M-F, 30
min before PT x 3
wks
Rivermead motor
assessment
More improvement in
Rivermead in those on
levodopa plus PT at end of
3 wks p <0.004
Ischemic stroke 3
wks to 6 mo before
Then PT, M-F x 3
more wks both
groups
At end of 6 wks same
finding p=.02
PT sessions 1 hr
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Continuum of Recovery of Consciousness:
(Adapted from Laureys, 2003)
Department of Physical Medicine & Rehabilitation
Harvard Medical School
AWARENESS
AROUSAL
AWARENESS
AWARENESS
AROUSAL
AWARENESS
Vegetative State
Acute
Minimally
Conscious State Confusional State
AROUSAL
Coma
AROUSAL
AWARENESS
AROUSAL
Normal
Consciousness
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
32
Incidence of diagnostic error
 37% (Childs et al, Neurol, 1993)
 43% (Andrews et al, BMJ, 1996)
 41% (Schnakers et al, Brain Injury, 2008)
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
33
184 subjects
4- 16 weeks
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Giacino J Whyte J et al
NEJM 2012
34
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Zolpidem Treatment Effects
Naming/Repetition Task
Brefel-Courbon, et al., 2007
Paradoxical Excitation, Cerebral Metabolism, and Electroencephalographic (EEG) Activity in Stages of
Coma Recovery.
DBS
Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Brown EN, Lydic R, and Schiff, ND, N Engl J Med 2010;363:2638-2650
Spinal Cord Injury
38
Clonidine
Barbeau et al Spinal Cord 2003
39
5HT
• Choi et al- Teng group
• 5HT- 8OH-DPAT
• Other studies with Buspar
40
Cholinergic hypothesis
Jordan et al J of Neurofronteir 2014
Yu et al- PNAS 2012
41
4-AP
• 15 subjects
• Ambulatory spinal cord injury
subjects
• DB Placebo controlled cross
over trial
– 40mg/ day- 2 weeks
• Positive reports from subjects
• No difference in metrics of
ambulation
DeForge et al Spinal Cord 2004
42
Summary of facilitated ambulation
Domingo et al J of Neurotrauma
43
Chronic Intermittent Hypoxia In SCI
• Triggers synthesis of
BDNF and activation
fo TrkB
• Strengthens
synaptic input
• 19 subject RCT
• 15 90 second
hypoxia episodes for
5 days
Hayes et al .Neurology2014
Spinal Cord Stimulation
Lower
extremity
EMG
activity
during
voluntary
movement
Angeli et al, Brain, 2014
Transcranial Magnetic Stimulation:
physics and physiology
Capacitor
Figure 8 coil
http://www.biomag.hus.fi/tms/
Rehab Caveats
Suggestion
Gliosis
Neurobehavioral
Psychosocial
47
Placebo response: is the stadium the issue ?
• Huge issue in post acute studies
– Issues we may need to consider
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Observer issues!!!
Placebo run in
SPCD design
Placebome – the elephant in the room
48
The Placebome: Genetics and the placebo effect
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Levine et al 1978- Nature
Biologic response to psychosocial enviornment
Genetics variation can raise the possibility of placebo
response– an example COMT-Met/MET- low activity
high tone
Raise the possibility of genetics screening
Placebo genetic drug interaction
Interaction as possible major factor in RCT
The need for NO treatment groups
Hall et al Trends in Molecular
Medicine 2015
49
Conclusion
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Tremendous heterogeneity
Site based variability
Links to biomarkers
Some advantage to targeting
behavior or status!
Need to refine outcome
metrics
Placebo based issues
Defining extremes
Not all bad news
50
Our new home
51