Interventions to Enhance Motor Neurorecovery: Lessons...
Transcript of Interventions to Enhance Motor Neurorecovery: Lessons...
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Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
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
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Disclosures• None related to this presentation
• NIH, NIDRR, DOD, CIMIT, NFLPA
• My thanks!!!!
– Randi Black Schaffer
• Comments welcome
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Objectives
• 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
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CNS system is the most complicated organ
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Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
minuteshours
days
minutes
hours
days
Brain Trauma is a process, notan event.
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Genetics link: TRACK+ COBRIT+UW
Yue et al
Neurogenetics 2015 6
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Post acute: what if behavior is the target?
Perhaps targeting what we are dealing with might work!
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Acute Stroke: Diffusion Weighted MRI
Lesion Volume = 62 cc
Treatment: citicoline 2000 mg per day for 6 weeks
Chronic Stroke: T2-Weighted MRI
Lesion Volume = 17 cc
Baseline
Week 12
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DATA POOLING ANALYSISTotal Recovery
25.2 20.2
0
5
10
15
20
25
30
%
Citicoline (Total) Placebo
OR 1.33 [1.10;1.62]; p = 0.0034Stroke, 33 (2002) 9
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ICTUS: European Stroke study
• 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 201210
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Benefit analysis- Caution
Davalos et al,Lancet 201211
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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
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• Noradrenergic agonists
• Serotonergic agonists
• Dopamine agonists
Drugs that may positively
influence recovery
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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
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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
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Dextroamphetamine for stroke motor recovery in humans
Author N Dose Measure Results
Walker-Batson D, et al 1995
10
2-4 wks
post infarct
10 mg 2x/wk x 10 doses of drug or placebopaired with PT
Fugl-Meyer Motor Scale (FMMS)
p=.047 at conclusion and 12 mo.
Sonde L, et al. 2001 39
<4 wkspost infarct
10 mg 2x/wk x 10 doses of drug or placebopaired with PT
FMMS, Barthel Index
No signif.Differencesat conclusion
Trieg T, et al2003
24<6 wks post infarct
10 mg 2x/wk x 10 dosesof drug or placebo paired with PT-NDT
Rivermead, Barthel Index
No signif.Differences at 3 mo.
Gladstone DJ, et al 2006
71
5-10 days post infarct
10 mg 2x/wk x 10 doses of drug or placebopaired with PT-NDT
FMMSFIMChedoke-McMaster
No signif.DifferencesAt 6 wks, 3 mo.
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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
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Serotonergic agents (SSRIs) - CNS effects
• Inhibit inflammatory cytokines
• Increase axonal sprouting
• Promote synaptogenesis
• Upregulate BDNF
• Induce VEGF expression
• Stimulate pyramidal cells in motor cortex
• Reduces contralatesionalhemisphere cortical excitability
• Increase hippocampalneurogenesis
Fluoxetine
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Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Trial design N Drug/dose OutcomeMeasures
Results
Multi-center (9 sites), Double blind
First infarct, hemiparesisNIHSS<21
5-10 days after stroke
57
56
Fluoxetine20 mgvs.Placebo
Daily x 90 days
Plus usual inpatient rehabilitation care
FMMS
mRS 0-2
At 90 Days:Fluoxetine +34 ptsPlacebo +24 ptsp = .003
Fluoxetine 34%Placebo 11%p = .021
Chollet, F, et al. Fluoxetine for motor recovery after acute
ischaemic stroke (FLAME): a randomised placebo-controlled
trial. Lancet Neurol 2011.
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Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Day 90 FluoxetineMean (SD)
PlaceboMean (SD)
Difference (95% CI)
P value
Total Score 53.7 (27.8) 35.1 (22) 18.6 (9.2 to 27.9)
.0006
Upper Limb 29.7 (22.2) 16.2 (16.6) 13.5 (6.2-20.8) .001
Lower Limb 24 (7.9) 18.9 (8.2) 5.1 (2.1 to 8.1) .001
Change from day 0 to 90
Total Score 36.4 (21.3) 21.9 (16.7) 14.5 (7.3 to 21.6)
.003
Upper Limb 24.2 (19.8) 11.8 (14.8) 12.4 (5.9 to 18.9)
.002
Lower Limb 12.2 (6.8) 10.1 (6.8) 2.1 (-.4 to 4.6) .01
Fugl-Meyer motor scale (FMMS) scores
Chollet et al. 2011
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SSRIs for stroke Recovery: Review andMeta-analysis
Mead, GE, et al. Stroke 2013. Cochrane Library
• 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
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SSRIs for stroke Recovery: Review and Meta-analysisMead, GE, et al. Stroke 2013. Cochrane Library
Results:
• 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
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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
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Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Halstead Finger Tapping
Symbol Digit Modalities
PET Imaging
Stroop Color-Word Test
CSF dihydroxyphenylalanine
CSF dihydroxyphenylacetate
TMS
Stroke Lesion
Dopamine
Deficient
Moderately
Dopamine
Deficient
Minimally
Dopamine
Responsive
Adequate
Dopaminergic
Signaling
Dopaminergic
Treatment
Persons with Stroke
Patients who Qualify
for Robotic Therapy
Combination
Therapy
Fugl-Meyer
Modified Ashworth
Minimal Limb Pain
Command Following
Patients Not
Qualified for
Robotic Therapy
Non-Dopaminergic
Neurotransmitter
Treatment
Conventional Therapy
Robotic
Therapy
Genetic Risk Score
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Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Normal
Consciousness
AR
OU
SA
L
AW
AR
EN
ES
S
Coma
AR
OU
SA
L
AW
AR
EN
ES
S
Vegetative State
AR
OU
SA
L
AW
AR
EN
ES
S
Acute
Confusional State
AR
OU
SA
L
AW
AR
EN
ES
S
Minimally
Conscious State
AR
OU
SA
L
AW
AR
EN
ES
S
Continuum of Recovery of Consciousness: (Adapted from Laureys, 2003)
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Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
Incidence of diagnostic error
37% (Childs et al, Neurol, 1993)
43% (Andrews et al, BMJ, 1996)
41% (Schnakers et al, Brain Injury, 2008)
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At Least 1
FUP - Overall
Sample
N=337
Age (quartiles) 20/27/41
Male 72%
Race
White 67%
Black 23%
Hispanic 7%
Other 3%
Education
<12 years 29%
≥ 12 years 46%
Missing 25%
Cause of Injury
N Motor (%) 66%
ED GCS 7/9/10
Rehab Admit
GCS
3/8/8
Acute LOS 21/31/42
Rehab LOS 29/46/71
Recovery of consciousness During rehabilitation = 68% (n=268/337)
After rehab discharge (n=128)
By 1 year = 59% (n=76)
By 2 years = 66% (n=85) +9
By 5 years = 74% (n=95) +10
Recovery of Function (n=337 w/ at least
1 f-u between 1 and 5 yrs post-injury)
Independent living = 20% (n=66)
Employable = 23% (n=63)
Deaths = 8% (n=28; M of 2.1 years)
Longitudinal outcome of patients with disordered
consciousness in the NIDRR TBI Model Systems
Programs: (Nakase-Richardson, Whyte, Giacino, et al, J
Neurotrauma, 2011)
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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
184 subjects
4- 16 weeks
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Department of Physical Medicine & Rehabilitation
Harvard Medical School
Spaulding Rehabilitation Hospital
Massachusetts General Hospital
Brigham & Women’s Hospital
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5HT
• Choi et al- Teng group
• 5HT- DOPAT
• Other studies with Buspar
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Rehab Caveats
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SuggestionGliosis
NeurobehavioralPsychosocial
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Placebo response: is the stadium the issue ?
• Huge issue in post acute studies
– Issues we may need to consider
• Observer issues!!!
• Placebo run in
• SPCD design
• Placebome – the elephant in the room
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Our new home
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