Interventions to Enhance Motor Neurorecovery: Lessons...

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


Vice President Medical Affairs

The Spaulding Rehabilitation Hospital Network

Chief Physical Medicine and Rehabilitation


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

2

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

3

CNS system is the most complicated organ

4






minuteshours

days

minutes

hours

days

Brain Trauma is a process, notan event.

5

Genetics link: TRACK+ COBRIT+UW

Yue et al

Neurogenetics 2015 6

Post acute: what if behavior is the target?

Perhaps targeting what we are dealing with might work!

7

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

8

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

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

Benefit analysis- Caution

Davalos et al,Lancet 201211

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

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

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.

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

• Stimulate pyramidal cells in motor cortex

• Reduces contralatesionalhemisphere cortical excitability

• Increase hippocampalneurogenesis

Fluoxetine






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.






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

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

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

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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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






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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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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Giacino J Whyte J et al

NEJM 2012

184 subjects

4- 16 weeks

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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

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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Interventions to Enhance Motor Neurorecovery: Lessons...

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