Harvard Medical School. Vice President Medical Affairs The Spaulding Rehabilitation Hospital Network Chief Physical Medicine and Rehabilitation

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1 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

2 Disclosures None related to this presentation NIH, NIDRR, DOD, CIMIT, NFLPA My thanks!!!! Randi Black Schaffer Comments welcome 2

3 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

4 CNS system is the most complicated organ 4

5 Brain Trauma is a process, not an event. Department of Physical Medicine & Rehabilitation Harvard Medical School minutes hours days minutes hours days Spaulding Rehabilitation Hospital Massachusetts General Hospital Brigham & Women s Hospital 5

6 Genetics link: TRACK+ COBRIT+UW Yue et al Neurogenetics

7 Post acute: what if behavior is the target? Perhaps targeting what we are dealing with might work! 7

8 Baseline Acute Stroke: Diffusion Weighted MRI Treatment: citicoline 2000 mg per day for 6 weeks Lesion Volume = 62 cc Week 12 Chronic Stroke: T2-Weighted MRI 8 Lesion Volume = 17 cc

9 DATA POOLING ANALYSIS Total Recovery % Citicoline (Total) Placebo OR 1.33 [1.10;1.62]; p = Stroke, 33 (2002) 9

10 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 odds ratio Adverse events similar between groups Davalos et al,lancet

11 Benefit analysis- Caution Davalos et al,lancet

12 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

13 Drugs that may positively influence recovery Noradrenergic agonists Serotonergic agonists Dopamine agonists

14 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

15 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

16 Dextroamphetamine for stroke motor recovery in humans Author N Dose Measure Results Walker-Batson D, et al Sonde L, et al wks post infarct <4 wks post infarct 10 mg 2x/wk x 10 doses of drug or placebo paired with PT 10 mg 2x/wk x 10 doses of drug or placebo paired with PT Fugl-Meyer Motor Scale (FMMS) FMMS, Barthel Index p=.047 at conclusion and 12 mo. No signif. Differences at conclusion Trieg T, et al <6 wks post infarct 10 mg 2x/wk x 10 doses of drug or placebo paired with PT-NDT Rivermead, Barthel Index No signif. Differences at 3 mo. Gladstone DJ, et al days post infarct 10 mg 2x/wk x 10 doses of drug or placebo paired with PT-NDT FMMS FIM Chedoke- McMaster No signif. Differences At 6 wks, 3 mo.

17 Why little positive effect in humans? Dose 1-2 mg/kg in rats = 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

18 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 contralatesional hemisphere cortical excitability Increase hippocampal neurogenesis Fluoxetine

19 Chollet, F, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol Trial design N Drug/dose Outcome Measures Multi-center (9 sites), Double blind First infarct, hemiparesis NIHSS< days after stroke Fluoxetine 20 mg vs. Placebo Daily x 90 days Plus usual inpatient rehabilitation care FMMS mrs 0-2 Results At 90 Days: Fluoxetine +34 pts Placebo +24 pts p =.003 Fluoxetine 34% Placebo 11% p =.021 Department of Physical Medicine & Rehabilitation Harvard Medical School Spaulding Rehabilitation Hospital Massachusetts General Hospital Brigham & Women s Hospital

20 Fugl-Meyer motor scale (FMMS) scores Day 90 Fluoxetine Mean (SD) Placebo Mean (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 ( ).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) Upper Limb 24.2 (19.8) 11.8 (14.8) 12.4 (5.9 to 18.9) Lower Limb 12.2 (6.8) 10.1 (6.8) 2.1 (-.4 to 4.6).01 Department of Physical Medicine & Rehabilitation Spaulding Rehabilitation Hospital Harvard Medical School Massachusetts General Hospital Chollet et al Brigham & Women s Hospital

21 SSRIs for stroke Recovery: Review and Meta-analysis Mead, GE, et al. Stroke 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

22 Results: SSRIs for stroke Recovery: Review and Meta-analysis Mead, GE, et al. Stroke Cochrane Library 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

23 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 23

24 Persons with Stroke Stroke Lesion Dopamine Deficient PET Imaging Stroop Color-Word Test Symbol Digit Modalities Moderately Dopamine Deficient Dopaminergic Treatment Halstead Finger Tapping CSF dihydroxyphenylalanine CSF dihydroxyphenylacetate Genetic Risk Score TMS Minimally Dopamine Responsive Adequate Dopaminergic Signaling Non-Dopaminergic Neurotransmitter Treatment Combination Therapy Fugl-Meyer Modified Ashworth Patients who Qualify for Robotic Therapy Robotic Therapy Command Following Minimal Limb Pain Department of Physical Medicine & Rehabilitation Harvard Medical School Patients Not Qualified for Robotic Therapy Conventional Therapy Spaulding Rehabilitation Hospital Massachusetts General Hospital Brigham & Women s Hospital

25 AROUSAL AWARENESS AROUSAL AWARENESS AROUSAL AWARENESS AROUSAL AWARENESS AROUSAL AWARENESS Continuum of Recovery of Consciousness: (Adapted from Laureys, 2003) Normal Consciousness Coma Vegetative State Minimally Conscious State Acute Confusional State Department of Physical Medicine & Rehabilitation Harvard Medical School Spaulding Rehabilitation Hospital Massachusetts General Hospital Brigham & Women s Hospital 25

26 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 26

27 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 3/8/8 GCS Acute LOS 21/31/42 Rehab LOS 29/46/71 Longitudinal outcome of patients with disordered consciousness in the NIDRR TBI Model Systems Programs: (Nakase-Richardson, Whyte, Giacino, et al, J Neurotrauma, 2011) 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) 27

28 184 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

29 Department of Physical Medicine & Rehabilitation Harvard Medical School Spaulding Rehabilitation Hospital Massachusetts General Hospital Brigham & Women s Hospital

30 5HT Choi et al- Teng group 5HT- DOPAT Other studies with Buspar 30

31 Rehab Caveats Suggestion Gliosis Neurobehavioral Psychosocial 31

32 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 32

33 Our new home 33