1 Pharmacological Approaches to Promote Brain RecoverySheryl Martin-Schild, MD, PhD Louisiana Emergency Response Network – Stroke Medical Director Medical Director of Neurology & Stroke - New Orleans East Hospital and Touro Infirmary Dr. Brain Inc. – President & CEO
2 No relevant financial disclosures Speakers’ Bureau for Genentech
3 Stroke research & treatmentAcute treatment Rehabilitation and recovery Prevention Neuroprotection Reperfusion Limit infarct volume Impact behavior
4 Rehabilitation & RecoveryAcute therapy Subacute therapy Chronic therapy Therapy Restoration Compensation Modification Brain Regeneration Adaptation Neuroplasticity
5 Rehabilitation & RecoveryAcute therapy Subacute therapy Chronic therapy Advancement is dependent on deficits, participation, and resources. Is there a role for adjunctive restorative therapies during any of these stages to augment function?
6 Enhancement strategiesNeuropharmacology Transcranial magnetic stimulation Constraint-induced movement therapy Stem cell transplantation
7 Neuropharmacology Modulation of noradrenergic, serotonergic, or dopaminergic, acetylcholinergic systems Robust animal literature plasticity augmentation of recovery of function Focus on motor and language deficits Numerous completed trials: Small sample sizes Heterogeneous patients Heterogeneous methods Heterogeneous outcome measures
8 What is meant by plasticity?Ability to change Establish new connections (new skills/functions) Let go of unused connections (memories)
9 How can plasticity be proven?
10 Maximizing neuroplasticityThe peri-infarct areas need to be accessed Rehabilitation interventions must be task specific and goal-directed. Repetition leads to establishing new connections. tasks must be challenging and interesting enough to maintain an individual’s attention
11 Candidate medications to augment neuroplasticityNoradrenergic – Stimulants D-amphetamine Methylphenidate Reboxetine Modafinil Serotonergic – SSRIs – fluoxetine, citalopram, escitalopram Dopaminergic – levodopa, amantadine Acetylcholine esterase inhibitors – donepezil, rivastigmine Other – Peracitam, Lithium
12 Noradrenergic medicationsAmphetamine – conflicting results in small RCTs AMPH (n=10), mx doses 45min before PT x 10 sessions, 15-30d post stroke Significantly greater gains FMMS at 12mo Not replicated (n=21), followed by more negative One study (n=10) showed benefit for aphasia Reboxetine – noradrenaline reuptake inhibitor; improved speed and grip strength (n=10)
13 Noradrenergic medicationsMethylphenidate (DA and NE) – RCT (n=21) during IPR 15mg twice daily x 3wks depression (HAM-D, p=0.028; ZDS, p=0.055) cognition (MMSE, p=ns) motor function (FMMS, p=0.075; M-FIM, p=0.032)
14 Serotinergic medications5HT – modulates cognitive functions Response inhibition Memory consolidation Modulates learning and emotion SSRI – High affinity for serotonin transporter Inhibits removal of serotonin from synaptic cleft Downregulates and desensitizes serotonin receptors Dampens negative feedback on serotonin release
15 SSRI – Reduce neural inflammation Enhance neurotrophin activityIncrease neurogenesis Facilitate intracortical synapses Reduces intracortical inhibition Regulation of rhythmic activity in spinal motor circuits
16 Serotinergic medicationsMost frequently studied = fluoxetine Fluoxetine reduced development of depression (n=31), and improved motor recovery, independent of depression measures FLAME study, RCT, (n=118), fluoxetine 20mg vs placebo x 90d within 5-10d from onset HP stroke Age 18-85, FMMS <55 Excluded for NIHSS >20, premorbid disability, severe aphasia, depression
17 FLAME results
18 NNT = 6
19 Escitalopram and enhancement of cognitive recovery following strokeOne hundred twenty-nine patients were treated within 3 months following stroke. The 12-month trial included 3 arms: a double-blind placebo-controlled comparison of: escitalopram (n=43) placebo (n=45) nonblinded arm of Problem Solving Therapy (n=41) Randomized within 3 months of an index stroke Age 50-90, ICH or AIS, excluded for severe depression, severe comprehension deficit, impaired decision-making capacity
20 Escitalopram and enhancement of cognitive recovery following strokeBaseline differences – escitalopram group was younger, less frequently had HTN, trend for higher baseline NIHSS scores No adverse event associated with escitalopram Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Escitalopram associated with improvement in global cognitive functioning, driven by improvement in verbal and visual memory functions Impact of escitalopram was independent on measures of depression
21 Serotinergic medicationsOther studies: Sertraline also prevented post-stroke depression (n=137) within 6 weeks Numerous other small studies Better self care and ambulation than adrenergic medications Beneficial effects on motor recovery, independent on effect on mood Prevention of depression Meta-analysis – longterm benefits on disability, neuro deficits, and depression
22 SSRIs and functional outcomeMost patients were 60-70yo and able to consent (no significant aphasia or cognitive impairment) Benefit of SSRI in patients without depression
23 Pre-stroke use of SSRI 239 patients, age 69 +/- 14y; 42% men, baseline median NIHSS 7 [IQR,10]. 51 taking SSRI before stroke and continued vs 188 prescribed SSRI during admission Adjusted multivariate logistic regression – SSRI before stroke associated with OR 4.00, 95% CI , P<0.005 for mRS 0-2 OR 2.35, 95% CI , p=0.02 for improved early clinical recovery (4 or more point improvement in the NIHSS from baseline to discharge or NIHSS score of 1or less at discharge) OR 1.82, 95% CI , p<0.01 for superior motor recovery
24 Dopaminergic medicationsDopamine regulates Neuronal excitability, synaptic transmission, plasticity, protein trafficking, and gene transcription Reward, learning, movement, plasticity
25 Dopaminergic medicationsLevodopa – precursor of dopamine, but some adrenergic activity Motor aphasia is associated with dopaminergic neurotransmission disturbances (mesocortical pathway) Several case reports
26 Dopaminergic medications -aphasiaRCT levodopa 100mg/d with SLP vs SLP alone early (2-8 wks) post-stroke patients with aphasia BDAE (Boston Diagnostic Aphasia Exam) Levodopa (n=20) or placebo (n=19) 30min before 45min SLP sessions 5x/wk x 3 wks Improvement in animal naming and repetition of high-frequency phrases/sentences Low statistical power No adverse reactions
27 Dopaminergic medications- motor53 patients, RCT, 100mg daily levodopa vs placebo, 30min before therapy x 3wks 3wks – 6 mths post stroke Rivermead motor assessment Improved motor function compared to therapy alone at 3 and 6 wks Levodopa associated with gait independence and earlier Study not able to be replicated Ongoing trial, targeting 572 pts nonambulatory after stroke levodopa + carbidopa vs placebo with PT x 6wks with POM independent gait at 8wks
28 Dopaminergic medications- otherSingle dose levodopa to augment TMS induced movement; encoding of motor memory? Bromocriptine (D2RA) – positive effect on working memory and executive function Improved chronic non-fluent aphasia (n=11)
29 Acetylcholine esterase inhibitors- otherDonepezil vs placebo (n=26) x 16wks – drug-associated improvement in Aphasia Quotient of the Aphasia Test Battery Open label galantamine or donepezil vs historical controls in 40 pts ≥60yo while IPR X12 wks Donepezil 14pt greater improvement on FIM- motor compared to galantamine and controls, p<0.0001
30 Piracetam Unknown mechanism of actionPiracetam 4800mg daily vs placebo (n=203) x 12 wks -> reduced aphasia on Aachener Aphasie Test Piracetam 4800mg daily vs placebo (n=24) x 12 wks within 14d of stroke x 6wks -> improved spontaneous speech -> improved semantic and syntactic structure -> PET – increased activity in language centers
31 Lithium Mechanism – reduced excitotoxicity, BDNF, inhibition of apoptosis + effects in animal models 80 pts with 1st stroke, noncardioembolic MCA, randomized to lithium 300mg bid or placebo within 48hrs of stroke x 30d Improved NIHSS and Fugl-Meyer for cortical strokes only No serious adverse events
32 Cerebrolysin and Recovery After Stroke (CARS)Cerebrolysin, a neuropeptide shown to be neuroprotective in animal models of stroke Inhibits excitotoxicity Inhibits apoptosis Neurotrophic Reduction in infarct volume Improvement in functional recovery Earlier the better In humans, post hoc subgroup analysis (n=252) trend in favor of Cerebrolysin for improved outcome and a reduction in mortality if NIHSS>12 Given <48hrs after stroke
33 Cerebrolysin and Recovery After Stroke (CARS)prospective, randomized, double-blind, placebo-controlled, multicenter, parallel- group study Cerebrolysin (30 mL/d) or a placebo (saline) once daily for 21 days, beginning at 24 to 72 hours after stroke onset. standardized rehabilitation program for 21 days initiated within 72 hours after stroke onset The primary end point was the Action Research Arm Test score on day 90. 208 patients enrolled; no major baseline differences
34 Cerebrolysin and Recovery After Stroke (CARS)Action Research Arm Test
35 Cerebrolysin and Recovery After Stroke (CARS)
36 PSROP – Post-Stroke Rehabilitation Outcomes ProjectDatabase of 1,291 patients 6 in US and 1 in New Zealand Started in 2001 until a sample of convenience sample of 200 patients Determine whether rehab outcomes are affected by neuropharmacology during IPR 20% received one or more neurostimulants (methylphenidate, modafinil, levodopa, amantadine, or bromocriptine) 2% received tx ≤3 days and were not included in the analyses
37 PSROP – Post-Stroke Rehabilitation Outcomes ProjectPatients tx with neurostimulants ≥4 days Longer LOS (25.7 d vs 17.1 d, p<0.0001) Increases in motor FIM scores were similar (21.1 vs 22.4) Increases in cognitive FIM scores were similar (4.1 vs 4.9) Did not influence discharge disposition NOT A RANDOMIZED TRIAL LIKELY SELECTION BIAS
38 PSROP – Post-Stroke Rehabilitation Outcomes ProjectAnalysis of individual medications 59 patients received amantadine 5 patients received bromocriptine 61 patients received methylphenidate 29 patients received modafinil Low overall use No convincing benefit, but all of the flaws of a registry based study
39 Rehab pharmacology – side effects & safetyAmphetamines – nervousness, insomnia, loss of appetite, and addiction Methylphenidate – reports vary from no adverse events to exacerbated BP and HR Reboxetine – nausea Modafinil – headache, increased irritability, aggressiveness SSRIs – transient digestive disorders; lower development of depression
40 Rehab pharmacology – side effects & safetyLevodopa – reasonably safe, no serious side effects Amantadine – no significant difference in adverse events Acetylcholinesterase inhibitors – irritability, insomnia and tiredness during titration; seizures questionable; GI Piracetam – nonsignificant increase in death at one month, no significant increase in adverse events
41 Neuropharmacology to avoidMedications with a negative impact on brain plasticity and recovery Neuroleptics Benzodiazepines Antiseizure medications Antihistamines Impede synaptic formation in animal models Inhibition of long-term potentiation
42 Rehabilitation & RecoveryAcute therapy Subacute therapy Chronic therapy Factors complicating progress in rehab pharmacology: Patient selection Timing post stroke Coupling of drug to therapy Measurements Task-specific augmentation Intensity and duration of treatment
43 Ongoing rehab pharmacology trials –clinicaltrials.govThe Efficacy of Citalopram Treatment in Acute Stroke (TALOS) The Neurotrophic Effects of Lithium Carbonate Following Stroke: A Feasibility Study Combining drugs or drug and other technology Neurobiological Principles Applied to the Rehabilitation of Stroke Patients Sinemet, ritalin, amphetamine, and placebo combined with TMS The Effect of Combining Robotic-Assisted Therapy With Levodopa/Carbidopa in Chronic Post-Stroke Upper-Limb Hemiparesis Effects of Contralesional Repetitive Magnetic Stimulation Combined With Fluoxetine on Motor Recovery in Acute Stroke Patients
44 Case 1 48yo RH BF s/p RMCA infarction, NIHSS 15Initial evals on day 2: SLP – able to attain attention, unable to sustain attention more than 30 seconds, strict NPO OT & PT – max A ADLs and dependent for gait; unable to tolerate 3 hrs of therapy, recommend SNF Day 4 – no major improvement noted, but cleared for puree with thin liquids when awake Day 4 – started on fluoxetine 20mg and modafinil 200mg
45 Case 1 Day 5 evals – SLP improved attention and communication, OT & PT – “Pending ability to participate for 3hrs of therapy” Day 6 evals – all recommend IPR Day 8 -> IPR with mRS 4 Day 20 -> home with outpatient therapies, mRS 3 Did the fluoxetine and/or modafinil impact her natural history? Is there a role for rehab pharmacology to promote a higher level of subacute rehab care? Are we ready for a clinical trial with primary outcome measure of change in recommendation for discharge to IPR vs SNF?
46 Case 2 63 year old African-American woman with aphasia and R HPhistory of hypertension, diabetes mellitus, occasional alcohol use no reported tobacco or illicit drug use Premorbid mRS = 0. Baseline NIHSS = 4. MRI revealed distal L ACA infarct. 24hr NIHSS = 10; neuroworsening d/t stroke progression.
47 Case 2 Day 10 – Day 13 - the patient was discharged to IPROT - she required increased time to arouse PT – consistent cueing was necessary for wakefulness Methylphenidate 20mg/10mg started Day 12 – OT & PT note improved LOC and attention -> IPR Day 13 - the patient was discharged to IPR NIHSS of 3 and a mRS score of 4. Following her 14 days in IPR, she was discharged home.
48 Case 3 56 year old Caucasian man presented with sudden onset inability to speak and right-sided weakness noted upon waking. history of coronary artery disease status post-coronary artery bypass grafting, radiculopathic pain, occasional alcohol use and a current smoker. Pre-morbid mRS = 0. Baseline NIHSS of 16. Imaging revealed a left middle cerebral artery distribution ischemic stroke with occlusion of the left common carotid artery to internal carotid artery at its origin.
49 Case 3 Speech language pathology (SLP) documented that the patient was only able to maintain a wakeful state for 2-3 minutes at a time and required verbal and tactile cues for participation. OT documented that the patient was distractible by external stimuli. Day 5 - modafinil (200 mg daily) was given. Day 9 - therapy recommended discharge to IPR due to improved wakefulness and attention. Day 10 – Discharge to IPR; NIHSS was 13 with a mRS score of 5. After twenty-two days in IPR -> being discharged home.
50 Case 4 68 year old Caucasian woman presented immobile after two days of left-sided weakness. history of hypertension with no reported tobacco, alcohol, or illicit drug use. Pre-morbid mRS = 4. Baseline NIHSS = 19 with depressed LOC. Imaging revealed ICH (13cc) extending from the right centrum semiovale to the right thalamus with surrounding edema and IVH. 24hr NIHSS = 22 -> external ventricular drain placement for obstructive hydrocephalus.
51 Case 4 Initial therapy evaluations were delayed by 12d due to the patient being medically unstable, intubated, and sedated. Modafinil (200 mg daily) and later methylphenidate (20 mg daily) were administered before the patient was deemed appropriate for therapy evaluations. OT documented drowsiness and impaired attention. PT documented an obtunded state that impaired learning. After 18d modafinil and 10d methylphenidate, PT and OT recommended IPR due to increased arousal and ability to follow commands.
52 Case 4 She developed new onset paroxysmal atrial fibrillation leading to discontinuation of the neurostimulants. At the time of discharge, she was drowsy with an NIHSS of 19 and a mRS of 5. After 48d hospital stay, the patient was discharged to IPR. After 22d in IPR -> admitted to a skilled nursing facility.
53 Case discussion Neurostimulants can augment attention and LOC in the acute post-stroke phase. By increasing alertness, neurostimulants have the potential to help stroke patients meet IPR criteria. Following treatment with methylphenidate, modafinil, or both, all four patients demonstrated improved participation resulting in upgraded recommendations for the next appropriate level of rehabilitation care.
54 Case discussion The patient in case 4 required neurostimulant discontinuation due to development of paroxysmal atrial fibrillation. While it is not known whether the neurostimulant caused her atrial fibrillation, methylphenidate is associated with tachycardia. Neurostimulants may not be tolerated by all acute stroke patients. Neurostimulants, particularly when administered to the elderly or in combination, may pose risk for some acute stroke patients. Thus, further study is necessary to establish the safety of FDA approved stimulants in patients with moderate-to- severe strokes in the acute stage.
55 Case discussion Neurostimulants can augment attention and LOC in the acute post-stroke phase. By increasing alertness, neurostimulants have the potential to help stroke patients meet IPR criteria. Following treatment with methylphenidate, modafinil, or both, all four patients demonstrated improved participation resulting in upgraded recommendations for the next appropriate level of rehabilitation care.