Download Nerurostimulants

Sheryl 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
No relevant financial disclosures
Speakers’ Bureau for Genentech
Acute
treatment
Prevention
Neuroprotection
Limit infarct
volume
Rehabilitation
and recovery
Reperfusion
Impact
behavior
Acute
therapy
 Therapy
 Restoration
 Compensation
 Modification
Subacute
therapy
Chronic
therapy
 Brain
 Regeneration
 Adaptation
 Neuroplasticity
Acute
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?
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Neuropharmacology
Transcranial magnetic stimulation
Constraint-induced movement therapy
Stem cell transplantation
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Modulation of noradrenergic, serotonergic, or
dopaminergic, acetylcholinergic systems
Robust animal literature
◦ plasticity
◦ augmentation of recovery of function
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Focus on motor and language deficits
Numerous completed trials:
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Small sample sizes
Heterogeneous patients
Heterogeneous methods
Heterogeneous outcome measures
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Ability to change
◦ Establish new connections (new
skills/functions)
◦ Let go of unused connections
(memories)
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The 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
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Noradrenergic – Stimulants
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D-amphetamine
Methylphenidate
Reboxetine
Modafinil
Serotonergic – SSRIs – fluoxetine,
citalopram, escitalopram
Dopaminergic – levodopa, amantadine
Acetylcholine esterase inhibitors –
donepezil, rivastigmine
Other – Peracitam, Lithium
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Amphetamine – 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
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Reboxetine – noradrenaline reuptake
inhibitor; improved speed and grip
strength (n=10)
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Methylphenidate (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)
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5HT – modulates cognitive functions
◦ Response inhibition
◦ Memory consolidation
◦ Modulates learning and emotion
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SSRI –
◦ High affinity for serotonin transporter
 Inhibits removal of serotonin from synaptic cleft
 Downregulates and desensitizes serotonin
receptors
 Dampens negative feedback on serotonin release
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Reduce neural inflammation
Enhance neurotrophin activity
Increase neurogenesis
Facilitate intracortical synapses
Reduces intracortical inhibition
Regulation of rhythmic activity in spinal
motor circuits
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Most 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
NNT = 6
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One 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)
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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
◦ Baseline 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
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Other studies:
◦ Sertraline also prevented post-stroke depression
(n=137) within 6 weeks
◦ Numerous other small studies
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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
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Most patients
were 60-70yo
and able to
consent (no
significant
aphasia or
cognitive
impairment)
Benefit of SSRI in
patients without
depression
◦ 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 1.68-9.57, P<0.005 for mRS 0-2
 OR 2.35, 95% CI 1.15-4.81, 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 0.90-3.68, p<0.01 for superior motor
recovery
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Dopamine regulates
◦ Neuronal excitability, synaptic transmission,
plasticity, protein trafficking, and gene
transcription
◦ Reward, learning, movement, plasticity
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Levodopa – precursor of dopamine, but
some adrenergic activity
Motor aphasia is associated with
dopaminergic neurotransmission
disturbances (mesocortical pathway)
Several case reports
RCT 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
53 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
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Single 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)
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Donepezil 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 FIMmotor compared to galantamine and controls,
p<0.0001
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Unknown mechanism of action
Piracetam 4800mg daily vs placebo
(n=203) x 12 wks
◦ -> reduced aphasia on Aachener Aphasie Test
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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
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Mechanism – reduced excitotoxicity, BDNF,
inhibition of apoptosis
◦ + effects in animal models
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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
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Cerebrolysin, a neuropeptide shown to be
neuroprotective in animal models of stroke
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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
Cerebrolysin and Recovery After
Stroke (CARS)
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prospective, randomized, double-blind,
placebo-controlled, multicenter, parallelgroup 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
Action
Research
Arm Test
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Database of 1,291 patients
◦ 6 in US and 1 in New Zealand
◦ Started in 2001 until a sample of convenience
sample of 200 patients
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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
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Patients 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
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NOT A RANDOMIZED TRIAL
LIKELY SELECTION BIAS
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Analysis of individual medications
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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
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Amphetamines – 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
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Levodopa – 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
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Medications with a negative impact on
brain plasticity and recovery
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Neuroleptics
Benzodiazepines
Antiseizure medications
Antihistamines
Impede synaptic formation in animal
models
Inhibition of long-term potentiation
Acute
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
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The 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
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48yo RH BF s/p RMCA infarction, NIHSS 15
Initial 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
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Day 4 – no major improvement noted, but cleared for
puree with thin liquids when awake
Day 4 – started on fluoxetine 20mg and modafinil 200mg
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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?
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63 year old African-American woman with
aphasia and R HP
◦ history of hypertension, diabetes mellitus, occasional
alcohol use
◦ no reported tobacco or illicit drug use
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Premorbid mRS = 0.
Baseline NIHSS = 4.
MRI revealed distal L ACA infarct.
24hr NIHSS = 10; neuroworsening d/t stroke
progression.
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Day 10 –
◦ OT - 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.
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Following her 14 days in IPR, she was
discharged home.
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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.
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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.
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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.
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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.
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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.
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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.
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After 18d modafinil and 10d methylphenidate, PT
and OT recommended IPR due to increased arousal
and ability to follow commands.
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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.
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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.
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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-tosevere strokes in the acute stage.
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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.