Enhancing Rehabilitation After Stroke

Stroke is a leading cause of disability in the US (Thom 2006). The total number of stroke
survivors (currently estimated as 5.5 million Americans) will continue to increase as the
population ages and as the medical management of acute stroke continues to improve. Given
stroke's devastating impact on activities of daily living and the large numbers of Americans
afflicted, improving acute medical rehabilitation outcomes after stroke is of great public
health importance.

Predictors of poor functional recovery post-stroke include impairments in cognition and
motivation. Recent evidence indicates that acetylcholinesterase inhibitors may improve
cognition and motivation; hence, their use post-stroke may lead to improved rehabilitation
outcomes. Our group has demonstrated that use of the acetylcholinesterase inhibitor
donepezil is associated with improved functional recovery in a pilot sample (n = 40) of
elderly, cognitively impaired stroke survivors undergoing inpatient rehabilitation.
Specifically, in this 12 week open-label study, those subjects receiving donepezil
experienced a clinically meaningful 14 point greater improvement on the Functional
Independence Measure (FIM) than an archival comparator group.

Based on these promising pilot study results, we propose a 12-week randomized, double-blind,
placebo-controlled trial (followed by a 12 week off-drug observation period) in order to
test the efficacy of donepezil to promote post-stroke functional recovery in older,
cognitively impaired stroke survivors undergoing inpatient rehabilitation. We will also use
this randomized controlled trial to examine the drug's effect on cognition post-stroke;
specifically, the drug's effect on those cognitive domains (attention/working memory,
information psychomotor speed, and episodic memory) that are relevant to functional
outcomes.

Inclusion Criteria:

1. male or female;

2. aged 18 or older;

3. new ischemic stroke within the preceding 30 days; and

4. admitted to the an inpatient facility of the UPMC Institute for Rehabilitation and
Research for post-stroke rehabilitation.

Exclusion Criteria:

1. primary hemorrhagic stroke;

2. current use of a cholinomimetic drug including tacrine, donepezil, galantamine, and
rivastigmine;

3. contraindication to AchEi therapy including bradycardia (< 50 bpm), severe asthma or
COPD requiring nebulized medication, and active upper GI bleed or untreated gastric
ulcer;

4. myocardial infarction, poorly controlled congestive heart failure, or coronary bypass
surgery within the last 3 months;

5. current required use of an anticholinergic medication (e.g., for bladder spasm);

6. current aphasia severe enough to prevent valid neuropsychiatric assessment (e.g., a
score < 9 on the Token Test, part I and a score of < 14 (or <80% accuracy) on the
repetition task of the Boston Diagnostic Aphasia Examination);

7. current Major Depressive Episode AND HRSD > 20;

8. current active suicidal ideation, plan, or intent;

9. current mania or hypomania;

10. current psychosis;

11. meeting DMS-IV TR alcohol or substance abuse or dependence criteria within the
preceding 3 months;

12. subject and/or family informant do not speak English;

13. history of a progressive or unstable CNS disease (e.g., multiple sclerosis,
Parkinson's disease, HIV with CNS involvement);

14. medically unstable (determined by review of the subject's medical status with the
treating (clinical) physician and by review of standard blood tests); and

15. history of sensitivity to donepezil;

16. for potential subjects without a pacemaker or implantable defibrillator, exclusion
criteria will include (a) ECG evidence of second or third degree heart block ( b )
ECG evidence of a tri-fascicular block (LBBB and 1st degree AV Block; RBBB, left
anterior or left posterior hemiblock, and 1st degree AV block) or ( c ) history of
syncope within 1 year with a RBBB or a LBBB.

17. For females of child-bearing age, current pregnancy, plan to become pregnant while on
study drug, or refusal to avoid pregnancy while on study drug.

18. For females of child-bearing age, current breast feeding.

19. suicidal attempt in the past one year,

20. an inpatient admission for depression in the past one year