Pharmacological Therapies to Enhance Motor Recovery and Walking After Stroke

Emerging Strategies

Wieslaw Oczkowski

Disclosures

Expert Rev Neurother. 2013;13(8):903-909. 

In This Article

Can Recovery of Motor Weakness & the Ability to Walk be Enhanced by Pharmacotherapy?

Presently, the only pharmacological agent that has been shown to alter the natural history and recovery after stroke is tissue plasminogen activator given within 4.5 h after stroke onset.[27] However, a new era in pharmacotherapy to improve recovery after brain injury may be near.

Giacino et al.[28] randomized patients with severe traumatic brain injury to amantidine, an indirect dopamine agonist, or placebo, between 4 and 16 weeks after injury. Patients were treated for 4 weeks and then assessed at 6 weeks. Amantidine increased the speed of recovery during the active treatment phase. Although the Disability Rating Scale (DRS) between baseline and at 6 weeks was similar in both groups, a post hoc analysis at the end of 4 weeks of treatment showed that more patients on amantidine had an improvement in their Disability Rating Scale scores and categories. It would now seem that another pharmacological intervention changes the course of 'natural' recovery after brain injury.

Ongoing and more recent research has suggested that there is potential to change the course of recovery after brain injury due to stroke with pharmacotherapy. Dopaminergic agents and selective serotonin-reuptake inhibitors (SSRIs) have to date shown the most promise in altering the natural history of recovery after stroke.[29]

Dopamine is a neurotransmitter that may promote neuroplasticity in the cerebral cortex and that may also be important in working memory and learning.[30] Animal studies suggest that dopamine is an important neurotransmitter for learning and memory.[31] A single oral dose of 100 mg of levodopa and 25 mg of carbidopa can enhance the ability of patients with chronic stroke to encode an elementary motor function.[32] In 2001, Scheidtmann et al. randomized 53 patients between 3 weeks and 6 months after stroke to either 3 weeks of 100 mg of levodopa with carbidopa or placebo, daily, 5 days per week, before physiotherapy. Patients who received levodopa had a significant improvement in motor recovery and in particular many more achieved the ability to walk early and independently.[33] Subsequent small studies using levodopa with or without methylphenidate[34] or levodopa with or without amphetamine[35] could not show a difference in motor recovery or improvement in functional outcomes with treatment. An ongoing study, started in 2010, will enroll 572 patients with a new stroke who cannot walk 10 m, to receive 100 mg of levodopa and 25 mg of carbidopa, or placebo, 1 h before physiotherapy. Patients will be treated for a maximum of 6 weeks. The primary outcome will assess the number of patients walking independently at 8 weeks after randomization.[101]

SSRIs are important in regulation of memory, mood and sleep. They have also been implicated in modulating neuronal plasticity.[30] Animal studies suggest that SSRIs may be involved in neurogenesis and activation of cortical motor areas.[31] A single dose of citalopram can normalize the balance in cortical excitability, as measured by transmagnetic stimulation, of the affected as compared to the unaffected hemisphere in stroke patients.[36] Patients more than 6 months after stroke, in a single dose crossover experiment with citalopram, showed improved hand dexterity as measured by the nine-hole peg test, while using the affected hand.[37] A single dose of fluoxetine given to patients, 2 to 3 weeks after stroke, showed improved motor skills on the nine-hole peg test, and increased activation of the affected side on functional magnetic resonance imaging.[38]

These results suggest that SSRIs alter motor recovery and motor function. Chollet et al. randomized 118 acute ischemic stroke patients, within 5 to 10 days of stroke, to fluoxetine (20 mg/day by mouth) or placebo.[39] After 90 days of treatment, patients were assessed using the Fugl–Meyer motor scale (motor score varies from 0 to 100, 66 points upper limb, 34 points lower limb; movements measured as none, partial or full). The mean improvement in the total Fugl–Meyer motor scale from baseline to 90 days was significantly higher in those patients treated with fluoxetine. The improvement was present both in the arm and the leg. Patients treated with fluoxetine were more likely to reach functional independence as measured by the modified Rankin Scale (score varies from 0 to 6, 0 = normal, 6 = death).

A recent meta-analysis of randomized controlled trials that recruited stroke patients treated with an SSRI compared to usual care or placebo identified 52 trials for analysis.[40] Although the use of SSRIs seems to be associated with an improvement in dependence, disability, neurological impairment and depression, methodological limitations call for large randomized trials to confirm these findings.

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