Study of the Effects on Motor Recovery of Early Post-stroke Spasticity Treatment

Background: Stroke is the first cause of motor impairment and disability in adults. 80% of post-stroke survivors have a motor weakness resulting in hemiplegia. Post-stroke patients partially recover from their motor impairments . These patients reach their maximum motor score round the first 20 weeks. In all cases, motor recovery period is considered completed beyond the sixth month. There is a consensus of epidemiological studies and of more fundamental works on brain plasticity, for the positive effect of rehabilitation on post stroke motor recovery. Then the main objective of rehabilitation during the first six months following stroke is to facilitate motor recovery.

There are many arguments in animals and humans for the pharmacological modulation of post-stroke motor recovery. In animals, the experimental data suggesting efficacy of amphetamine in motor recovery after brain injury, are numerous. The administration of amphetamine in rats dramatically improves motor recovery after brain injury. This action appears to be related to the α noradrenergic activity of amphetamines and their properties of norepinephrine precursor. In contrast molecules that reduce the release of norepinephrine, which increase its metabolism, or blocking its post-synaptic effects such as gabaergic drugs or clonidine have a deleterious effect on motor recovery after brain injury.

In humans, the results of studies concerning the action of amphetamine are much more contrasted. A study in functional imaging has shown that a single dose of methylphenidate was able to modulate brain plasticity in post-stroke patients by increasing the activity of substitute neural networks in the lesioned hemisphere. However, if some clinical studies confirm the positive result, others at the opposite show no behavioral effect on recovery as compared to placebo group.

In humans, there is also some arguments for the positive effect of serotonin reuptake inhibitors (SRI) drugs. Functional neuroimaging studies have shown the SRI modulating action on brain plasticity of sensorimotor cortex. Single dose SRI is responsible for an increase in neuronal activity of sensorimotor cortex correlated with an improvement in behavioral tests in healthy subjects as in post-stroke patients. In small clinical trial, Dam et al has shown a positive effect on motor recovery after prescription of fluoxetine associated with rehabilitation, irrespective of antidepressant activity of this molecule. A randomized controlled multicentre trial (FLAME), comparing the effects on post-stroke motor recovery assessed by the Fugl-Meyer score, of a treatment with fluoxetine or with placebo was published. This trial confirms the positive effect of fluoxetine on recovery of motor function in post stroke hemiplegics.

Regarding the deleterious drug GABAergic and especially diazepam has been tested in animal models of recovery after brain injury. The administration of these molecules has a negative impact on functional recovery. Golsdtein studied the impact on motor recovery of prescription of GABAergic drugs with benzodiazepine or neuroleptic during the recovery phase of brain injured patients. It shows that regardless of the indications of drugs there is a negative effect on the recovery of patients.

Conjointly 15% to 40% of post-stroke hemiplegics develop a spasticity which is responsible for an increase of disability. Spasticity is a symptom characterized by an increase of resistance to passive mobilization in relation to a post-stroke exaggeration of spinal reflexes and to a later muscular component. Usual antispastic drugs have an action on the reflex component and not on the muscular one. Then many physicians want to treat spasticity early after stroke even during the recovery phase, before development of the muscular changes. Until recently in France, most of patients were treated by oral tablets of baclofen. Now the number of patients receiving intramuscular injections of botulinum A toxin is increasing. However in the literature, these drugs have been tested in post-stroke spasticity during chronicle phase, after the sixth month and their action on motor recovery remain largely unknown. Botulinum toxin can increase weakness of injected muscles and baclofen belongs to the family of gabaergic drugs which have demonstrated a deleterious effect in animal models of recovery.

• Purpose: In the specific population of post-stroke hemiplegics, antispastic drugs should reduce spasticity while at least respecting functional recovery. Then it study wants to compare the effect on motor recovery of two usual antispastic treatments administrated before the end of second month after stroke: botulinum toxin versus oral baclofen. Our hypothesis is that botulinum toxin is more respectful of motor recovery than Baclofen and may be promotes the functional recovery.