Comparative Efficacy of Three Preparations of Botox-A in Treating Spasticity

Spasticity is one of the most debilitating complications of neurologic conditions, such as
stroke, brain injury, spinal cord injury, cerebral palsy, and multiple sclerosis. Although
the exact pathophysiology is unknown, it is believed to result from an imbalance of ascending
excitatory influences on and descending inhibitory components of the central nervous system.
Clinically, spasticity manifests as abnormally increased muscle tone, associated with loss of
range of motion, increased muscle stretch reflexes, clonus, weakness, and incoordination. If
inadequately treated, spasticity leads to more disability and increase health care costs.
Common complications of inadequately treated spasticity include joint and muscle contracture,
pain, difficulty with performing activities of daily living and hygiene, and impaired
transfers and ambulation.

Acquired brain injuries (ABI), including stroke, traumatic brain injury, and encephalopathy,
often lead to long-term impairments, including spasticity. In severe cases, spasticity is
difficult and frustrating to treat in this patient population, since the individuals may not
tolerate the side effects of conventional therapies because of ABI-related deficits in
arousal and cognition. Systemic medications, such as baclofen and tizanidine, are effective
in controlling spasticity; however, they may also cause sleepiness and drowsiness, and impair
memory and thinking processes---adverse effects that individuals with ABI may not tolerate.

Thus, "local" treatments, such as neurolysis and chemodenervation using botulinum toxin, have
become superior treatment options in individuals with ABI, since they are devoid of the usual
side effects of systemic medications. They are also effective in controlling spasticity, yet
they do not impair arousal and cognition. The medical literature is replete with reports of
the efficacy of botulinum toxin-A in the management of spasticity. Thus, the current
challenge for clinicians and researchers at this time is to find ways to further enhance the
efficacy of botulinum toxin. One way to achieve this is by exploiting certain properties of
the toxin. Animal studies and clinical experience have shown that the effects of the drug is
dose-dependent. One other property is the flexibility in preparing the volume of drug
injected. Since botulinum toxin, as it is currently available (as BOTOX-A®) in the United
States, requires reconstitution with preservative-free saline, there is flexibility for
clinicians to manipulate the volume of solution that will be administered, without altering
the dose.

We recently completed a trial comparing the effects of two volume preparations of BOTOX-A® on
wrist and finger flexor spasticity of individuals with ABI. One group of patients received
BOTOX-A® prepared as 100 units/cc, while another received BOTOX-A® prepared as 50 units/cc.
Although there was no statistically significant difference between the two groups, there was
a trend in favor of the group that received the higher volume, i.e.; they appeared to improve
more based on decrease in muscle tone (measured by the Modified Ashworth Scale). This was
compared by the clinician's global impression that the high volume group improved more. The
latter measure achieved statistical significance. One possible reason for the absence of
statistical significance was that the "high" volume (50 units/cc) was not high enough. Thus,
we are proposing this study to investigate the comparative effects of three preparations of
BOTOX-A®.

Inclusion Criteria -

- Spasticity resulting from ABI (stroke, including vascular malformations, traumatic
brain injury)

- Ashworth Score (resting) of at least 2 of the primary ankle plantarflexor
(gastrocnemius)

- Onset of primary illness at least six months prior to study inclusion

- At least 12 years of age

Exclusion Criteria -

- Hypersensitivity or allergy to botulinum toxin

- History of myasthenia gravis or other neuromuscular disease

- Current use of aminoglycosides

- Botulinum toxin or phenol injection to study limb within six months prior to
recruitment

- Current use of other spasmolytic drug, such as diazepam, baclofen, dantrolene,
tizanidine

- Presence of contracture or significant muscle atrophy

- Pregnancy