NEJM
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Botulinum toxin is in the news these days. First came September 11 and fears of chemical terrorism. One gram of this "most poisonous poison" could kill a million people were it not for problems of delivery. Then, in April 2002, the Food and Drug Administration (FDA) approved the use of botulinum toxin for the treatment of "frown lines" at the glabella, between and above the eyes. This cosmetic use of the toxin has already attracted the interest of countless people who want to look younger. The toxin is also used to erase "crow's feet" � wrinkles at the lateral margin of each eye.
In this issue of the Journal, Brashear and colleagues (see pages 395�400) report that local intramuscular injections of botulinum toxin can ameliorate disability of the wrist and fingers after a stroke. In a double-blind, randomized, controlled trial, subjects picked their own "principal target of treatment": hygiene, dressing, pain, or limb posture. Six weeks after the injections, 62 percent of the subjects who received botulinum toxin reported improvement, as compared with 27 percent of those who received placebo. There were no serious adverse effects. The benefits lasted for at least 12 weeks.
Each year, approximately 750,000 Americans have a stroke. Roughly a third die, making stroke the third leading cause of death after myocardial infarction and cancer. Another third recover, and a third are disabled. Of the approximately 4 million people who have survived a stroke, many have hemiplegia and impairment of the hands.
Two questions arise. To what extent is disability caused by spasticity? Why is botulinum toxin used to treat it?
If the corticospinal tracts on one side of the brain are injured, the immediate effect is contralateral hemiparesis or hemiplegia. If the injury is mild, there may be serious loss of dexterity with only slight weakness. These are the "negative" effects of upper-motor-neuron lesions. Immediately or within days, the "positive" signs appear: overactive tendon reflexes, Hoffmann and Babinski signs, clonus, and hypertonia, or increased resistance of muscle to passive movement. Over time, the spasticity may worsen, causing fixed flexion contractures at the elbows, wrists, and fingers. These complications are the target of therapy. Spasticity is attributable to overactivity of monosynaptic muscle-stretch reflexes, hypertonia, or both.
William Landau, in Clinical Neuromythology and Other Arguments and Essays, Pertinent and Impertinent (Armonk, N.Y.: Futura, 2001), argues that disability in these circumstances arises from the negative symptoms, not from spasticity. It is fruitless, he concludes, to expect functional improvement from the treatment of spasticity. Yet there is a huge literature on anti-spasticity treatments. Physical therapy is one approach. Another is the administration of baclofen or tizanidine to reduce spinal cord reflex activity. Taken by mouth, however, baclofen has limited effectiveness. Therefore, implanted pumps have been used to deliver baclofen directly to the cerebrospinal fluid. This approach is not an option for treating hand spasticity because cervical cerebrospinal fluid is too close to the brain, which tolerates baclofen poorly. The limitations of oral drug therapy also apply to spasticity of the legs, which has been treated with intrathecal injections of phenol or surgical resection of dorsal nerve roots (rhizotomy) to diminish reflex activity. The multiplicity of treatments is ipso facto evidence that there is no optimal treatment. Moreover, although such treatments have led to improvements in measured joint angles or scales of limb mobility, it has been difficult to demonstrate functional improvement in walking or use of the hands.
Therapeutic use of botulinum toxin bypasses some of these problems. The toxin prevents acetylcholine vesicles from binding with proteins needed for fusion to surface membranes and exocytosis. This inhibitory effect reduces the number of presynaptic transmitter vesicles, impeding neuromuscular transmission and weakening the muscle (see Figure). In contrast to treatment with phenol and rhizotomy, the effects of botulinum toxin are not permanent, persisting only until new neuromuscular junctions are formed in weeks or months. And in contrast to drug therapy, which may induce sedation or somnolence, injections of toxin have only local effects.
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The use of botulinum toxin to treat neurologic disease dates back to around 1970, when the toxin was used to reduce the overactivity of extraocular muscles in patients with strabismus. This approach was approved by the FDA in 1989 and rapidly replaced muscle surgery, which had previously been the standard treatment. By 1990, botulinum toxin had also been used � successfully and safely � to treat involuntary-movement disorders attributable to overactivity of local groups of muscles, including blepharospasm, hemifacial spasm, cervical dystonia (torticollis), and writer's cramp. These uses of the toxin were welcomed as major therapeutic advances in neurology.
In the past decade, botulinum toxin has been used to treat spasticity caused by cerebral palsy, spinal cord injury, multiple sclerosis, and stroke. Injections in leg muscles are said to help relieve bothersome muscle spasms, allow a caregiver to wash and dress the patient, and relieve pain.
The findings reported by Brashear et al. warrant further study because questions remain. Which patients are the best candidates for botulinum toxin? Can functional improvement be expected? Will this treatment help patients regain independence in activities of daily living? Why did so many patients have a response to placebo? The appropriate role of botulinum toxin in the management of spasticity after stroke will surely be tested in more trials to come.
Lewis P. Rowland, M.D.
Columbia�Presbyterian Medical Center
New York, NY 10032