How does botulinum toxin work?

Injection of botulinum toxin has been a major advance in neurological therapeutics. It is useful in treatment of focal dystonias, spasticity, and a variety of other types of muscle spasms. The logic of botulinum toxin appears simple. There is an undesirable involuntary muscle contraction, and botulinum toxin blocks neuromuscular transmission and weakens the muscle. Hence, there will be less involuntary contraction. To a certain extent, this logic is correct, but it has never seemed like the whole story. While clinical benefit roughly parallels weakness, there are certainly cases in which the benefit seems out of proportion and, conversely, where there is marked weakness but still significant spasm. Is there some other way that botulinum toxin can work? One reason for benefit to outstrip weakness was suggested by us in this journal several years ago: botulinum toxin should be more effective in blocking the neuromuscular junctions of the most active muscle fibers. For this reason, if only part of the muscle is involved in the involuntary spasm, that part would be more likely to be affected and significant strength could be preserved. We attempted to test this in a crossover study of 8 patients with writer’s cramp by asking them to write after the injection or have their injected arm immobilized. There was greater weakness after writing, but we could not demonstrate better clinical improvement. Another reason is that botulinum toxin affects the intrafusal as well as the extrafusal neuromuscular junctions. This means that muscle spindle output will be diminished, and since muscle activity is supported by afferent feedback, there may be reduced a-motoneuron drive. This might be particularly true in the case of dystonia, in which muscle vibration can produce a dystonic spasm. Such a mechanism was demonstrated by Kaji and colleagues using muscle afferent block with lidocaine and alcohol to improve dystonia. Botulinum toxin may also invade the central nervous system and directly affect synaptic activity. The toxin is retrogradely transported to some degree, and effects have been demonstrated in animal models. One of the most convincing is the effect on the Renshaw cell, since the synaptic input onto it comes from a cholinergic recurrent collateral of the motor axon itself. Such a mechanism has not been demonstrated for certain in humans. On the other hand, influences on the central nervous system (CNS) have been demonstrated. In dystonia, there is a deficiency of inhibition in a number of phenomena, including the presynaptic phase of spinal reciprocal inhibition and intracortical inhibition in the motor cortex. Berardelli and colleagues showed several years ago that injection of botulinum toxin normalizes reciprocal inhibition and, in this issue of Annals, that it normalizes intracortical inhibition. The deficiency of inhibition in dystonia seems to be a critical aspect of its pathophysiology. Lack of inhibition leads to excessive muscle activity, which manifests as the dystonic movements. Improvement in inhibition should improve the disorder at its fundamental basis, and botulinum toxin seems to do that. This logic has been used to suggest a new mode of therapy for dystonia. Slow rates of repetitive transcranial magnetic stimulation delivered over the motor cortex will increase inhibition. Siebner and associates did this in patients with focal hand dystonia. The patients had an increase in intracortical inhibition and some improvement in performance. How is it possible for an injection of botulinum toxin to modify inhibition in the CNS? One possibility is its effect on spindle afferent input. In addition to spindle input having an immediate, direct effect on motor output, it should have some effect on sensorimotor system organization. Indeed, we have learned in recent years that all peripheral changes will lead to CNS changes; some change is inevitable. Complete, chronic deafferentation of a limb, as is seen with amputation, has been extensively studied and leads to loss of inhibition. With the selective deafferentation produced by botulinum toxin, there is an increase in inhibition. Evidence for changes in cortical organization after botulinum toxin injection come from studies of mapping of muscle representation areas in the primary motor cortex using transcranial magnetic stimulation. Patients who have hand dystonia have abnormal maps with extensions of the lateral border and emergence of almost discrete secondary areas. After botulinum toxin injection, the map transiently becomes more normal looking. An increase in cortical inhibition should diminish the size of maps, so this finding is compatible with the new results. Thus, botulinum toxin works not only because of its effect on the neuromuscular junction but also because of its effect on altering sensory input and the inevitable secondary changes that ensue. This might be taken as further evidence for the importance of sensory features in the production of dystonic movement. Botulinum toxin is far from simple, and it is likely that there are a multiplicity of direct and indirect effects that will be responsible for its widening clinical roles. For example, if botulinum toxin really is effective