Pathophysiology of dystonia

Abstract

Dystonia is a syndrome characterized by involuntary movements of sustained muscle contractions, causing prolonged movements or abnormal postures. There are three types of etiologies. Genetic dystonias include idiopathic torsion dystonia, most commonly DYT1 dystonia due to a gene defect in the protein torsin-A, and Segawa's disease, due to a gene defect in OTP cyclohydrolase I. Secondary dystonias result from a defined neurologic disorder including discrete lesions, most commonly in the putamen. Some focal dystonias, such as writer's cramp, appear in the setting of repetitive movements. Physiological studies of patients with dystonia seem to converge on the concept that there is loss of intracortical inhibition in motor cortex. This abnormality can be demonstrated directly with paired-pulse transcranial magnetic stimulation (TMS) studies. Other data from TMS, EEC and neuroimaging are compatible. Loss of inhibition can certainly give rise to excessive motor commands that would produce the signature features of cocontraction and overflow. How an abnormality of the basal ganglia can produce this loss of inhibition is not clear. Cellular activity in the pallidum, recorded in patients undergoing pallidotomy, shows a reduced rate of firing. A simple model of basal ganglia circuitry would suggest that this should lead to reduced thalamic inhibition and consequent increased cortical excitation. However, the net effect of thalamic influence on the cortex is not certain. If the basal ganglia loop provides an excitatory signal with an inhibitory surround, then the thalamic influence is at least a combination of excitation and inhibition. An alternative explanation for the effect of pallidal changes on the motor system is that it is the pattern of activity, and not rate, that is important. Studies of focal dystonia provide a variety of lines of evidence that this form of the disorder could arise from aberrant motor learning, possibly on a substrate of an abnormal motor system produced by a genetic or other abnormality. In an animal model, a facial palsy and dopamine deficiency can produce blepharospasm. Facial palsy can be a precedent to blepharospasm in humans, and can increase blink reflex excitability. In another animal model, repetitive activity of the hand can induce a motor disorder akin to dystonia that is associated with enlargement of somatosensory receptive fields of neurons in primary sensory cortex. Such enlarged somatosensory fields are seen in thalamic neurons in patients with dystonia. Studies of the sources of somatosensory evoked potentials from the thumb and little finger show that they are closer together than normal, also compatible with enlargement of overlap of receptive fields. Moreover, patients with dystonia may process kinesthetic input incorrectly and have increased threshold for somatosensory temporal discrimination. A disordered sensory system, perhaps from loss of inhibition, could be a primary abnormality.