Pathology No agreement has been reached concerning the pathologic substrate of the disease. None of the features of symptomatic dystonia are found, such as the ferrocalcinosis of PKAN, the lesions of Wilson disease, kernicterus, état marbré of neonatal hypoxia, or the cavitation of familial striatal necrosis. However, in the hereditary forms of dystonia, which are the subject of this section, one cannot be certain of any specific lesions that would account for the clinical manifestations. The brain is grossly normal and ventricular size is not increased. According to Zeman, who reviewed all the reported autopsy studies up to 1970, there were no significant changes in the striatum, pallidum, or elsewhere. This means only that the techniques being used (qualitative analysis of random sections by light microscopy) are inadequate or the problem is subcellular. The report by McNaught and colleagues of perinuclear inclusions in periaqueductal neurons by the use of special immunostaining methods is provocative. There had been tentative interest in elevations of dopamine β-hydroxylase in patients with the autosomal dominant form of the disease, but the meaning of these findings is not clear.
Treatment Early in the course of the illness, several drugs including l-dopa, bromocriptine, carbamazepine, diazepam, and tetrabenazine seem to be helpful, but only in a few patients, and the benefit is not lasting. Intrathecal baclofen has been somewhat more successful in children. The rare hereditary form of dystonia-parkinsonism (described below) responds well to small doses of l-dopa and dopamine agonists and is exceptional in this respect. Burke and coworkers advocate the use of very high doses (up to 30 mg daily or more) of trihexyphenidyl (Artane). Apparently, dystonic children can tolerate these high doses if the medication is raised gradually, by 5-mg increments weekly. In adults, high-dose anticholinergic treatment is less successful but worthy of a trial. Clonazepam is beneficial in some patients with segmental myoclonus.
Impressive results were obtained in the past by the use of stereotactic techniques that made lesions in the ventrolateral nuclei of the thalamus or in the pallidum-ansa lenticularis region. Some frightfully disabled children, unable to sit or stand, were restored to near normalcy for a time. Approximately 70 percent of the patients in Cooper’s series in the 1950s were moderately to markedly improved by unilateral or bilateral operations and, based on a 20-year followup study, the improvement was usually sustained. More recent studies report a somewhat less favorable but nonetheless clear improvement (see Tasker et al; Andrew et al, de Bie et al). The main risk of the operation was a corticospinal tract lesion, produced inadvertently by damaging the internal capsule. Bilateral lesions have sometimes been disastrous, causing pseudobulbar palsy. The production of lesions has been supplanted, with success over longer periods, by bilateral stimulation of the internal segments of the globus pallidus (Vidailhet and colleagues).
Hereditary Dystonia-Parkinsonism (Segawa Syndrome, Juvenile Dopa-Responsive Dystonia, GCH1 Mutation)