TABLE 28–1 Some drugs with antimuscarinic properties used in parkinsonism.
If medication is to be withdrawn, this should be accomplished gradually rather than abruptly to prevent acute exacerbation of parkinsonism. For contraindications to the use of antimuscarinic drugs, see Chapter 8.
Ablative surgical procedures for parkinsonism have generally been replaced by functional, reversible lesions induced by high-frequency deep brain stimulation, which has a lower morbidity.
Stimulation of the subthalamic nucleus or globus pallidus by an implanted electrode and stimulator has yielded good results for the management of the clinical fluctuations or the dyskinesias occurring in moderate parkinsonism. The anatomic substrate for such therapy is indicated in Figure 28–1. Such procedures are contraindicated in patients with secondary or atypical parkinsonism, dementia, or failure to respond to dopaminergic medication. The level of antiparkinsonian medication can often be reduced in patients undergoing deep brain stimulation, and this may help to ameliorate dose-related adverse effects of medication.
In a controlled trial of the transplantation of dopaminergic tissue (fetal substantia nigra tissue), symptomatic benefit occurred in younger (less than 60 years old) but not older parkinsonian patients. In another trial, benefits were inconsequential. Furthermore, uncontrollable dyskinesias occurred in some patients in both studies, perhaps from a relative excess of dopamine from continued fiber outgrowth from the transplant. Additional basic studies are required before further trials of cellular therapies— in particular, stem cell therapies—are undertaken, and such approaches therefore remain investigational.
Among the compounds that have been investigated as potential neuroprotective agents to slow disease progression are antioxidants, antiapoptotic agents, glutamate antagonists, intraparenchymally administered glial-derived neurotrophic factor, and anti-inflammatory drugs. None of these agents has been shown to be effective in this context, however, and their use for therapeutic purposes is not indicated at this time. Coenzyme Q10, creatine, pramipexole, and pioglitazone have not been found to be effective despite early hopes to the contrary. The possibility that rasagiline has a protective effect was discussed earlier. Active and passive immunization against α-synuclein is being explored.
Several phase 1 (safety) or phase 2 trials of gene therapy for Parkinson’s disease have been completed in the USA. All trials involved infusion into the striatum of adeno-associated virus type 2 as the vector for the gene. The genes were for glutamic acid decarboxylase (GAD, to facilitate synthesis of GABA, an inhibitory neurotransmitter), infused into the subthalamic nucleus to cause inhibition; for aromatic acid decarboxylase (AADC), infused into the putamen to increase metabolism of levodopa to dopamine; and for neurturin (a growth factor that may enhance the survival of dopaminergic neurons), infused into the putamen. All agents were deemed safe, and the data suggested efficacy. A phase 2 study of the GAD gene has been completed and the results are encouraging, but one for neurturin infused into the substantia nigra as well as the putamen was disappointing. A phase 2 trial of AADC is planned. The results of a European study involving bilateral intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy with three genes (decarboxylase, tyrosine hydroxylase and GTP-cyclohydrolase 1) aimed at restoring local and continuous dopamine production in patients with advanced Parkinson’s disease, have also been encouraging.