Current medical and surgical therapies for PD are symptomatic and lack significant disease-modifying effect. Indeed the most effective medical therapy continues to be levodopa mixed with a peripheral decarboxylase inhibitor (S28–S30). The most recent advances in available symptomatic medical therapies in the United States have revolved around prolonging the effect of levodopa through the use of COMT inhibition and by changing the availability and formulation of older medications such as selegiline and apomorphine. The latter, given subcutaneously with an oral antiemetic, can temporarily rescue patients during disabling motor “off” time (time spent with reduced levodopa effect) (S31). Looking beyond dopaminergic therapy, other symptomatic medical therapies showing promise in published clinical trials include istradefylline, an adenosine A2 antagonist that reduces “off” time (S32), and sarizotan, a serotonin agonist that reduces levodopa-induced dyskinesias (S33, S34).
There are data suggesting that deferring levodopa therapy in favor of dopamine agonists such as ropinerole or pramipexole may delay motor complications such as dyskinesias (S29, S30). The dopamine agonists are less effective than levodopa in symptomatic relief, and nearly all patients with advancing PD will require levodopa at some point. The reduced risk of dyskinesias with the dopamine agonists may be related to their longer half-life, and thus more stable receptor stimulation, relative to levodopa. Supporting these data are studies showing that continuous infusion of levodopa or an agonist has benefit over oral interval dosing (S35–S37). These findings have led to the development of experimental therapies including the transdermal patch (for delivery of rotigotine) and infusion delivery systems (for Duodopa) that reduce pulsatile drug delivery. In addition, this concept has given rise to the theory that COMT inhibitors given with levodopa may reduce the risk of future dyskinesias by prolonging brain exposure to a given levodopa dose (S38).
Surgical DBS is perhaps the most influential development in symptomatic PD therapy since levodopa and is reviewed in detail elsewhere (S39). In this procedure, an electrode is inserted through the skull to reach and stimulate the globus pallidus, subthalamic nucleus (STN), or ventral intermediate thalamus. A pacemaker-like device is implanted and connected to the electrode through wires buried beneath the skin. The results of this therapy can be quite marked and include the reduction of “off” time, increased “on” time without dyskinesias, reduction of levodopa dose, and improved tremor. The STN has recently emerged as the preferential target due to improved symptom control and a reduced energy requirement (S40). Currently this procedure is largely reserved for advanced cases of PD in which motor complications and/or medication intolerance have led to an unacceptable decline in quality of life. In addition, disabling tremor that is not responsive to medical therapy may respond well to DBS. Very encouraging are the recent, albeit small, studies showing the benefits of electrode implantation into the pedunculopontine nucleus with resultant improvement in bradykinesia, gait freezing, and postural stability (S41).
A newer, experimental field of study is the use of transcranial magnetic stimulation (TMS). In this process a current is passed through a coil to generate a magnetic field. The coil is placed near the head to induce stimulation in the nearby brain structures. TMS studies show that PD patients have a measurable abnormality in the inhibitory control of the cortex that results in a shortened “silent period.” Also seen are inconsistently measurable changes in motor threshold and abnormal activation during voluntary input (S42). Some of these abnormalities normalize with medical and surgical PD therapies. The effect of repetitive TMS (rTMS) is now being explored as a possible therapeutic intervention. A meta-analysis of available data has shown a small but significant effect of rTMS (approximately 20% improvement on the motor Unified Parkinson’s Disease Rating Scale [UPDRS]). Other large studies have failed, prompting concern regarding the standardization of technique. In addition, a measurable placebo effect, as detected by PET scan, can be seen with rTMS that may be confounding study results (S43). A well-defined protocol including rTMS applied while in the “on” state, inclusion of a placebo control, and specific parameters for intensity and frequency of stimulation was used in a recent study, showing improvement of limb bradykinesia and gait for at least one month after a course of rTMS therapy (S44). The magnitude of improvement was thought to be similar to the effect of a single levodopa dose. These results require duplication, and the cumulative effect and clinical significance of this therapy must be subjected to further study before rTMS can be recommended for routine treatment. The paucity of adverse effects of rTMS does make the optimization of this treatment an attractive field of study.
A review of symptomatic PD therapies would not be complete without consideration of progress made in the treatment of non-motor sequelae. Given the good response of motor symptoms to medical and surgical therapies, it is often poor balance, sleep interruption, cognitive impairments, anxiety, depression, and drooling that become most disabling (S45). Indeed the recognition of widespread pathology in PD suggests that these affected areas lying outside of the dopaminergic motor pathway are contributing to patients’ symptoms. Specifically, abnormalities in the noradrenergic and serotonin nuclei may lead to anxiety and depression as well as the autonomic, sleep, and visual disturbances seen in PD, while changes in the neocortex, limbic system, and cholinergic nucleus basalis may be involved in cognitive decline later in the disease. Treatment of these symptoms can be rewarding and involves interventions including agents such as midodrine and pyridostigmine for blood pressure support (S46), atropine drops for symptomatic control of salivation (S47), cholinesterase antagonists for cognitive decline (S48), antidepressants (serotonin selective reuptake inhibitors and possibly others) for treatment of depression (S49), and atypical antipsychotics (most commonly clozapine and quetiapine) for treatment of psychosis (S50). A recent study by Ondo et al. has cast some doubt on the effectiveness of quetiapine for the treatment of psychosis, underscoring the need for more rigorous trials of therapies aimed at the treatment of nonmotor PD symptoms (S51).