Dopaminergic treatment and nonmotor features of Parkinson disease

Several years ago, Eric Ahlskog published a colorful and cogent review entitled “Beating a dead horse.” He argued that “we have reached the point of diminishing therapeutic returns with drugs acting on dopamine systems and more dopaminergic medications will provide only modest incremental benefit over current therapies.”¹ Ahlskog argued correctly that excessive focus on dopaminergic features and pathology led to neglect of crucial nondopaminergic/nonmotor clinical features and pathologies. This argument was based, in part, on the perception that most of the nonmotor symptoms (NMS) in Parkinson disease (PD) would be related to degeneration in nondopamine responsive systems and that improvements in dopaminergic therapy would have little impact on NMS. Accumulated evidence now indicates the need to modify this concept.

As Ahlskog suggested, several subsequent studies substantiate the great functional burden related to NMS, their progression, and negative effect on quality of life in PD.² Additional evidence indicates interesting relationships between striatal dopaminergic function and NMS. The basal ganglia are implicated in the modulation and integration of sensory information and pain; bladder function is under control of both inhibitory (D1) and facilitatory (D2) dopaminergic inputs; and reduced dopaminergic activity in the mesocortical and mesolimbic pathways is involved in the development of several NMS including mood, motivational, and cognitive alterations.³

These data are further supported by clinical pharmacologic studies. Some NMS fluctuate in response to dopaminergic treatment and are relieved by dopamine replacement therapy.⁴ Intraduodenal infusion of levodopa produces beneficial effects in 6 of the 9 domains of an NMS scale: cardiovascular, sleep/fatigue, attention/memory, gastrointestinal, urinary, and sexual function.⁵ Oral and transdermal dopamine agonist therapy produces significant improvements in depression⁶ and sleep disorders,⁷ highlighting the importance of studies designed to specifically address NMS features.

In this issue of Neurology^®, Storch et al.⁸ report results of a large survey in 100 patients with fluctuating PD using a structured examination and visual analogue scales to quantify NMS. Their major findings are that some NMS are associated with motor fluctuations while others are not. Depression and anxiety are more prone to fluctuate while other symptoms appeared to be relatively unaffected by the motor state. These results are concordant with the modest prior literature and general clinical experience. Storch et al. thoughtfully evaluated NMS in both structured interviews and home-based ratings diaries. Results were similar for both the home ratings and the structured interview. Another interesting observation was that there was little correlation between several disease features and NMS frequency patterns.

These results point to complicated relationships between residual striatal dopaminergic function, dopaminergic replacement therapies, extra-nigrostriatal pathologies, and NMS. These results also indicate considerable heterogeneity of patients with PD with respect to NMS and motor fluctuations. Storch et al. are to be commended for undertaking this demanding study and their methods are very likely to be useful in future studies of this important topic.

This and prior work suggest that optimizing dopaminergic therapies is a viable avenue to improve control of some disabling NMS in PD and a worthwhile area for further clinical research. Improving consistency of delivery of dopaminergic therapies and targeting NMS specifically in well-designed studies may yield incremental but important improvements in quality of life for patients with PD. These kinds of experiments may also cast light on interesting biology related to striatal dopaminergic functions and other brain systems. The horse lives.

• © 2013 American Academy of Neurology