A Modern View of Parkinson's Disease: Much More than Nigrostriatal Dopamine Deficiency
Abstract & commentary
By Melissa J. Nirenberg, MD, PhD, Assistant Professor, Neurology and Neuroscience, Weill Cornell Medical College. Dr. Nirenberg reports she has participated in consulting for Biovail and clinical research trials sponsored by Boehringer-Ingleheim.
Synposis: Many of the disabling symptoms of Parkinson's disease are unrelated to nigrostriatal dopamine deficiency, and unresponsive to dopamine replacement therapy.
Source: Lim SY, Fox SH, Lang AE. Overview of the extranigral aspects of Parkinson disease. Arch Neurol 2009;66: 167-172.
In recent years, it has become increasingly clear that Parkinson's disease (PD) consists of much more than the well-known motor features attributed to nigrostriatal dopamine deficiency. In this review paper, the authors provide a detailed discussion of these extranigral symptoms, as well as their underlying anatomy, biochemistry, and pathophysiology. They note that many of the symptoms of PD are attributable to the dysfunction of dopaminergic cells outside the substantia nigra, and/or the more widespread involvement of non-dopaminergic neurons throughout the nervous system.
The authors first discuss motor symptoms of PD that are unresponsive to levodopa. While two of the early cardinal features of PD rigidity and bradykinesia are highly responsive to dopaminergic medications, rest tremor is often partially or completely unresponsive. As the disease advances, more devastating, levodopa-unresponsive motor symptoms develop, largely due to extranigral neurodegeneration. These include postural instability/falls, freezing of gait, dysarthria, and dysphagia.
They next discuss the "premotor" symptoms of PD, which begin years, and sometimes decades, before the motor symptoms develop. These may include hyposmia, sleep disorders (REM sleep behavior disorder, excessive daytime sleepiness), psychiatric symptoms (depression, anxiety), autonomic impairment (constipation, erectile dysfunction, cardiac sympathetic denervation, orthostatic hypotension, urinary urgency), and executive dysfunction. These premotor symptoms are attributable to involvement of extranigral brain regions that occur before the substantia nigra is clinically affected.
After that, the authors discuss symptoms that occur in PD as a consequence of dopaminergic therapy. These include levodopa-induced dyskinesias and end-of-dose wearing off, both of which commonly develop with chronic levodopa use. They note that wearing-off symptoms include both motor deficits and non-motor manifestations such as anxiety, dysphoria, apathy, diaphoresis, urinary urgency, and pain. Other side effects of dopaminergic medications may include impulse control disorders such as compulsive eating, compulsive buying, pathological gambling, and hypersexuality; these are most commonly associated with dopamine agonists. More rarely, patients may become "addicted" to levodopa or other dopaminergic medications, a phenomenon referred to as dopamine dysregulation syndrome.
Finally, they discuss the extranigral features of advanced PD. As the disease spreads to limbic and cortical areas, dementia and visual hallucinations develop. Patients also develop increased "midline symptoms" levodopa-unresponsive motor symptoms such as postural instability, falls, freezing of gait, dysarthria, and dysphagia. Together, these symptoms are associated with markedly increased morbidity and mortality.
Commentary
Until recently, the management of PD has focused on motor signs and symptoms attributed to nigrostriatal dopamine deficiency. As medical and surgical strategies for overcoming these motor deficits have become increasingly effective; however, levodopa-unresponsive motor and non-motor symptoms have emerged as the major challenge for both patients and physicians.
In this review, the authors provide a thorough and detailed discussion of the limitations of dopamine replacement therapy. There are a several important take home messages: (1) not all motor features of PD are responsive to levodopa early symptoms such as rest tremor, and late symptoms such as postural instability, freezing of gait, and dysphagia often fail to respond; (2) the cardinal motor features of PD are only a small facet of the disease non-motor symptoms are also a major cause of morbidity; and (3) the major problem in advanced PD is not that levodopa loses effectiveness over time, but rather that patients develop a progressively increasing burden of levodopa-unresponsive symptoms and medication side effects.
In the levodopa era, the most disabling symptoms of PD are those that are caused by or unresponsive to dopamine replacement therapy. Treatment strategies that focus solely on the repletion of nigrostriatal dopamine or correcting the abnormal circuitry in these pathways are destined to failure. What are desperately needed are disease-modifying therapies that control or prevent the full spectrum of PD pathology.
Many of the disabling symptoms of Parkinson's disease are unrelated to nigrostriatal dopamine deficiency, and unresponsive to dopamine replacement therapy.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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