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Supplements Best Practices for Treating Parkinson’s Disease: A Focus on Symptoms and Considerations for Manage
The Economic and Quality of Life Burden Associated With Parkinson's Disease: A Focus on Symptoms
Deborah F. Boland, DO, MSPT, and Mark Stacy, MD
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Daniel L. Murman, MD, MS, FAAN
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Improving Outcomes Through Early Diagnosis of Parkinson's Disease
Fernando L. Pagán, MD

Improving Outcomes Through Early Diagnosis of Parkinson's Disease

Fernando L. Pagán, MD
Current diagnostic modalities in Parkinson’s disease (PD) are limited by the fact that they identify PD by the presence of motor symptoms; by this point, over 60 percent of all dopamine neurons within specific regions of the basal ganglia may have been lost. Nonmotor symptoms manifest in PD long before motor symptoms, and the early presence of nonmotor symptoms offers an opportunity for early diagnosis and early treatment of PD, with consequent benefits to patient quality of life and potential treatment cost savings. Numerous different premotor symptoms have been identified; diminished olfactory function and REM behavioral sleep disorders (RBDs) may be particularly suitable for the purposes of early diagnosis. Olfactory testing, while in itself not specific for PD, has been shown to offer very high degrees of sensitivity and specificity in distinguishing PD from healthy controls and from other forms of parkinsonism, particularly when accompanied by other means of detection, such as sonography, motor symmetry evaluation, and magnetic resonance imaging (MRI)/diffusion tensor imaging. Biological biomarkers—including protein panels and autoantibody testing—have demonstrated excellent diagnostic capacity, and a recently identified 5-gene panel has been shown to have high specificity and sensitivity in distinguishing early PD from healthy controls and advanced PD. Increasingly sophisticated neuroimaging techniques are also proving capable of early PD detection and differentiation from other parkinsonian types. These recent developments in PD diagnosis underscore the necessity of rethinking what PD is and how, and when, it can be diagnosed.

(Am J Manag Care. 2012;18:S176-S182)

Why Is Early Detection of Parkinson’s Disease Important?

Although the exact prevalence of Parkinson’s disease (PD) in the United States is difficult to accurately determine, one estimate puts the number of currently diagnosed US patients in excess of 645,000, a figure that does not include the many undiagnosed cases. If estimated undiagnosed cases are included, the figure climbs to approximately 849,000 people in the United States with PD.1 The annual costs incurred for PD in the United States have been estimated at nearly $11 billion, including $6.2 billion in direct costs.2 The largest proportion of costs incurred in PD occur in the later stages of the disease, when symptoms are at their most severe.3 Thus, from a purely economic standpoint, any strategy that would maintain PD symptoms in the earlier stages of the disease (ie, fewer and less severe) would likely prove substantially beneficial toward limiting expenditures. From a patient quality-of-life (QoL) perspective, much the same is true. Considering that the effect of PD on patient QoL is one of the most severe of all chronic diseases, and because the most severe symptoms occur in more advanced disease, management strategies aimed at early detection and treatment have the potential to improve the experience of living with PD.4

Currently the diagnosis of PD relies on the clinician’s recognition of motor symptoms and response to medication (eg, levodopa). However, by the time motor symptoms emerge, significant neurological damage has already occurred. Estimates vary as to the precise degree of neuronal loss required to produce symptomatic disease. Guttman et al found that an approximate loss of half of the dopamine neurons in the posterior putamen was required for symptoms to begin to manifest based on PET scans in patients with “early” PD, which is to say, patients who had already received a conventional diagnosis of PD when motor symptoms were clearly present.5 In post-mortem studies, Pakkenberg et al found a reduction in neurons of 66% in the brains of 7 PD subjects compared with 7 matched controls.6 A similar study, performed by Kish et al, found almost complete neuronal depletion in the putamen.7 These figures describe a wide range, although it should be stated that the assumption is widely held that dopamine neuronal loss of 60% to 80% constitutes the threshold at which symptomatic disease occurs.8 All of these data point to the fact that PD diagnosis by conventional means identifies a disease which is already advanced, and that any possibility of delaying disease progression, not to mention neuroprotection, may already be out of reach. The goal of slowing the progression of PD, preserving the neurophysiological integrity of the neurons, and thereby reaping the benefits in patient QoL with potential cost savings, is contingent upon diagnosing and treating PD well before the destructive structural changes have taken place. Treatment approaches in early PD is the subject of another article in this supplement. In the present article, we will focus on the value, practicality, and means of achieving early diagnosis in PD.

Misdiagnosis and Nondiagnosis in PD

PD, in the clinical setting, is commonly missed or misdiagnosed. A UK autopsy study of 100 subjects who had been diagnosed with PD found a misdiagnosis rate of 24%.9 The likelihood of misdiagnosis appears to be strongly contingent upon who is doing the diagnosing and whether or not the clinician is applying diagnostic criteria from clinical guidelines—although application of the clinical criteria is still far from a guarantee of diagnostic accuracy. For example, when the Parkinson’s Disease Society Brain Bank criteria were applied to subjects from the UK autopsy study previously discussed, the diagnostic accuracy improved from 76% to 82%.10 When, in a later autopsy study, diagnosis was performed by a neuropathologist, the diagnostic accuracy improved to 90%.11 The importance of who is undertaking a potential PD diagnosis is underscored by data showing that nearly half (47%) of PD diagnoses are incorrect when performed in the primary care setting, and specialists whose expertise is not specific movement disorders have an error rate of approximately 25%, while movement disorder specialists are mistaken in only 6% to 8% of cases.12

Many symptoms of PD are also common to other diseases both neurodegenerative and non-neurodegenerative in nature. Among neurodegenerative diseases, those most often confused with PD are multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), dementia with Lewy bodies, normal pressure hydrocephalus (NPH), and Alzheimer’s disease.13,14 Essential tremor is also a common source of confusion in PD diagnosis, although many of these patients will go on to develop PD.15 Complicating the issue is the fact that drug-induced parkinsonism is very common and may constitute the second-most common cause of parkinsonism.16-18

A number of indicators of potential PD misdiagnosis have been identified, including rapid disease progression, a lack of asymmetry in symptoms, the presence of autonomic features such as postural hypotension, early postural instability, and poor initial response to levodopa.14,15 Table 1 offers a list of some of the most common indicators of misdiagnosis.14,19-21 It should be noted, however, that these indicators are suggestive rather than determinative, as evidenced, for example, by the fact that as many as 23% of people who prove to have PD fail to experience an initial positive response to levodopa.20

Achieving Early Diagnosis of PD

If early intervention to slow or halt disease progression in PD is to be achieved, it is necessary that the skills and resources for early detection of the disease become more refined and widely disseminated. This means that misdiagnosis of PD must become less common and that knowledge of the means of early detection of PD must become more widespread. At present, no single diagnostic test is available for PD, and accurate diagnosis—early or otherwise—has been a significant challenge, particularly among clinicians without particular expertise in movement disorders. The subjective nature of PD diagnosis, which relies on a group of physical and neurological assessments—none of which are, in themselves, diagnostically conclusive—has been an obstacle to accurate diagnosis. Nevertheless, the situation for PD diagnosis is improving and, recently, a number of new and diverse techniques for diagnosis, including early PD diagnosis, have been emerging and have the potential to considerably alter the diagnostic landscape.

Premotor Symptoms

Despite the reliance on motor symptoms for the standard diagnosis of PD, premotor symptoms hold promise for the early diagnosis of PD, and considerable progress has been made in recent years in establishing premotor symptoms as a means of identifying PD much earlier than in the past. One important observation—and one that may require rethinking certain assumptions about the fundamental nature of PD—is that PD is not simply a central nervous system (CNS) disease in which the peripheral nervous system (PNS) plays a minor part. Rather, there appears to exist a much larger role for the PNS than previously assumed, particularly in the early stages of the disease. Many of the premotor symptoms that arise in early PD emerge in PNS structures, such as the sympathetic cardiac plexus and vesicoprostatic plexus, and there is compelling evidence to suggest that PD actually begins in the PNS.22,23

The manifestations of premotor symptoms in PD are diverse, affecting olfactory structures, gastrointestinal and urinary function, and mood and sleep, as well as a variety of cognitive and autonomic functions. Gastrointestinal dysfunctions that manifest as premotor symptoms include gastroparesis and constipation. Urinary frequency, urgency, and nocturia constitute primary urinary dysfunctions in early PD. Sexual dysfunction in both men (erectile and ejaculation dysfunction) and women (poor vaginal lubrication and difficulty achieving orgasm) have also been observed as PD premotor symptoms. Mood disorders, including depression and anxiety, are well documented in the premotor phase, while sleep disturbances, including REM behavior disorder and excessive daytime sleepiness, are common premotor symptoms. Other nonmotor PD symptoms that may play a role in the premotor phase include pain, apathy, restless legs syndrome, fatigue, and poor ability to discriminate colors.23

Hyposmia, a well-known feature of PD,24 may be the most notable of nonmotor symptoms observed in the premotor stage, in part because of the growing quantity of data demonstrating and explicating the role of olfactory loss in PD, but also because it may represent a highly useful means of achieving diagnosis of PD much earlier than has been possible up until the present. Indeed, a number of studies have sought, and are seeking, to determine its utility in PD diagnosis, with promising, if not yet fully utilizable, results. However, it should be noted that hyposmia is also associated with other conditions, including Alzheimer’s disease and dementia with Lewy bodies, and thus the presence of hyposmia may be useful for the identification of persons at risk for PD, rather than being diagnostic of PD.25

One early study of olfactory function in parkinsonism (published in 1995), conducted by Wenning et al, employed the 40-odorant forced-choice University of Pennsylvania Smell Identification Test (UPSIT) to examine olfactory patterns in patients with idiopathic PD as well as several other parkinsonian syndromes, while also evaluating the utility of the UPSIT itself in this context. The patient population included 118 subjects with PD, 29 with MSA, 15 with PSP, and 7 with CBD.26 The investigators found that compared with PSP, CBD, and MSA patients, PD patients scored significantly lower on the UPSIT. The UPSIT demonstrated a sensitivity of 77% and specificity of 85% in distinguishing PD from the atypical parkinsonian syndromes.26 These results are certainly encouraging, if not conclusive, in positioning olfactory testing as a means of early PD detection.

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