Improving Outcomes Through Early Diagnosis of Parkinson’s Disease

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