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Early Diagnosis of Parkinson's Disease: Recommendations From Diagnostic Clinical Guidelines
Rajesh Pahwa, MD; and Kelly E. Lyons, PhD
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Early Diagnosis of Parkinson's Disease: Recommendations From Diagnostic Clinical Guidelines

Rajesh Pahwa, MD; and Kelly E. Lyons, PhD
The genetic contribution to the development of PD is, at present, unclear and has little, if any, bearing on the diagnosis or management of the disease. However, genetic associations with PD have been identified, and approximately 20% of patients with PD have a first-degree relative with the disease.20 Genetic studies have identified at least 9 genes with mutations that may cause 10% to 15% of PD cases.23 The leucine-rich repeat kinase 2 (LRRK2) and parkin mutations are the most studied.20 LRRK2 occurs in 5% to 8% of patients with a first-degree family history compared with 0.4% to 1.6% without such a history. Parkin mutations are seen at a much higher frequency in patients with early-onset disease, but quite rarely in patients over the age of 30 years. The SIGN guidelines do not recommend routine genetic testing because interpretation of results is problematic, and the results do not guide treatment.20

Uncertainty and Referrals for PD Diagnosis

Achieving a reliable PD diagnosis early in the course of the disease is often quite difficult. Thus, the clinical guidelines underscore the importance of clinicians continuing to evaluate their patients, whether they have already diagnosed a given patient with PD or are unsure of the diagnosis, and determining after repeated visits whether their diagnoses and assumptions are correct.19-21 The NCCCC guidelines suggest that patients with early and mild PD, whether or not they are receiving treatment, be reassessed every 6 to 12 months so clinicians can review their diagnosis and determine treatment needs. After treatment has been initiated, these guidelines suggest follow-up every 2 to 3 months.21

Noting the poor specificity of clinical diagnosis in early PD, the SIGN guidelines suggest caution on the part of clinicians when discussing a PD diagnosis with a patient.20 It is also recommended that diagnosis be performed by a movement disorder specialist rather than a primary care practitioner (PCP), that such a diagnosis is performed prior to treatment initiation, and that referral to a movement disorder specialist occurs without delay.20,21 The SIGN guidelines point out that in the Scottish primary care setting (which is likely comparable to that in the United States), the average PCP will see a new patient with PD once every 3.3 years, making it unlikely that a clinician would have an opportunity to develop refined diagnostic skills in PD.20 The NCCCC guidelines report data indicating that community-based PCPs misdiagnose PD approximately 47% of the time, neurologists lacking expertise in movement disorders misdiagnose PD 25% of the time, and movement disorder specialists have a misdiagnosis rate between 6% and 8%.21

Differential Diagnosis

PD in its early stages can easily be mistaken for any number of disorders. PD is most likely to be confused with other forms of parkinsonism, such as MSA, PSP, corticobasal degeneration, and Lewy body dementia.20 Other degenerative diseases, such as Alzheimer's disease and primary lateral sclerosis, can also be mistaken for PD, as can nondegenerative conditions, such as essential tremor, dystonic tremor, vascular parkinsonism, and drug-induced parkinsonism.

Clinical Features of PD Versus Other Forms of Parkinsonism

Apart from the clinical features previously described for PD diagnostic criteria, there are a number of additional clinical manifestations that can be useful in distinguishing PD from other conditions. Falls are a common clinical feature related to PD, and the onset of falling with respect to disease duration can be important in the differential diagnosis. A study in a group of patients with various forms of parkinsonism found that recurrent falls within the first year of initial symptom onset was predictive of a non-PD form of parkinsonism.24 PD was found to have a much longer latency period (time from first symptoms to onset of recurrent falls) than MSA, dementia with Lewy bodies, corticobasal degeneration, and PSP.

Because MSA is commonly mistaken for PD, a detailed analysis of the differentiating features of the 2 conditions is particularly useful for diagnosis. Wenning et al examined 100 consecutive pathologically confirmed cases of PD and 38 pathologically confirmed cases of MSA from the United Kingdom Parkinson's Disease Society Brain Bank, to determine the specificity and sensitivity of various clinical features for differential diagnosis.25 The mean age of patients in the MSA group was 55.9 years compared with 62.4 years in the PD group, and there was a significant difference in mean disease duration prior to death. MSA patients survived an average of 6.8 years after symptom onset compared with 13.2 years in patients with PD (P <.0005).25 Initial modeling for diagnostic criteria was based on signs and symptoms recorded by investigators from the time of first patient encounter to their death. Subsequent modeling limited data to that from the first 5 years of symptom onset. Four clinical features were found to represent significant predictors of MSA compared with PD: (1) autonomic features present (defined as symptomatic postural hypotension, urinary urge incontinence, fecal incontinence, urinary retention requiring catheterization, or persistent erectile failure), (2) poor initial response to levodopa, (3) early motor fluctuations, and (4) initial rigidity. The presence of any 2 of these features provided a sensitivity of 87.1% and a specificity of 70.5% for distinguishing MSA from PD.25

A total of 23% of patients with PD (based on the longer-term data) had a poor initial response to levodopa; although this percentage was much smaller compared with patients with MSA (58% poor initial response), it demonstrates the limitations of levodopa challenge in the absence of other clinical variables.25 (See further discussion of drug challenge below.)

Another smaller study, also originating from the United Kingdom Parkinson's Disease Society Brain Bank, sought to identify clinical features that could be used to distinguish MSA, PD, and PSP.26 The study compared 20 patients with pathologically diagnosed PD, 16 with pathologically diagnosed MSA, and 16 with pathologically diagnosed PSP. The investigators found that while no tremor was present at disease onset in 8 (40%) patients with PD, tremor was absent in 14 (88%) patients with MSA and in 10 (62%) patients with PSP. Orthostatic hypotension occurred in only 1 (5%) patient with PD, compared with 11 (69%) patients with MSA and none with PSP. Lack of response to levodopa occurred in 31% of patients with MSA and 75% of patients with PSP, whereas all of the patients with PD responded to levodopa.26 Consistent with the Wenning et al25 study, disease progression was considerably faster in MSA (and PSP) compared with PD, whereas symmetrical symptom onset was a feature particularly common in patients with PSP.

Drug Challenge

Acute challenge testing with levodopa or apomorphine is a long-used method for diagnosing PD. The clinical treatment guidelines are divergent on the question of the utility of drug challenge for PD diagnosis. The AAN guidelines recognize the acute challenges as a valid diagnostic test when there is doubt about the diagnosis; however, they also highlight the approximately 30% chance of a false negative and the 20% to 30% chance of a false positive. In contrast, the NCCCC and SIGN guidelines regard acute levodopa and apomorphine challenges as lacking clinical merit. The AAN recommendations are based, in part, on data from Merello et al, who studied 82 symptomatic patients without a specific diagnosis who were given acute levodopa challenge and followed for 24 months. An improvement of 30% with the challenge was considered a positive response. When patients were stratified by UPDRS score, those with a score of 10 or less could be diagnosed with PD with a sensitivity of 71% and a specificity of 100%. However, for those with UPDRS scores of 21 or greater, sensitivity was reduced to 36% and specificity to 87%.27

The AAN guidelines also cite an Italian study in which 134 patients (83 with a clinical PD diagnosis, 28 with MSA, 6 with PSP, and 17 with unclassified parkinsonism) were given acute challenge with levodopa and apomorphine.28 Motor response was evaluated by UPDRS score 1 hour after administration of levodopa and 20 minutes after each subcutaneous administration of apomorphine. Patients with PD had significantly better UPDRS scores than the other patients for both drug challenges, regardless of the dose administered (all, P <.001). Levodopa challenge had a sensitivity of 77% and a specificity of 71%, while apomorphine challenge (4.5-mg dose) yielded a sensitivity of 76% and a specificity of 67%.28

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