Diagnosing Parkinson's Disease Still Challenging

Megan Brooks

July 31, 2014

Making an accurate clinical diagnosis of Parkinson's disease (PD) remains a challenge, particularly early in the course of disease, a new study indicates.

Even if the patient is responsive to dopaminergic medication, the clinical diagnosis of PD early on has "relatively poor accuracy," the study team reports.

"Currently there is no diagnostic test for PD, so we rely on clinical findings," first author Charles H. Adler, MD, PhD, from the Parkinson's Disease and Movement Disorders Center at the Mayo Clinic in Scottsdale, Arizona, told Medscape Medical News.

The clinical signs of PD (tremor, rigidity, slowness, gait disorder, and so on) are not unique to the disease but also can be found in many other disorders including other neurodegenerative disorders, he explained.

"While the longer you follow a patient and monitor response to medication, the higher the probability of making the correct diagnosis, early on the clinical findings may be due to PD or many of these other disorders," Dr. Adler said.

The study was published online June 27 and in the July 29 issue of Neurology.

'Very Sobering' Data

Dr. Adler and colleagues used data from the Arizona Study of Aging and Neurodegenerative Disorders to assess diagnostic accuracy of a clinical diagnosis of PD, using neuropathologic diagnosis as the gold standard. They used 2 clinical diagnostic "confidence levels":

  • Possible PD (PossPD), defined as 2 of the 3 cardinal signs of PD (rest tremor, bradykinesia, rigidity), no symptomatic cause, symptoms or signs present for 5 years or less, and never treated or not clearly responsive to dopaminergic therapy), and

  • Probable PD (ProbPD), defined as 2 of the 3 cardinal signs, no symptomatic cause, and responsive to medications.

They included 232 patients with parkinsonism at the first visit: 34 had PossPD, 97 had ProbPD (15 for <15 years and 82 for 5 years or longer), and 101 had other types of parkinsonism.

For PossPD (never treated or not clearly responsive), only 9 (26%) of 34 patients had neuropathologically confirmed PD at the time of first visit (mean symptom duration, 0.7 years). "This is a critical finding given the number of studies attempting to find biomarkers or disease-modifying treatments in very early PD cases," the researchers say.

For ProbPD (responsive to medication), longer disease duration improved diagnostic accuracy. PD was confirmed in 72 (88%) of 82 ProbPD cases having symptoms for 5 years or longer, but in only 8 (53%) of 15 patients with symptoms present for less than 5 years. The authors say this finding was "unexpected."

Using final diagnosis at time of death, 91 (85%) of 107 ProbPD cases had confirmed PD. Medication response, motor fluctuations, dyskinesias, and hyposomia were the clinical variables that improved diagnostic accuracy.

These data are "very sobering and have significant implications" for studies that enroll patients with early PD, Dr. Adler and colleagues note in their article. "The inaccuracy has the potential of severely compromising the likelihood of observing an adequate effect size in a trial," they point out.

"As clinical research studies attempt to find the earliest possible biomarkers for PD and early, disease-modifying treatments for PD, the low diagnostic accuracy at this stage needs to be addressed and will continue to be a critical impediment until autopsy- or biopsy-verified diagnostic biomarkers are developed," they conclude.

Effect on Research, Not Clinical Care

Dr. Adler told Medscape Medical News that he expects "at some point we will have...a blood, [cerebrospinal fluid], or saliva test, certainly to predict high risk. Additionally, we are working on using submandibular gland needle biopsy as a diagnostic test for PD."

"Maybe most importantly right now, it is not absolutely critical for the clinician to distinguish between PD and other parkinsonian disorders, as the treatment of the patient will likely be the same. It is really critical for research into the diagnosis and treatment of PD that the correct diagnosis be made," Dr. Adler said.

The coauthors of an editorial published with the study agree that these findings are "sobering" and point out that the "clinical diagnostic capabilities for PD have not advanced substantially over the last 23 years."

The authors are Ali H. Rajput, MBBS, FRCPC, and Alex Rajput, MD, FRCPC, both from the Movement Disorders Program Saskatchewan, University of Saskatchewan/Saskatoon Health Region in Canada.

They say that for now, clinical diagnosis of PD is best made when 2 of the 3 motor features (resting tremor, bradykinesia, and rigidity, without clinical features indicating any other neurologic disease) are observed.

Having symptoms for at least 5 years "improves diagnostic accuracy, but the challenge is to find methods or tools to predict accurately the underlying pathology in the earlier cases," they conclude.

In comments to Medscape Medical News, Dr. Rajput noted that at the moment, a definite diagnosis of PD is based on pathological findings of marked substantia nigra neuronal loss and neuronal inclusions (Lewy bodies).

"When we make a clinical diagnosis of PD, we assume that the brain has those pathological findings," Dr. Rajput explained. "However, there are some patients that have all the clinical features of PD, have substantia nigra damage, but do not have Lewy body inclusions. We have studied and reported several such cases. We could not distinguish those cases from the patients that had the classical Parkinson pathology. The best that we could do is to say that this patient has substantia nigra-based PD."

"If we continue to define PD exclusively, as the Lewy body disease, we will continue to have [a] significant number of inaccurate clinical diagnoses. Unless we have biological markers to identify the Lewy bodies in the brain in living subjects, we will have diagnostic accuracy problems," Dr. Rajput said.

Funding for the study was provided by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Arizona Department of Health Services, the Arizona Biomedical Research Commission, the Michael J. Fox Foundation for Parkinson's Research, and the Mayo Clinic Foundation. Dr. Adler has received research funding from Phytopharm, Avid Radiopharmaceuticals, the Michael J. Fox Foundation, the National Institutes of Health, the US Department of Defense, and the Arizona Biomedical Research Foundation, and has received consulting fees from Impax, Ipsen, Merz, Novartis, Teva, and Xenoport. A complete list of disclosures for authors and editorial writers is available with the original article.

Neurology. 2014;386-387,406-412. Article abstract, Editorial extract

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