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Differences in Mortality Rates and the Natural History of Synucleinopathies Reported in New Study: Experts Say Data Are Helpful for Counseling Patients

Talan, Jamie

doi: 10.1097/01.NT.0000520857.66056.7d
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A unique population-based epidemiological study in Olmstead County, MN, has allowed researchers at the Mayo Clinic to track the survival of patients with different types of synucleinopathies, finding marked differences among different disorders, according to data published in the May 15 issue of JAMA Neurology.

The scientists, led by physician-scientist Rodolfo Savica, MD, PhD, assistant professor of neurology at the Mayo Clinic in Rochester, MN, also looked at causes of death to understand whether the neurodegenerative disease ended their life, or whether they died of other causes.

No one had ever compared survival rates in various types of parkinsonism linked to accumulation of abnormal alpha-synuclein proteins, Dr. Savica told Neurology Today.

“Understanding the long-term outcomes could be useful for clinicians and their patients who want to know the expected duration of the disease and how they should plan for their future,” said Dr. Savica. “We have very little ability to predict the natural history of these diseases. For the first time, our findings will give physicians an idea of how long their patients might live.”

The research team used detailed medical information gathered through the Rochester Epidemiology Project to determine survival rates and causes of death in hundreds of people with multiple system atrophy (MSA), dementia with Lewy Bodies (DLB), Parkinson's disease with dementia (PDD), and Parkinson's disease without dementia.

Among their findings, people with MSA died an average of four years earlier than those with a clinical presentation of pure Parkinson's disease. People with DLB lived about a year longer than people with MSA, and those with a PDD died on average about a year before people with PD without dementia.

People with any synucleinopathy died an average of two years earlier than an age-and-gender matched group of people without any neurodegenerative disease. The mortality in PD patients was only slightly shorter, about a year, than those without neurodegenerative disease.

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STUDY METHODS, FINDINGS

Dr. Savica and his colleagues identified 461 patients with synucleinopathies who were diagnosed at the Mayo Clinic between 1991 and 2010: 309 patients (67 percent) had pure PD, 81 patients (17.6 percent) had DLB, 55 patients (11.9 percent) had PDD, and 16 patients (3.5 percent) had MSA. Not surprisingly, neurodegenerative disease was listed as the most frequent cause of death. By comparison, the primary cause of death in the reference population was cardiovascular disease.

The scientists looked for any mention of parkinsonism in the ICD-9 codes in the medical records of participants in the Rochester Epidemiology Project. A movement disorders specialist looked at the chart to determine the onset of symptoms and the diagnosis. People entered into the analysis had at least two out of four signs of parkinsonism: rest tremor, rigidity, bradykinesia, and impaired postural reflexes. They excluded patient records of those that indicated other neurological problems such as head injury that could have triggered parkinsonism so that they could have a pure PD population. Then, they reviewed the available autopsy records to validate their diagnoses and note the primary cause of death. (There was about 82 percent agreement between the pathological diagnosis and the clinical one.)

The researchers matched each patient with a referent patient who was free of tremor or parkinsonism. There were 452 people in the referent group. The patients with a synucleinopathy were on average about 75.8 years old and had developed parkinsonism symptoms. Their mean age of death was 84.7 years. The average age of the referent study subjects was 75.6 years, and their mean age at death was 87.8.

All patients and referents in the study were followed through to death or until the study ended in summer 2015. By that time, there were 316 patients with synucleinopathies (68.6 percent) who died and virtually all of them had a primary cause listed on the death certificate. By comparison, 220 of the people in the referent group (almost 50 percent) had died. The researchers had access to death certificates on 216 of them.

According to Dr. Savica, the survival curves in patients with synucleinopathies started to look different than those in the referent group within the first two years after the initial diagnosis. Patients had a two-fold increase in mortality compared to those in the referent group. Then, it became obvious that the survival curves were different even between those with different types of synucleinopathies.

The mortality was highest in those with MSA. Sex and age did not predict mortality in any of the diagnostic groups.

The Mayo Clinic scientists wanted to understand why the patients died when they did. Neurodegenerative disease was the most frequently listed primary cause of death among patients for all synucleinopathies (31 percent) and 25.6 percent in those with a pure PD diagnosis. Cardiovascular problems were the second most common cause of death listed in 16 percent of the patients. By contrast, cardiovascular events were the most common cause of death in a quarter of the referent population, followed by cancer (18 percent).

“This study is a stepping stone to use this data set to predict, anticipate and provide prognostic value to patients with these conditions,” said Dr. Savica.

Among the limitations of the analysis, the scientists noted, were that the cases of dementia with Lewy bodies without parkinsonism were not identified by their methods; however, the majority of patients with DLB had parkinsonism. The numbers in each of the groups, especially the MSA patients, was “relatively small,” but there was enough power to identify the differences between groups, said Dr. Savica.

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EXPERTS WEIGH IN

“The power of this paper is that the scientists had a unique opportunity to look back at the diagnostic history, the time of onset, and the clinical course, and follow it through to post-mortem findings,” said Caroline M. Tanner, MD, PhD, FAAN, director of the Parkinson's Disease Research Education and Clinical Center at San Francisco Veteran's Affairs Medical Center and professor of neurology at the University of California, San Francisco. “This information will be useful for families. Our dialogue with patients goes on over time, and I can use this as an important part of my discussion with them. It's important for end-of-life planning and decision-making.”

“Although it does not change management, it helps with counseling patients and families,” added Christopher Goetz, MD, FAAN, professor of neurological sciences and pharmacology at Rush University Medical Center, and director of the Rush Parkinson's Disease and Movement Disorders Program. “As long as parkinsonism remains only a motor disability, life expectancy is lower than the reference population, but modestly so,” he explained. “However, when dysautonomia (MSA) or cognitive and behavior complications (LBD and PDD) superimpose, the mortality dramatically increases.

“These solid data mimic my own clinical experience, and the data highlight the importance of focusing on new treatments for orthostatic hypotension, dementia, hallucinations, and delusional thinking. Fortunately, there is a wider appreciation of these comorbidities that increase mortality risk, new treatments are now available, and newer ones are being developed.”

“This is something we always thought, but it's good to have evidence that it is true,” added David Eidelberg, MD, FAAN, professor and head of the Feinstein Center for Neurosciences at Northwell Health in Great Neck, NY. “Identifying the clinical syndrome is what counts and predicts longevity. But this is a group finding, and the numbers are probably variable and can't necessarily filter down to the individual patient.”

Nikolaus McFarland, MD, PhD, assistant professor of neurology at University of Florida College of Medicine and Wright/Falls/Simmons director of the PSP/Atypical Parkinsonism Program, also called the findings “significant.”

In contrast to prior studies, he said that all synucleinopathies, genders, and incident cases (not just hospital-based) were included, thereby reducing bias. The study also utilized disease onset rather than time of diagnosis, which can often be delayed due to early misdiagnosis, he noted.

“The results of this study may not necessarily extrapolate to populations in other geographic locations,” he added. “Nevertheless, this study provides a unique insight into natural history and survival risk of synucleinopathies. Though not unexpected, the results nicely document the survival risk for each of these disorders and will be helpful to advise patients and families about prognosis.”

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LINK UP FOR MORE INFORMATION:

•. Savica R, Grossardt BR, Bower JH, et al Survival and causes of death among people with clinically diagnosed synucleinopathies with parkinsonism: A population-based study http://jamanetwork.com/journals/jamaneurology/fullarticle/2625134. JAMA Neurol 2017; Epub 2017 May 15.
© 2017 American Academy of Neurology