Is Pure Autonomic Failure a Warning Sign of LBD?

Many people with one specific form of LBD, called dementia with Lewy bodies or DLB, develop problems with their autonomic nervous system. This is the part of the nervous system that regulates functions like heart rate, blood pressure and digestion. In fact, many people with DLB may develop autonomic dysfunction several years before any motor or memory problem appears. When autonomic dysfunction occurs by itself, the condition is referred to as pure autonomic failure (PAF). A careful follow-up of individuals with PAF (i.e., a study of its natural history) reveals that over time, people with PAF may convert to either DLB, Parkinson’s disease (PD) or multiple system atrophy (MSA).

Primary investigator, Horacio Kauffman, MD of New York University School of Medicine and colleagues in the Autonomic Disorders Consortium followed 74 people (70% males) with PAF over 5 years. They evaluated the study participants for symptoms of autonomic dysfunction, including problems with blood pressure regulation (orthostatic hypotension), constipation, urinary incontinence, sweating problems and erectile dysfunction. They were also assessed for features of PD, DLB and MSA such as motor symptoms, cognitive impairment, REM sleep behavior disorder and loss of smell. Once a year, the participants were re-assessed and if new symptoms presented, they were re-diagnosed accordingly.

The conversion rate to DLB, PD or MSA was overall 14% per year. 18% of participants progressed to DLB, compared to 8% to PD and 8% to MSA.

Evaluations Not yet due for
annual follow-up
Left study Passed Away Total subjects assessed Diagnosis changes to DLB Diagnosis changed to PD Diagnosis changed to MSA Diagnosis remained PAF
1 year eval.   1 2 71 4 2 5 60
2 year eval. 12 3 0 45 4 1 1 39
3 year eval. 8   1 31 2 2 0 27
4 year eval. 12     15 3 1   11
        TOTAL: 13 6 6  

Of the 42 patients who still had a PAF at their last evaluation, only 12 were completely free of signs suggesting neurological progression.

Risk Factors for Conversion to Lewy Body Disorders

The presence of REM sleep behavior disorder in people with PAF was most strongly associated with the future progression to PD/DLB or MSA. (This is not surprising, as RBD has been recently identified as a risk factor for the development of PD, DLB and MSA.) In addition to having REM sleep behavior disorder, study participants who progressed to DLB or PD were more likely to exhibit: age at onset of orthostatic hypotension in the mid-60’s, subtle changes in movement, and loss of smell. Also, having an insufficient increase in heart rate when standing up was also associated with a higher risk of developing PD or DLB. Of note, patients developing PD or DLB had been in the autonomic-only phase for almost 10 years on average.

On the other hand, in addition to having REM sleep behavior disorder, study participants who progressed to MSA were more likely to have a younger age (early 50’s) at onset of orthostatic hypotension, more severe urinary symptoms and constipation requiring treatment. Interestingly, those with preserved sense of smell were more likely to progress to MSA (in contrast to those with impaired sense of smell, who were more likely to develop to PD and DLB). Levels of plasma norepinephrine, a hormone which helps to regulate blood pressure, in the normal/high range were also associated with higher risk for developing MSA. Patients developing MSA had been in the autonomic-only phase for less than 5 years, in keeping with the more aggressive nature of MSA.

This study suggests that REM sleep behavior disorder, loss of smell, and subtle changes in movement indicate that the disease is not purely autonomic anymore, and that these are, instead, early signs of DLB, PD or MSA.

Some patients with PAF did not have REM sleep behavior disorder and had preserved smell; none of these develop PD, DLB or MSA. Whether these patients have any unique factors that protect them from developing PD, DLB or MSA, or whether they will eventually develop any of these disorders is still unknown.

This study was published in Annals of Neurology and was supported by the National Institutes of Health Rare Disease Clinical Research Network.