Natural history of pure autonomic failure: A United States prospective cohort

Abstract

Objective: To define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.

Methods: One hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the United States. Seventy-four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests.

Results: At enrollment, patients were 68 ± 12 years old (median ± interquartile range) and had had autonomic failure for 5 ± 7 years. Within 4 years of follow-up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt > 10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell.

Interpretation: Patients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287-297.

Figure 1. Outcomes of the natural history of pure autonomic failure

Arrows describe subject flow through the natural history study. Endpoint outcomes are listed on the left. 74 patients met eligibility criteria and agreed to follow-up longitudinal evaluations. At the time of writing, follow-up data of 1-year or more was available in 96% of patients (n=71). The first year saw 39 of patients continue with autonomic failure as the only clinical feature, and 12-patients convert to full synucleinopathy. By year two (n=45), only 39 remained with pure autonomic failure and 6 patients converted to a full synucleinopathy. By year 3 (n=31), Only 27 remained with pure autonomic failure and another 4 converted to a Lewy body disorder. In year 4 (n=15), 11 remain as pure autonomic failure Lost to follow-up rates in participants that agreed to longitudinal visits range from 1 to 3 patients/year. This 4-year prospective study suggests a >10% cumulative risk of conversion to full synucleinopathy per year. DLB, dementia with Lewy bodies; PD, Parkinson disease; PAF, pure autonomic failure.

Figure 2. CNS manifest synucleinopathy risk in patients with PAF

Rates of conversion to manifest CNS synucleinopathy according to the time of onset of neurogenic orthostatic hypotension symptoms in the 74 patients from the cohort.

Figure 3. Relationship between olfaction, plasma norepinephrine levels in the supine position (top) and heart rate response after 3 minutes of head up tilt (bottom)

Patients with autonomic failure and were later diagnosed MSA (red) had normal olfactory function, tended to have plasma norepinephrine levels that were not low, and greater chronotrophic response to head up tilt. Those that converted to PD or DLB (grey) had impaired olfaction, tended to have lower norepinephrine levels, and a lesser heart rate response to tilt. Patients who remained as pure autonomic failure without signs of CNS involvement are shown in white. Circles represent clusters of patient groups. UPSIT: University of Pennsylvania Smell Identification Test.