Pure autonomic failure: Predictors of conversion to clinical CNS involvement

Abstract

Objective: Based on the observation that a subset of patients originally diagnosed with pure autonomic failure (PAF) eventually develops extrapyramidal or cerebellar involvement consistent with multiple system atrophy (MSA), Parkinson disease (PD), or dementia with Lewy bodies (DLB), we aimed to identify predictors of progression of PAF to more sinister synucleinopathies.

Methods: In this retrospective cohort study, we reviewed patients seen at Mayo Clinic Rochester by autonomic specialists between 2001 and 2011 and during initial evaluation diagnosed with orthostatic hypotension consistent with PAF (possible PAF). In order to assess for the presence or absence of progression, we identified patients with 3 years or more of in-person follow-up (stable PAF) or documented progression to another synucleinopathy (converters). To identify predictors of conversion, we assessed odds of conversion based on clinical, autonomic, and laboratory variables.

Results: Among 318 patients fulfilling criteria for possible PAF, we identified 41 with stable PAF and 37 (12%) converters. Of those who evolved, 22 developed MSA, 11 developed PD/DLB, and 4 remained indeterminate. Several variables were identified to predict conversion to MSA: (1) mild degree of cardiovagal impairment, (2) preganglionic pattern of sweat loss, (3) severe bladder dysfunction, (4) supine norepinephrine >100 pg/mL, and (5) subtle motor signs at first presentation. Separate variables were found to predict conversion to PD/DLB. Composite conversion scores were generated based on individual predictors.

Conclusions: Over 10% of patients originally diagnosed with PAF eventually evolve to develop CNS involvement, most commonly MSA. A combination of variables allows for prediction of conversion.

Figure 1. Study flowchart

DLB = dementia with Lewy bodies; MSA = multiple system atrophy; PAF = pure autonomic failure; PD = Parkinson disease.

Figure 2. Pathologic confirmation of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) conversion

(A–E) Central Lewy body pathology in an 81-year-old woman who converted from pure autonomic failure (PAF) to DLB (postmortem delay [PMD] 12 hours). (A) Hematoxylin & eosin (H&E) of midbrain (arrows; Lewy bodies). (B) Midbrain, α‐synuclein immunostain in the substantia nigra. (C) H&E of anterior cingulate. (D) Anterior cingulate, α‐synuclein immunostain. (E) Basal ganglia, α‐synuclein immunostain. (F) MSA pathology (glial cytoplasmic inclusions) in a 53-year-old man who converted to MSA (PMD 10 hours); basal ganglia, α‐synuclein immunostain. Bar = 50 μm.

Figure 3. Multiple system atrophy (MSA) and Parkinson disease (PD)/dementia with Lewy bodies (DLB) conversion scores

Conversion scores derived from identified risk factors for future (A, C) MSA and (B, D) PD/DLB conversion in stable pure autonomic failure (light columns) vs converters (dark columns). An MSA conversion score >2 is highly predictive of future conversion to MSA, while a PD/DLB conversion score >1 predicts future conversion to PD or DLB with high sensitivity and specificity.