Predictors of Phenoconversion in Pure Autonomic Failure: A Systematic Review and Meta-Analysis
Sara Massucco1, Elizabeth Coon3, Vincenzo Donadio4, Horacio Kaufmann5, Christopher Gibbons1, Pushpa Narayanaswami2, Roy Freeman1
1Department of Neurology, Beth Israel Deaconess Medical Center, 2Beth Israel Deaconess Medical Center, 3Department of Neurology, Mayo Clinic, 4IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, 40139, Italy, 5NYU Langone Health - NYU Dysautonomia Center
Objective:
To quantitatively determine predictors of phenoconversion in pure autonomic failure (PAF) and estimate phenoconversion frequency through meta-analysis.
Background:
PAF is an alpha-synucleinopathy with predominantly peripheral autonomic features, often accompanied by rapid eye movement sleep behavior disorder or anosmia. A subset of patients develop motor or cognitive features meeting criteria for Lewy body diseases (LBDs), including Parkinson’s disease and dementia with Lewy bodies, or multiple system atrophy (MSA). While phenoconversion predictors have been proposed, their accuracy remains uncertain. As disease-modifying therapies for alpha-synucleinopathies advance, determining these predictors and their accuracy is an urgent need.
Design/Methods:
Following PRISMA guidelines, we searched PubMed, Scopus, and Web of Science through July 10, 2025, for longitudinal studies of PAF patients with documented conversion to LBDs or MSA. Study quality was assessed with the Newcastle-Ottawa Scale. Random-effects models estimated pooled odds ratios (ORs) with 95% confidence intervals (CIs) for predictors reported in ≥3 studies. Phenoconversion rates were estimated with Freeman-Tukey transformation and inverse-variance weighting.
Results:
Among 774 records screened, 11 studies met inclusion criteria, and eight cohorts (855 patients) contributed to meta-analyses. Pooled, 32% (95% CI: 26–39%) converted: 20% (12–28%) to LBDs and 10% (7–14%) to MSA. Predictors of overall phenoconversion were dream enactment behavior (OR 3.23, 95% CI: 1.81–5.74), subtle motor signs (OR 5.41, 0.99–29.56), and urinary dysfunction/catheterization (OR 2.42, 1.57–3.75; OR 3.63, 1.73–7.64). LBD conversion was predicted by dream enactment (OR 3.47, 1.50-8.06) and hyposmia (OR 2.05, 1.16-3.62); MSA by dream enactment (OR 3.78, 2.07-6.91), constipation (OR 2.34, 1.21-4.51), subtle motor signs (OR 7.22, 1.11-48.08), urinary symptoms (OR 7.06, 3.67-13.61), and catheterization (OR 8.16, 3.76-17.71).
Conclusions:
This systematic review and meta-analysis provides a comprehensive synthesis of predictors of phenoconversion in PAF. Identifying these predictors may improve prognostic accuracy and enable earlier intervention, which is of particular importance with emerging disease-modifying therapies.
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