# Alternative diagnoses of suspected paraneoplastic neurological syndromes: a population-based study

## TL;DR

This study identifies common alternative diagnoses in patients suspected of having paraneoplastic neurological syndromes, helping to reduce misdiagnosis.

## Contribution

The study introduces the PNS DDx Score, a tool to identify patients at risk of misdiagnosis during PNS workup.

## Key findings

- Alternative diagnoses were most common in patients under 55 years and those without high-risk syndromes.
- The PNS DDx Score incorporates age, syndrome type, and tumor status to predict misdiagnosis risk.
- Autoimmune and degenerative conditions were frequent alternative diagnoses in central nervous system cases.

## Abstract

The diagnosis of paraneoplastic neurologic syndromes (PNS) requires exclusion of alternative etiologies. However, the spectrum of alternative diagnoses encountered during PNS workup (“better explanations”) has not been systematically examined. We aimed to characterize this spectrum.

Retrospective population-based study in Friuli-Venezia-Giulia (Italy). Among 878 consecutive patients tested for PNS antibodies at a centralized tertiary center serving three hospitals (2009–2017), alternative diagnoses were identified. Results of a logistic regression model were used to develop the PNS DDx Score.

Among 661 patients with alternative diagnoses, median age was 66 years, and 51% were male. CNS involvement predominated in 397 patients (60%), peripheral in 215 (33%), and extra-nervous system in 49 (7%). Etiologic diagnosis was reached in 269 with central involvement, including degenerative (97, 36%), autoimmune (47, 17%), and vascular (37, 14%). In peripheral presentations, a diagnosis was reached in 112 and included autoimmune (51, 45%), toxic-metabolic (40, 36%), and vasculitis (11, 10%). PNS antibody testing increased by 96% from 2009 to 2017; diagnostic yield remained low (7% vs. 8%). Intermediate-risk or other syndromes (OR 7.97, CI95% 3.07–23.80; OR 192.82 CI95%, 66.11–739.59) and low-risk/absence of tumor (OR 6.90, CI95% 2.75–18.92) were associated with alternative diagnoses, whereas increasing age (OR 0.95, CI95% 0.92–0.97) was inversely associated. These variables (age, syndrome, and tumor type) were incorporated in the PNS DDx Score.

Alternative diagnoses during PNS workup are common in patients < 55 years and those without high-risk syndromes. The PNS DDx Score can be used to identify patients at risk of misdiagnosis.

The online version contains supplementary material available at 10.1007/s00415-026-13737-w.