# Diaphragmatic Palsy Due to a Paraneoplastic Autoimmune Syndrome Revealed by Checkpoint Inhibitors

## TL;DR

This paper reports three cases where diaphragmatic palsy occurred due to a paraneoplastic autoimmune syndrome triggered by immunotherapy, leading to life-threatening respiratory failure.

## Contribution

The study highlights diaphragmatic palsy as a rare but severe immune-related adverse event linked to pre-existing paraneoplastic conditions.

## Key findings

- Diaphragmatic palsy was confirmed in three patients using ultrasonography and other diagnostic tests.
- All patients had pre-existing subclinical paraneoplastic syndromes with onconeural antibodies detected before immunotherapy.
- Immune checkpoint inhibitors may trigger flare-ups of silent autoimmune conditions, leading to severe complications.

## Abstract

Background and Clinical Significance: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but may underlie diverse and potentially life-threatening immune-related adverse events (irAEs). They may cause various conditions leading to respiratory failure, including myasthenic syndromes and myositis. However, diaphragmatic paralysis (DP) has rarely been reported. To describe patients with diaphragmatic paralysis in a pharmacovigilance registry, we searched the prospective REISAMIC registry at the Gustave Roussy Cancer Center (Villejuif, France) for cases of diaphragmatic palsy (DP) occurring from September 2014 to December 2021. Case Presentation: We identified three patients, in whom DP was confirmed by diaphragmatic ultrasonography, pulmonary function tests, and/or diaphragmatic electroneuromyogram. Diaphragmatic palsy was life-threatening in all patients, as it caused respiratory failure requiring mechanical ventilation. In all cases, a pre-existing subclinical paraneoplastic syndrome was detected. Onconeural antibodies (anti-titin and anti-VGCC) were detected in these patients before and after the initiation of ICI therapy, suggesting a mixed paraneoplastic syndrome with features overlapping those of myasthenic syndrome (myasthenia gravis in one patient and Lambert–Eaton syndrome in another) and myositis. Conclusions: Diaphragmatic palsy is a severe irAE potentially resulting from different mechanisms, including myositis and neuromuscular junction involvement (myasthenia gravis, Lambert–Eaton). Antineuronal antibodies associated with such conditions were already present in our patients prior to immunotherapy initiation, suggesting ICIs could trigger flare-ups of pre-existing silent paraneoplastic autoimmune conditions.