Anti-Yo autoimmunity in patients with post-immune checkpoint inhibitors neurological syndromes
Antonio Farina1, Veronique Rogemond2, Elise Peter2, Valentin Wucher2, Macarena Villagran Garcia2, Do Le Duy2, Geraldine Picard2, Bastien Joubert2, Jerome Honnorat2, Virginie Desestret2
1Université Claude Bernard Lyon 1, Università degli Studi di Firenze, 2Université Claude Bernard Lyon 1
Objective:
We report for the first time the occurrence of Yo-antibodies (Abs) in the setting of post-immune checkpoint inhibitors (ICI) neurological syndromes.
Background:

Among Abs carrying a high risk for paraneoplastic neurological syndromes (PNS), anti-Yo-Abs are mostly detected in women with gynecological malignancies who develop a paraneoplastic cerebellar degeneration (PCD). 

Design/Methods:

Yo-Abs were initially detected in serum and cerebrospinal fluid (CSF) samples by commercial line dots (RAVO diagnostika and Euroimmun) and further confirmed with in-house techniques: immunohistochemistry on rat brain sections, cell-based assay and Western blot for cerebellar degeneration-related 2 (CDR2) and CDR2-like (CDR2L) proteins.

Results:

Three patients were referred to the French national reference center for PNS: 59-year-old woman and 60-year-old man with lung adenocarcinoma, and 63-year-old woman with ovarian adenocarcinoma, all developing the first neurological symptoms within 3 months of ICI (pembrolizumab) first dose. The woman with ovarian cancer and the man with lung adenocarcinoma had a PCD, while the woman with lung cancer had a myelitis. In all patients, CSF analysis disclosed pleocytosis and brain magnetic resonance imaging was normal. Yo-Abs were retrospectively detected in pre-ICI serum samples in the patient with ovarian cancer. Management consisted of permanent ICI discontinuation (3/3) and immunomodulation, including corticosteroids (3/3), immunoglobulins (2/3), rituximab (1/3), or cyclophosphamide (1/3). No patient substantially improved (modified Rankin Score pre- and post-treatment 4). In all cases, cancer progressed after ICI discontinuation and at last follow-up (4-16 months after neurological onset) the two patients with PCD were dead and the one with myelitis was in palliative care.

Conclusions:
While the pre-ICI Yo-Abs positivity in the patient with ovarian cancer suggests that ICI might have triggered a latent PNS, both the unusual cancer type association (lung) in the other two patients and the atypical clinical phenotype in one of them (myelitis) poses a challenge to the classic understanding of Yo-Abs associated PNS.
10.1212/WNL.0000000000203452