Relative Frequency and Distinctive Features of Anti-Ma2 Nonparaneoplastic Neurologic Disorders: A French Cohort Study.

BACKGROUND AND OBJECTIVES: Although anti-Ma2 antibodies (Ma2-Abs) typically associate with paraneoplastic encephalitis, a subset of patients with Ma2-Abs does not have any detectable tumor. The clinical specificities of these idiopathic cases are unknown. The aim of this study was to describe clinical phenotypes and outcomes of patients with idiopathic Ma2-Abs (I-Ma2) compared with patients with paraneoplastic Ma2-Abs (PNS-Ma2). METHODS: A retrospective review of the French Reference Center of Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis database was conducted to identify cases of Ma2-Abs-mediated syndromes diagnosed between January 2002 and December 2022. A systematic review of the existing literature was also performed to assess for reported I-Ma2 cases. RESULTS: Seventy patients with neurologic syndromes harboring Ma2-Abs were identified (50/70 men, 71.4%; median age 60 years, interquartile range (IQR) 47-67.5). Malignancies were detected in 46 of 70 (65.7%). When compared with the PNS-Ma2 cohort, the I-Ma2 cohort less frequently had an acute/subacute disease progression (5/20, 25%, vs 26/46, 56.5%; p = 0.037) and the time to diagnosis was longer (10 months, IQR 4-20, vs 3.5 months, IQR 1-6; p = 7.94 x 10-10). No differences were found in the subtype of clinical symptoms between patients with and without cancer. However, monofocal involvement, predominantly isolated limbic encephalitis, was more frequent in patients with I-Ma2 vs the PNS-Ma2 cohort (13/20, 65%, vs 18/46, 39.1%; p = 0.05). The other discriminative paraclinical finding was EEG alteration, which was more frequently abnormal in patients with I-Ma2 (I-Ma2 11/20, 55%, vs PNS-Ma2 12/46, 26%; p = 0.047). There were no differences in brain MRI and CSF inflammation. Systematic review of the literature revealed a longer follow-up, a greater use of second-line immunotherapies, and a higher proportion of patients with I-Ma2 in the French cohort (proportion of French I-Ma2 20/66 (30.3%) vs 10/109 (10.9%) in the literature, p = 0.00325, respectively). DISCUSSION: Patients with I-Ma2 are more common than anticipated and have insidious disease onset and a tendency for monofocal nervous system involvement. Recognition of patients with I-Ma2 is delayed and must be improved.