Paraneoplastic neuronal intermediate filament autoimmunity

Objective: To describe paraneoplastic neuronal intermediate filament (NIF) autoimmunity.
Methods: Archived patient and control serum and CSF specimens were evaluated by tissue-based indirect immunofluorescence assay (IFA). Autoantigens were identified by western blot and mass spectrometry. NIF specificity was confirmed by dual tissue section staining and 5 recombinant NIF-specific HEK293 cell based assays (CBAs, for alpha internexin, neurofilament light [NF-L], medium, or heavy chain, and peripherin). NIF-IgGs were correlated with neurological syndromes and cancers.
Results: Among 65 patients, NIF-IgG positive by IFA and CBAs, 33 were female (51%). Median symptom-onset age was 62 years (range, 18-88). Patients fell into 2 groups, defined by the presence of NF-L-IgG (21 patients, who mostly had ≥4 NIF-IgGs detected) or its absence (44 patients, who mostly had ≤2 NIF-IgGs detected). Among NF-L-IgG positive patients, 19/21 had ≥1 subacute onset CNS disorders: cerebellar ataxia (11), encephalopathy (11); myelopathy (2). Cancers were detected in 16 of 21 patients (77%): carcinomas of neuroendocrine lineage (10) being most common (small cell [5], Merkel cell [3], other neuroendocrine [2]). Two of 257 controls (0.8%, both with small cell carcinoma) were positive by both IFA and CBA. Five of 7 patients with immunotherapy data improved. By comparison, the 44 NF-L-IgG negative patients had findings of unclear significance: diverse nervous system disorders (p=0.006), as well as limited (p=0.003) and more diverse (p<0.0001) cancer accompaniments.
Conclusions: NIF-IgG detection by IFA, with confirmatory CBA testing that yields a profile including NF-L-IgG, defines a paraneoplastic CNS disorder (usually ataxia or encephalopathy) accompanying neuroendocrine lineage neoplasia.