Ζεκερίδου, Αναστασία

Abstract Background Lambert-Eaton myasthenic syndrome (LEMS) is caused by IgG-mediated disruption of certain voltage-gated Ca2+-channel (VGCC) functions and diminished peripheral motor nerve-stimulated release of acetylcholine by presynaptic terminals at the neuromuscular junction and selected autonomic synapses. Both P/Q-type (Cav2.1) and N-type (Cav.2) channels are the targets of IgG-mediated autoimmunity in LEMS. Functional presynaptic VGCCs at the healthy mature mammalian neuromuscular junction are P/Q-type. About 60% of LEMS cases are paraneoplastic, of which a majority are associated with small-cell lung cancer (SCLC-LEMS). LEMS can also have a non-paraneoplastic etiology (idiopathic, non-tumor LEMS [NT-LEMS]). It is important to have reliable autoantibody biomarkers to aid the serological diagnosis of LEMS and to distinguish between SCLC-LEMS and NT-LEMS, because the treatment and prognosis differ. Previous studies have reported seropositivity for SOX1/AGNA-1-IgG in ∼ 64% of SCLC-LEMS cases, but in no NT-LEMS cases. When coexisting with P/Q-type VGCC IgG in LEMS patients, IgGs of both N-type VGCC and SOX1/AGNA-1 IgG specificities have been suggested as useful biomarkers for predicting SCLC. Here we compared the clinical utility of serological tests for P/Q-type and N-type VGCCs and SOX1/AGNA-1 IgGs as diagnostic aids for LEMS and for differentiating paraneoplastic from idiopathic LEMS. Methods This is a retrospective study of 102 patients with a clinical (electrophysiologically confirmed) diagnosis of LEMS who were tested for both P/Q-type and N-type VGCC IgGs by radioimmunoprecipitation assays performed at the Mayo Clinic Neuroimmunology Laboratory. 95 patients had comprehensive clinical screening for cancer; 66 had NT-LEMS, 21 had SCLC-LEMS and 8 had LEMS with non-SCLC cancers. Historical data were reviewed retrospectively. Of the NT-LEMS and SCLC-LEMS patients, 76 were tested for SOX1/AGNA-1 IgG. 122 healthy sex and age-matched controls were tested. Results Among the 102 LEMS patients, 92 (90%) were P/Q-VGCC IgG positive (P/Q+) and 26 (26%) were N-VGCC IgG positive (N+); 67 (66%) were P/Q+ only, 1 (0.9%) was N+ only, 25 (25%) were P/Q+N+, and 9 (9%) were seronegative for both. Three of the 122 healthy control subjects (2.5%) were N+ only, the rest were seronegative. The frequency of isolated N-type VGCC seropositivity did not differ significantly for LEMS patients and healthy controls (P = 0.69). All 21 SCLC-LEMS cases (100%) were P/Q-VGCC IgG positive, compared with 58 of the 66 NT-LEMS cases (88%). The rate of N-type VGCC IgG positivity in P/Q+ LEMS patients did not differ significantly for SCLC-LEMS (5 of 21) and NT-LEMS (13 of 58) diagnoses (24% vs 22%, P = 0.90). The frequency of SOX1/AGNA-1 IgG was 35% for the SCLC-LEMS cases (7 of 20), but none of the NT-LEMS cases (n = 56) was SOX1/AGNA-1 IgG positive. Conclusion N-type VGCC improved neither sensitivity for LEMS nor positive predictive value for cancer and has limited diagnostic utility in assessing patients with suspected LEMS. PQ-type VGCC IgG negativity does not exclude a diagnosis of LEMS. SOX1/AGNA-1 positivity has high specificity but low sensitivity for SCLC. Therefore, while antibody testing confirms a diagnosis of autoimmune LEMS, electrophysiology (to confirm neurological diagnosis) and body imaging (for cancer detection) remain important for the diagnostic evaluation.

ObjectiveCo‐occurring anti‐tripartite motif‐containing protein 9 and 67 autoantibodies (TRIM9/67‐IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67‐IgG detection are not known.MethodsWe performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67‐IgG cases by tissue‐based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell‐based assay (CBA), and immunoblot. Cases in which TRIM9/67‐IgG was detected by at least 2 assays were considered TRIM9/67‐IgG positive.ResultsAmong these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67‐IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases.InterpretationTRIM9/67‐IgG is a rare but likely high‐risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086–1101

Autoimmune movement disorders are increasingly recognized, but isolated tremor is extremely rare. We describe a 70‐year‐old male with rapidly progressive, severe postural and intention tremor and weight loss. His cerebrospinal fluid was inflammatory and harbored a neural tissue‐restricted antibody. The autoantigen was identified by immunoprecipitation and mass spectrometry and confirmed by antigen‐specific assays to be specific for tenascin‐R. He was investigated for cancer and diagnosed with follicular lymphoma that expressed tenascin‐R suggesting a paraneoplastic origin; cancer treatment and immunotherapy led to complete recovery. With this individualized patient approach and antibody discovery, we expand the spectrum of antibodies accompanying autoimmune hyperkinetic movement disorders. ANN NEUROL 2023;94:502–507