Citations

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.

AbstractObjectiveSeizures are a common manifestation of paraneoplastic neurologic syndromes. The objective of this study was to describe the seizure characteristics and outcomes in patients with high‐risk paraneoplastic autoantibodies (>70% cancer association) and to determine factors associated with ongoing seizures.MethodsPatients from 2000 to 2020 with seizures and high‐risk paraneoplastic autoantibodies were retrospectively identified. Factors associated with ongoing seizures at last follow‐up were evaluated.ResultsSixty patients were identified (34 males, median age at presentation = 52 years). ANNA1‐IgG (Hu; n = 24, 39%), Ma2‐IgG (n = 14, 23%), and CRMP5‐IgG (CV2; n = 11, 18%) were the most common underlying antibodies. Seizures were the initial presenting symptom in 26 (43%), and malignancy was present in 38 (63%). Seizures persisted for >1 month in 83%, and 60% had ongoing seizures, with almost all patients (55/60, 92%) still being on antiseizure medications at last follow‐up a median of 25 months after seizure onset. Ongoing seizures at last follow‐up were associated with Ma2‐IgG or ANNA1‐IgG compared to other antibodies (p = .04), highest seizure frequency being at least daily (p = .0002), seizures on electroencephalogram (EEG; p = .03), and imaging evidence of limbic encephalitis (LE; p = .03). Death occurred in 48% throughout the course of follow‐up, with a higher mortality in patients with LE than in those without LE (p = .04). Of 31 surviving patients at last follow‐up, 55% continued to have intermittent seizures.SignificanceSeizures in the setting of high‐risk paraneoplastic antibodies are frequently resistant to treatment. Ongoing seizures are associated with ANNA1‐IgG and Ma2‐IgG, high seizure frequency, and EEG and imaging abnormalities. Although a subset of patients may respond to immunotherapy and achieve seizure freedom, poor outcomes are frequently encountered. Death was more common among patients with LE.

AbstractBackgroundStiff person spectrum disorder (SPSD) is heterogeneous, and accurate diagnosis can be challenging.MethodsPatients referred for diagnosis/suspicion of SPSD at the Mayo Autoimmune Neurology Clinic from July 01, 2016, to June 30, 2021, were retrospectively identified. SPSD diagnosis was defined as clinical SPSD manifestations confirmed by an autoimmune neurologist and seropositivity for high‐titer GAD65‐IgG (>20.0 nmol/L), glycine‐receptor‐IgG or amphiphysin‐IgG, and/or confirmatory electrodiagnostic studies (essential if seronegative). Clinical presentation, examination, and ancillary testing were compared to differentiate SPSD from non‐SPSD.ResultsOf 173 cases, 48 (28%) were diagnosed with SPSD and 125 (72%) with non‐SPSD. Most SPSD were seropositive (41/48: GAD65‐IgG 28/41, glycine‐receptor‐IgG 12/41, amphiphysin‐IgG 2/41). Pain syndromes or functional neurologic disorder were the most common non‐SPSD diagnoses (81/125, 65%). SPSD patients more commonly reported exaggerated startle (81% vs. 56%, p = 0.02), unexplained falls (76% vs. 46%, p = 0.001), and other associated autoimmunity (50% vs. 27%, p = 0.005). SPSD more often had hypertonia (60% vs. 24%, p < 0.001), hyperreflexia (71% vs. 43%, p = 0.001), and lumbar hyperlordosis (67% vs. 9%, p < 0.001) and less likely functional neurologic signs (6% vs. 33%, p = 0.001). SPSD patients more frequently had electrodiagnostic abnormalities (74% vs. 17%, p < 0.001), and at least moderate symptomatic improvement with benzodiazepines (51% vs. 16%, p < 0.001) or immunotherapy (45% vs. 13% p < 0.001). Only 4/78 non‐SPSD patients who received immunotherapy had alternative neurologic autoimmunity.InterpretationMisdiagnosis was threefold more common than confirmed SPSD. Functional or non‐neurologic disorders accounted for most misdiagnoses. Clinical and ancillary testing factors can reduce misdiagnosis and exposure to unnecessary treatments. SPSD diagnostic criteria are suggested.

Abstract Background and purpose Outcome and rechallenge data on central nervous system (CNS) autoimmunity triggered by immune checkpoint inhibitors (ICIs) are limited. We aim to describe a large series of patients with ICI‐triggered CNS autoimmunity, and to compare these patients with spontaneous paraneoplastic syndromes (PNS). Methods We retrospectively reviewed Mayo Clinic patients with ICI‐triggered CNS autoimmunity (February 2015–June 2021). Clinical characteristics were compared to spontaneous PNS patients (with antineuronal nuclear antibody [ANNA]‐1 or anti‐Hu neurological autoimmunity, and/or neuroendocrine tumors [NET]) evaluated within the same period. Results Thirty‐one patients were included (55% female, median age = 63 years, range = 39–76). Median time from ICI initiation was 3.65 months (range = 0.8–44.5). The most common associated malignancies were melanoma and small cell lung cancer. CNS manifestations included encephalitis ( n = 16), meningoencephalitis ( n = 8), cerebellar ataxia ( n = 4), demyelinating syndrome ( n = 2), and myelopathy ( n = 1). Magnetic resonance imaging was abnormal in 62%. Cerebrospinal fluid was inflammatory in 70%. Neural autoantibodies were identified in 47%, more frequently in patients with NET ( p = 0.046). ICI was discontinued in 97%; 90% received immunosuppressive treatment. After median 6.8 months follow‐up (range = 0.7–46), 39% had unfavorable outcomes (grade ≥ 3). This was associated with higher severity degree at onset, shorter period from ICI to neurological symptom onset, and encephalitis. Four patients were rechallenged with ICI, and one relapsed. Patients with NET and with ANNA‐1 ICI‐triggered CNS autoimmunity had associated peripheral nervous system manifestations more frequently than their spontaneous counterparts ( p = 0.007 and p = 0.028, respectively). Conclusions One third of ICI‐related CNS autoimmunity patients have unfavorable outcomes. Relapses may occur after ICI rechallenge. Neural autoantibodies are often present, more commonly in patients with NET.