Citations

ObjectiveTo report the identification of microtubule‐associated protein (MAP) 1B as the antigen of the previously described Purkinje cell cytoplasmic antibody type 2 (PCA‐2) antibody, its frequency, and clinical, oncological, and serological associations.MethodsArchival serum or cerebrospinal fluid (CSF) specimens were available from 96 of 118 consecutive PCA‐2‐IgG–seropositive patients identified during 1993–2016. The autoantigen, defined in mouse brain lysate by Western blot and mass spectrometry, was confirmed by dual immunohistochemical staining using commercial antibodies. The major antigenic region was defined by Western blot using recombinant protein fragments.ResultsIgG in 95 of 96 patients’ serum or CSF (but in none of 98 healthy or disease control subjects’ serum specimens) bound to recombinant MAP1B. A minority (17.5%) of patients’ IgG also bound to MAP1A. PCA‐2 was often accompanied by additional neural autoantibody markers of small‐cell carcinoma, including collapsin response‐mediated protein 5 (CRMP5) IgG (26%) or antineuronal nuclear antibody type 1 (ANNA‐1) IgG (also known as anti‐Hu; 13%). Neurological manifestations in 95 patients were (in decreasing frequency): peripheral neuropathy, 53%; cerebellar ataxia, dysmetria, or dysarthria, 38%; and encephalopathy, 27%. Cancer (majority small‐cell lung carcinoma [SCLC]) was detected in 66 of 84 evaluated patients (79%). The MAP1B (PCA‐2) autoantibody detection rate, among approximately 70,000 patients undergoing service neural autoantibody evaluation in 2015, was 0.024%, equaling amphiphysin IgG (0.026%) and more common than ANNA‐2 (also known as anti‐Ri; 0.016%) and PCA‐Tr (also known as delta/notch‐like epidermal growth factor‐related receptor [DNER]; 0.006%).InterpretationMAP1B, the PCA‐2 autoantigen, represents a novel target in paraneoplastic neurological disorders and has high predictive value for SCLC. Its relatively high prevalence, compared with other recognized paraneoplastic neural autoantibodies, justifies its testing in comprehensive paraneoplastic neural autoantibody evaluation. Ann Neurol 2017;81:266–277

ABSTRACT The glutamic acid decarboxylase 65‐kilodalton isoform (GAD65) antibody is a biomarker of autoimmune central nervous system (CNS) disorders and, more commonly, nonneurological autoimmune diseases. Type 1 diabetes, autoimmune thyroid disease, and pernicious anemia are the most frequent GAD65 autoimmune associations. One or more of these disorders coexists in approximately 70% of patients with GAD65 neurological autoimmunity. Neurological phenotypes have CNS localization and include limbic encephalitis, epilepsy, cerebellar ataxia, and stiff‐person syndrome (SPS), among others. Classic SPS is a disorder on the spectrum of CNS hyperexcitability which also includes phenotypes that are either more restricted (stiff‐limb syndrome) or more widespread (progressive encephalomyelitis with rigidity and myoclonus). GAD65 antibody is not highly predictive of a paraneoplastic cause for neurological disorders, but diverse cancer types have been occasionally reported. For all phenotypes, responses to immunotherapy are variable (approximately 50% improve). GAD65 autoimmunity is important to recognize for both coexisting nonneurological autoimmune associations and potential immunotherapy‐response. Muscle Nerve 56 : 15–27, 2017

ObjectiveNeuromyelitis optica (NMO) and its spectrum disorders (NMOSD) are inflammatory demyelinating diseases (IDDs) with a specific biomarker, aquaporin‐4–immunoglobulin G (AQP4‐IgG). Prior NMO/NMOSD epidemiological studies have been limited by lack of AQP4‐IgG seroprevalence assessment, absence of population‐based USA studies, and under‐representation of blacks. To overcome these limitations, we sought to compare NMO/NMOSD seroepidemiology across 2 ethnically divergent populations.MethodsWe performed a population‐based comparative study of the incidence (2003–2011) and prevalence (on December 31, 2011) of NMO/NMOSD and AQP4‐IgG seroincidence and seroprevalence (sera collected in 80–84% of IDD cases) among patients with IDD diagnosis in Olmsted County, Minnesota (82% white [Caucasian]) and Martinique (90% black [Afro‐Caribbean]). AQP4‐IgG was measured by M1 isoform fluorescence‐activated cell‐sorting assays.ResultsThe age‐ and sex‐adjusted incidence (7.3 vs 0.7/1,000,000 person‐years [p < 0.01]) and prevalence (10 vs 3.9/100,000 [p = 0.01]) in Martinique exceeded that in Olmsted County. The AQP4‐IgG age‐ and sex‐adjusted seroincidence (6.5 vs 0.7/1,000,000 person‐years [p < 0.01]) and seroprevalence (7.9 vs 3.3/100,000 [p = 0.04]) were also higher in Martinique than Olmsted County. The ethnicity‐specific prevalence was similar in Martinique and Olmsted County: 11.5 and 13/100,000 in blacks, and 6.1 and 4.0/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD cases in Martinique than Olmsted County (16% vs 1.4%; p < 0.01). The onset age (median = 35–37 years) and female:male distribution (5–9:1) were similar across both populations; 60% of prevalent cases were either blind in 1 eye, dependent on a gait aid, or both.InterpretationThis study reports the highest prevalence of NMO/NMOSD in any population (10/100,000 in Martinique), estimates it affects 16,000 to 17,000 in the USA (higher than previous predictions), and demonstrates it disproportionately affects blacks. Ann Neurol 2016;79:775–783