McKeon, Andrew

Summary Objective To validate predictive models for neural antibody positivity and immunotherapy response in epilepsy. Methods We conducted a retrospective study of epilepsy cases at Mayo Clinic (Rochester‐ MN ; Scottsdale‐ AZ , and Jacksonville‐ FL ) in whom autoimmune encephalopathy/epilepsy/dementia autoantibody testing profiles were requested (06/30/2014‐06/30/2016). An Antibody Prevalence in Epilepsy ( APE ) score, based on clinical characteristics, was assigned to each patient. Among patients who received immunotherapy, a Response to Immunotherapy in Epilepsy ( RITE ) score was assigned. Favorable seizure outcome was defined as >50% reduction of seizure frequency at the first follow‐up . Results Serum and cerebrospinal fluid (CSF) from 1,736 patients were sent to the Mayo Clinic Neuroimmunology Laboratory for neural autoantibody evaluation. Three hundred eighty‐seven of these patients met the diagnostic criteria for epilepsy. Central nervous system (CNS)–specific antibodies were detected in 44 patients. Certain clinical features such as new‐onset epilepsy, autonomic dysfunction, viral prodrome, faciobrachial dystonic seizures/oral dyskinesia, inflammatory CSF profile, and mesial temporal magnetic resonance imaging (MRI) abnormalities had a significant association with positive antibody results. A significantly higher proportion of antibody‐positive patients had an APE score ≥4 (97.7% vs. 21.6%, p < 0.01). Sensitivity and specificity of an APE score ≥4 to predict presence of specific neural auto‐antibody were 97.7% and 77.9%, respectively. In the subset of patients who received immunotherapy (77), autonomic dysfunction, faciobrachial dystonic seizures/oral dyskinesia, early initiation of immunotherapy, and presence of antibodies targeting plasma membrane proteins (cell‐surface antigens) were associated with favorable seizure outcome. Sensitivity and specificity of a RITE score ≥7 to predict favorable seizure outcome were 87.5% and 83.8%, respectively. Significance APE and RITE scores can aid diagnosis, treatment, and prognostication of autoimmune epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .

Objective A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)‐IgG as biomarker was recently characterized. Here, 102 patients with GFAP‐IgG positivity are described. Methods The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell‐based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell‐based (n = 323) assays. Results Median symptom onset age was 44 years (range = 8–103), and 54% were women. The predominant phenotype (83 patients; 81%) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94%), and highest sensitivity was for the GFAPα isoform (100%). Rare GFAP‐IgG positivity was encountered in serum controls by tissue‐based assay (0.5%) or cell‐based assay (1.5%), and in CSF controls by cell‐based assay (0.9%). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53%. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22%. Ovarian teratoma was most common and was predicted best when both N‐methyl‐D‐aspartate receptor–IgG and aquaporin‐4–IgG coexisted (71%). Six patients with prolonged follow‐up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency. Interpretation GFAPα‐IgG, when detected in CSF, is highly specific for an immunotherapy‐responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298–309

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