Honorat, Josephe A.

Background and ObjectivesWe sought to determine clinical significance of neuronal septin autoimmunity and evaluate for potential IgG effects.MethodsSeptin‐IgGs were detected by indirect immunofluorescence assays (IFAs; mouse tissue and cell based) or Western blot. IgG binding to (and internalization of) extracellular septin epitopes were evaluated for by live rat hippocampal neuron assay. The impact of purified patient IgGs on murine cortical neuron function was determined by recording extracellular field potentials in a multielectrode array platform.ResultsSeptin‐IgGs were identified in 23 patients. All 8 patients with septin‐5‐IgG detected had cerebellar ataxia, and 7 had prominent eye movement disorders. One of 2 patients with co‐existing septin‐7‐IgG had additional psychiatric phenotype (apathy, emotional blunting, and poor insight). Fifteen patients had septin‐7 autoimmunity, without septin‐5‐IgG detected. Disorders included encephalopathy (11; 2 patients with accompanying myelopathy, and 2 were relapsing), myelopathy (3), and episodic ataxia (1). Psychiatric symptoms (≥1 of agitation, apathy, catatonia, disorganized thinking, and paranoia) were prominent in 6 of 11 patients with encephalopathic symptoms. Eight of 10 patients with data available (from 23 total) improved after immunotherapy, and a further 2 patients improved spontaneously. Staining of plasma membranes of live hippocampal neurons produced by patient IgGs (subclasses 1 and 2) colocalized with pre‐ and post‐synaptic markers. Decreased spiking and bursting behavior in mixed cultures of murine glutamatergic and GABAergic cortical neurons produced by patient IgGs were attributable to neither antigenic crosslinking and internalization nor complement activation.InterpretationSeptin‐IgGs are predictive of distinct treatment‐responsive autoimmune central nervous system (CNS) disorders. Live neuron binding and induced electrophysiologic effects by patient IgGs may support septin‐specific pathophysiology. ANN NEUROL 2022;92:1090–1101

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