Zivelonghi, Cecilia

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

Abstract Objectives To describe CSF‐defined neuronal intermediate filament (NIF) autoimmunity. Methods NIF‐IgG CSF‐positive patients (41, 0.03% of 118599 tested, 1996–2019) were included (serum was neither sensitive nor specific). Criteria‐based patient NIF‐IgG staining of brain and myenteric NIFs was detected by indirect immunofluorescence assay (IFA); NIF‐specificity was confirmed by cell‐based assays (CBAs, alpha internexin, neurofilament light [NF‐L]), heavy‐[NF‐H] chain). Results Sixty‐one percent of 41 patients were men, median age, 61 years (range, 21–88). Syndromes were encephalopathy predominant (23), cerebellar ataxia predominant (11), or myeloradiculoneuropathies (7). MRI abnormalities (T2 hyperintensities of brain, spinal cord white matter tracts. and peripheral nerve axons) and neurophysiologic testing (EEG, EMG, evoked potentials) co‐localized with clinical neurological phenotypes (multifocal in 29%). Thirty patients (73%) had ≥ 1 immunological perturbation: cancer (paraneoplastic), 22; systemic infection (parainfectious [including ehrlichosis, 3] or HIV), 7; checkpoint‐inhibitor cancer immunotherapy, 4; other, 5. Cancers were as follows: neuroendocrine‐lineage carcinomas, 12 (small cell, 6; Merkel cell, 5; pancreatic, 1 [11/12 had NF‐L‐IgG detected, versus 8/29 others, P = 0.0005]) and other, 11. Onset was predominantly subacute (92%) and accompanied by inflammatory CSF (75%), and immunotherapy response (77%). In contrast, CSF controls (15684 total) demonstrated NIF‐IgG negativity (100% of test validation controls), and low frequencies of autoimmune diagnoses (20% of consecutively referred clinical specimens) and neuroendocrine‐lineage carcinoma diagnosis (3.1% vs. 30% of NIF cases), P < 0.0001. Median NF‐L protein concentration was higher in 8 NF‐L‐IgG‐positive patients (median, 6718 ng/L) than 16 controls. Interpretation Neurological autoimmunity, defined by CSF‐detected NIF‐IgGs, represents a continuum of treatable axonopathies, sometimes paraneoplastic or parainfectious.