Anastasia Zekeridou

Aquaporin-4 autoimmunity

Neuromyelitis optica (NMO) and a related spectrum of inflammatory CNS disorders are unified by detection of a serum autoantibody specific for the aquaporin-4 (AQP4) water channel, which is abundant in astrocytic foot processes. The classic clinical manifestations of NMO are optic neuritis and longitudinally extensive transverse myelitis. Newly recognized manifestations of AQP4 autoimmunity include lesions of circumventricular organs and skeletal muscle. NMO is commonly relapsing, is frequently accompanied by other autoimmune disorders, and sometimes occurs in a paraneoplastic context. The goals of treatment are to minimize neurologic disability in the acute attack and thereafter to prevent relapses and cumulative disability. The disease specificity of AQP4 immunoglobulin (Ig) G approaches 100% using optimized molecular-based detection assays. Clinical, immunohistopathologic, and in vitro evidence support this antibody being central to NMO pathogenesis. Current animal models yield limited histopathologic characteristics of NMO, with no clinical deficits to date. Recent descriptions of a myelin oligodendrocyte glycoprotein autoantibody in a minority of patients with NMO spectrum phenotype who lack AQP4-IgG predict serologic delineation of additional distinctive disease entities.

Frequency of Synaptic Autoantibody Accompaniments and Neurological Manifestations of Thymoma.

IMPORTANCE Thymoma is commonly recognized in association with paraneoplastic autoimmune myasthenia gravis (MG), an IgG-mediated impairment of synaptic transmission targeting the nicotinic acetylcholine receptor of muscle. Newly identified synaptic autoantibodies may expand the serological profile of thymoma. OBJECTIVE To investigate the frequency of potentially pathogenic neural synaptic autoantibodies in patients with thymoma. DESIGN, SETTING, AND PARTICIPANTS We retrospectively identified patients with histopathologically confirmed thymoma and serum available to test for synaptic autoantibodies (collected 1986-2014) at the Mayo Clinic Neuroimmunology Laboratory. We identified and classified 193 patients with thymoma into 4 groups: (1) lacking neurological autoimmunity (n = 43); (2) isolated MG (n = 98); (3) MG plus additional autoimmune neurological manifestations (n = 26); and (4) neurological autoimmunity other than MG (n = 26). MAIN OUTCOMES AND MEASURES Clinical presentation and serum profile of autoantibodies reactive with molecularly defined synaptic plasma membrane proteins of muscle, peripheral, and central nervous systems. RESULTS Of the 193 patients with thymoma, mean patient age was 52 years and did not significantly differ by sex (106 women) or group. Myasthenia gravis was the most prevalent clinical manifestation (64%) followed by dysautonomia (16 patients [8%]) and encephalopathy (15 patients [8%]); 164 patients (85%) had at least 1 synaptic autoantibody, and 63 of these patients (38%) had at least 1 more. Muscle acetylcholine receptor was most frequent (78%), followed by ganglionic acetylcholine receptor (20%), voltage-gated Kv1 potassium channel-complex (13%), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (5%). Less frequent were aquaporin-4, voltage-gated Kv1 potassium channel-complex related proteins (leucine-rich glioma-inactivated 1 and contactin-associated protein-like 2), glycine receptor, and γ-aminobutyric acid-A receptor. Synaptic autoantibodies were significantly more frequent in patients with neurological autoimmunity than in those without and were most frequent in patients with neurological manifestations other than or in addition to MG. CONCLUSIONS AND RELEVANCE Synaptic autoantibodies, particularly those reactive with ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily (namely α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, glycine, and γ-aminobutyric acid-A receptors), were prevalent in patients with thymoma. Autoantibodies of this extended spectrum may enhance autoimmune serological testing as an aid to preoperative thymoma diagnosis. Detection of currently known synaptic autoantibody specificities absent from this profile have potential algorithmic usefulness as negative predictors for thymoma (as recognized for neuronal voltage-gated calcium channel autoantibodies).

Autoimmune GFAP astrocytopathy: Prospective evaluation of 90 patients in 1 year

In this prospective evaluation of serum and CSF samples, all but two CSF GFAPα-IgG positive patients had autoimmune meningoencephalomyelitis while serum GFAPα-IgG positivity alone was less specific. Phenotypes were diverse among patients that were serum positive only. Adult and pediatric clinical presentations were similar. Most patients were immunotherapy responsive. Co-existing NMDA-R-IgG and cancer were associated with lack of response to first-line immunotherapy. Among patients with follow-up information, 18% had relapses. This study demonstrates CSF GFAPα-IgG is a specific autoimmune meningoencephalomyelitis biomarker, with favorable corticosteroid response. Lack of response should prompt evaluation for co-existing NMDA-R-IgG or malignancy.

A path to understanding autoimmune GFAP astrocytopathy

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy was first described in humans in 2016 at the Mayo Clinic, USA, and has been confirmed independently in Europe and Asia within the last year [1–4]. This disorder manifests as a distinctive corticosteroid-responsive meningoencephalomyelitis or limited form thereof, with lymphocytic pleocytosis often accompanied by a hallmark brain linear perivascular radial gadolinium enhancement [1–4]. It can be accompanied by a neoplasm in 20% (usually teratoma) [2]. The disease spectrum is unified by the detection of GFAP-specific immunoglobulin G (GFAP-IgG) in patients’ cerebrospinal fluid (CSF) [2]. GFAP-IgG is detected with indirect immunofluorescence by the characteristic staining of mouse pia, subpia and enteric ganglia [1,2]. The molecular specificity is confirmed with cells transfected with plasmids encoding various GFAP isoforms. To date, the a isoform has had the greatest clinical utility [2]. A fatal necrotizing meningoencephalitis, with GFAP-IgG as biomarker, was described in pug dogs before the discovery of the human form [5]. In this issue, Long et al. describe the clinical presentation, serological and pathological findings in Chinese patients with autoimmune GFAP astrocytopathy [6]. The authors confirm the neurological and radiological spectrum with prominent inflammatory meningeal involvement, encephalitis and myelitis. The classical magnetic resonance imaging finding of radial perivascular enhancement was commonly encountered. A higher proportion of spinal cord lesions was noted than previously published [2]. Of critical importance, all patients in this study had GFAP-IgG detected in CSF. CSF antibody detection is recommended due to greater sensitivity and specificity [2]. Caution is advised regarding clinical utility or expansion of the autoimmune GFAP astrocytopathy spectrum based on serum positivity alone [3]. The patients in this study were less immunotherapy responsive (steroids and intravenous immunoglobulin) than prior reports and some had progression despite treatment [6]. This may reflect a faster steroid taper or a more severe disease course in this Asian population. In our experience, this disease is usually steroid responsive if treated promptly, although prolonged oral high-dose corticosteroids (for 3–6 months) followed by a slow taper and transition to a steroid-sparing agent may be necessary to avoid relapse. A novel finding in this report is IgG specificity for the early progenitor (GFAPe) isoform in some patients, where GFAPa-IgG was negative [6]. GFAPe-IgG sometimes coexisted in other published cases, but GFAPaIgG was positive in all [1–3]. Testing for GFAPe-IgG might add to diagnostic sensitivity where the characteristic murine brain immunohistochemical staining is detected, but specificity is not confirmed by GFAPaIgG testing. In our laboratory, a GFAPa-IgG negative, GFAPe-IgG positive case is yet to be found. The difference in the pattern of immunohistochemical staining noted in this study (staining of Bergman glia in the cerebellum) is consistent with our own interspecies experience (rat in this study, mouse in prior studies) [1–3]. The major addition of Long et al. to the current understanding of GFAP autoimmunity is the description of the neuropathological findings in four patients [6]. A necrotizing inflammatory process with cytotoxic T cells infiltrating the meninges has been previously described in one patient (leptomeningeal biopsy) [3]. Brain biopsies in four cases showed inflammatory infiltrates (lymphocytes, monocytes and neutrophils) surrounding blood vessels and microglial activation [6]. The infiltrating lymphocytes were both T and B cells and there were also abundant plasma cells. As predicted by GFAP’s intracellular location, this autoimmune astrocytopathy is probably mediated by antigen-specific cytotoxic T cells and the autoantibodies do not have pathogenic potential. In vivo evidence for the pathogenic potential of GFAP-specific cytotoxic T cells to cause an inflammatory central nervous system (CNS) disease come from a mouse model of GFAP autoimmunity, where GFAP-specific CD8+ cytotoxic T cells caused CNS inflammation in different forms depending on the environmental trigger (from relapsing remitting to severe progressive meningoencephalitis) [7]. In one patient in the Long et al. study [6], loss of the aquaporin-4 water channel and GFAP staining could be interpreted as astrocyte loss in the lesion as a result of cytotoxic T cell attack; neuronal loss may occur secondary to astrocyte death. Alternatively, a multifaceted immune response targeting aquaporin-4,

Posttransplant autoimmune encephalitis

The causes of encephalopathy in the posttransplant setting are diverse and include medication toxicity (e.g., posterior reversible encephalopathy syndrome), infections (e.g., human herpes virus type 6 [HHV-6]), and neoplastic disease (posttransplant lymphoproliferative disorder). Autoimmune etiologies are not well recognized in this setting, although a few cases are described.1–5 Herein, we report 3 patients with posttransplant autoimmune encephalitis (AE).

Mutated cancer autoantigen implicated cause of paraneoplastic myasthenia gravis: Mutated Onconeural MG Antigen

Introduction: Antitumor immune responses are postulated to initiate paraneoplastic neurological disorders when proteins that are normally restricted to neural cells are expressed as oncoproteins. Mutated oncopeptides could bypass self‐tolerant T cells to activate cytotoxic effector T lymphocytes and requisite helper T lymphocytes to stimulate autoantibody production by B lymphocytes. Methods: We investigated muscle‐type nicotinic acetylcholine receptor (AChR) antigen expression at transcriptional and protein levels in a small‐cell lung cancer line (SCLC) established from a patient with AChR‐immunoglobulin G (IgG)‐positive myasthenia gravis. Results: We identified messenger RNA transcripts encoding the 2 AChR α1‐subunit isoforms and 7 alternative‐splicing products, 3 of which yielded premature stop codons. Despite detecting native muscle‐type AChR pentamers in the tumor, we did not identify mutant α1‐peptides. However, we found α1‐subunit‐derived peptides bound to tumor major histocompatibility complex (MHC)1‐protein. In a control SCLC from an antineuronal nuclear autoantibody, type 1 (anti‐Hu)‐IgG‐positive patient, we identified MHC1‐complexed Hu protein‐derived peptides but not AChR peptides. Discussion: Our findings support onconeural protein products as pertinent immunogens initiating paraneoplastic neurological autoimmunity. Muscle Nerve 58: 600–604, 2018

Pre-existing antiacetylcholine receptor autoantibodies and B cell lymphopaenia are associated with the development of myositis in patients with thymoma treated with avelumab, an immune checkpoint inhibitor targeting programmed death-ligand 1

Immune checkpoint inhibitors enhance the immune response against tumours but may also trigger immune-related adverse events (IRAEs). Myositis is a rare IRAE. For example, creatine kinase (CK) elevations occurred in just 0.3% of those treated with avelumab, an antiprogrammed death-ligand 1 antibody.1 Thymomas are the most common anterior mediastinal masses in adults. Since effective systemic therapies for thymic epithelial tumours are lacking, we included seven patients with recurrent thymoma and one patient with recurrent thymic carcinoma in a phase I trial of avelumab (NCT01772004). Details regarding this trial have been published separately.2 Myasthenia gravis and myositis occur in up to 30% and 5% of patients with thymoma, respectively.3 Although no patient had a history of autoimmunity or weakness and each had normal baseline CK levels, four patients developed weakness and elevated CK levels, ranging from 762 IU/L to 16 037 IU/L, within 5 weeks of avelumab administration (see online supplementary text and table 1). CK levels normalised in patients within weeks of stopping avelumab and starting immunosuppressive therapy. Of note, …

Elevated LGI1-IgG CSF index predicts worse neurological outcome

To determine whether CSF leucine‐rich glioma‐inactivated 1(LGI1)‐IgG titer, index or IgG subclass has prognostic significance, we tested serum and CSF specimens collected concomitantly from 39 seropositive patients. LGI1‐IgG index was elevated (>1) in 21 patients (54%), suggesting intrathecal synthesis. Patients with worse outcome at last follow‐up (modified Rankin Scale >2) had significantly higher index (median 6.57 vs. 0.5, P = 0.048) compared to those with better outcome. Higher CSF LGI1‐IgG4 subclass‐specific titer and index correlated with worse outcome (P < 0.005 for both). These data suggest that evidence of intrathecal LGI1‐IgG synthesis may correlate with neuronal injury and warrant consideration of aggressive immunotherapy.

LGI1 and CASPR2 neurological autoimmunity in children

The clinical phenotype of leucine‐rich glioma‐inactivated protein 1 (LGI1) and contactin‐associated proteinlike 2 (CASPR2) autoimmunity is well defined in adults. Data for children are limited (<10 cases). Among 13,319 pediatric patients serologically tested for autoimmune neurological disorders (2010–2017), 264 were seropositive for voltage‐gated potassium channel‐complex–IgG (radioimmunoprecipitation). Only 13 (4.9%) were positive by transfected cell‐binding assay for LGI1‐IgG (n = 7), CASPR2‐IgG (n = 3), or both (n = 3). This is significantly less than in adults. Encephalopathy, seizures, and peripheral nerve hyperexcitability were common, as was coexisting autoimmunity. No faciobrachial dystonic seizures or cancers were identified. Functional neurologic disorders were frequently the initial diagnosis, and immunotherapy appeared beneficial. Ann Neurol 2018;84:473–480