López‐Chiriboga, A. Sebastian

Abstract The discovery of pathogenic neuroglial surface-directed autoantibodies (NGSAbs) has fundamentally transformed clinical neurology, by enabling molecular-level diagnoses in potentially treatable, yet previously unrecognized, diseases. Annual descriptions of novel CNS-targeting antibodies create a continuous stream of new conditions in which to evaluate distinct phenotypes, specific tumour associations and immunotherapy responses. Alongside this clinical growth, increasing basic knowledge has highlighted origins and mechanisms underlying disease causation, most comprehensively interrogated in the well-established autoantibody-mediated conditions of autoimmune encephalitis (AE), neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The corresponding most common ‘big six’ autoantigens are LGI1, the N-methyl-D-aspartate (NMDA) receptor, CASPR2, IgLON5, in forms of AE, AQP4 and MOG. Each of these autoantigens associates with a homogenous set of basic clinical features, across age, sex, tumour associations and ethnicities, coupled with partly distinctive profiles of triggers and predispositions, paradigms of immune tolerance escape in the periphery, how cells and autoantibodies gain access to the CNS, and discrete mechanisms by which the CNS autoantibodies induce neuroglial dysfunction. These observations lead us to reconstruct a proposed chronological series of events as the ‘cascade to pathogenicity’, which together culminate in a rare CNS disease. By extension, we hypothesize elucidating the underlying biology of each condition will present differing precision medicine approaches to optimize patient care. Despite distinctions, there are also clinical and biological overlaps between these diseases, collectively creating opportunities to compare and contrast their individual features. Here, in each condition, we review current knowledge regarding the similarities and differences between the triggering events, underlying immunological processes and pathogenic mechanisms of autoantibodies. In some instances, we identify scientific clues that drive hypothetical pathways of pathogenesis and, for others, highlight striking observations that aim to generate hypothesis-driven next steps. Our aim is to construct a model across the major autoantibody-mediated CNS diseases to highlight distinct components of cascades to pathogenicity, which may offer targeted therapeutic approaches to improve patient outcomes, and identify key areas and questions for future research.

Background Psychiatric comorbidities are increasingly recognised in demyelinating diseases, yet their frequency and timing in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not well defined. We aimed to characterise the spectrum and temporal pattern of psychiatric illness in MOGAD and compare to multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) with aquaporin-4 antibody (AQP4-IgG). Methods We conducted a cross-sectional study of patients with MOGAD (n=388), age-matched and sex-matched MS (n=257) and AQP4-IgG-positive NMOSD (n=58) evaluated at Mayo Clinic (1991–2025). Psychiatric diagnoses, timing relative to the first attack and patient-reported outcomes were extracted from electronic health records (EHRs). Complementary analyses were conducted using the NeuroBlu real-world EHR database. Results Among 388 patients with MOGAD, 54.8% had ≥1 psychiatric disorder, most commonly anxiety (47.7%), depression (36.6%) and attention-deficit/hyperactivity disorder (ADHD, 9%). After the first attack, 33.3% of patients with MOGAD developed a new psychiatric disorder, often within the first year. MOGAD showed a lower frequency of depression versus MS (36.6% vs 47.5%, p=0.02) but similar rates of anxiety and ADHD. Temporal patterns differed: psychiatric disorders often appeared years before onset in MS but clustered shortly after onset in MOGAD. NeuroBlu analyses supported high rates of psychiatric disorders across the three conditions. Conclusion Psychiatric comorbidities are common in MOGAD, particularly depression and anxiety, typically emerging close after onset, whereas in MS they often preceded onset by years. These findings underscore the need for routine psychiatric screening in MOGAD and highlight unresolved questions regarding whether, and to what extent, MOG-IgG-mediated inflammatory demyelination contributes to psychiatric vulnerability.

Background: Acute disseminated encephalomyelitis (ADEM) is a demyelinating syndrome observed in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) but there are limited data on application of this definition to its cerebral attacks or in adults with this disease. Methods: We analyzed patients from the Mayo Clinic MOGAD cohort ( n = 263) with cerebral attacks. We assessed whether children (<18 years-old) and adults (⩾18 years-old) fulfilled the 2013 ADEM definition. Results: We identified 89 patients (children, 34; adults, 55) and 55/89 (62%) were of female sex. Acute magnetic resonance imaging (MRI) abnormalities included: poorly demarcated T2 lesions (white matter, 85 (96%); deep gray matter, 41 (46%); T1-hypointense lesions (42 (47%)). Forty-two patients did not fulfill the ADEM definition due to: monofocal syndrome, 9; or no encephalopathy, 33. The remaining 47 patients (53%: children, 27/34 (79%); adults, 20/55 (36%)) fulfilled the ADEM definition, and 14 had preceding attacks, and 34 had subsequent attacks relative to ADEM episode. The features in children and adults with ADEM were broadly comparable. Conclusion: Applying the ADEM definition to MOGAD cerebral attacks highlighted that an update of the 2013 ADEM definition would be beneficial and could explicitly state its application to both adults and children and allow it to be applied to attacks at any time during the disease course.

ABSTRACT Objectives To investigate the value of cytokine, chemokine, and neurofilament light chain (NfL) concentrations in predicting relapse risk, chronic epilepsy, and functional impairment in LGI1 autoimmune encephalitis (AE). Methods Cytokines/chemokines (IL‐1‐beta, IL‐2, IL‐4, IL‐5, IL‐6, IL‐8/CXCL8, IL‐10, IL‐12p70, IL‐13, IL‐17A, GM‐CSF, TNF‐alpha, IFN‐gamma, CXCL9, CXCL10, CXCL13, BAFF) and NfL concentrations were measured in CSF and paired serum from LGI1‐AE patients evaluated at Mayo Clinic (01/2015–02/2024), using a multiplex immunoassay system (ELLA, Bio‐Techne) and correlated with clinical outcomes. A laboratory‐based cohort of LGI1‐IgG‐positive patients and control cohorts, including patients with mixed non‐inflammatory disorders (MNID), Alzheimer's disease (AD), and temporal lobe epilepsy (TLE) were analyzed. Results Forty‐four patients with LGI1‐AE were included; 29 (66%) were male, with a median age of 68.5 years (range, 8–85). Median time from symptom onset to CSF sampling was eight months (IQR, 3–17); 19/42 (45%) experienced a clinical relapse and 27% developed chronic epilepsy. Serum IL‐6, serum and CSF IL‐8/CXCL8, and IL‐17A were higher in LGI1‐IgG positive patients than MNID ( p < 0.05). TLE cytokine/chemokine profiles were similar to LGI1 AE; AD patients had lower serum IL‐6 and CSF IL‐8/CXCL8 ( p = 0.04; p = 0.01), and higher serum IL‐17A and GM‐CSF ( p = 0.004; p = 0.01) than LGI1‐AE. Higher CSF IL‐6 and IL‐8/CXCL8 in LGI1‐AE associated with clinical relapse ( p < 0.05) and higher CSF NfL associated with chronic epilepsy ( p = 0.01). Conclusion Elevations in IL‐6, IL‐8/CXCL8, and IL‐17A were identified in this LGI1‐AE cohort. CSF IL‐6, IL‐8/CXCL8, and NfL levels are potential prognostic biomarkers for risk of relapse and chronic epilepsy in LGI1‐AE.

Background Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and multiple sclerosis (MS) have both overlapping and distinct MRI lesion features, which vary with imaging timing. This study identified distinguishing MRI characteristics using paired MRIs at clinical attack and remission. Methods We retrospectively identified Mayo Clinic patients with MOGAD and MS that: (1) fulfilled respective diagnostic criteria; (2) had paired attack (≤30 days) and remission MRI scans (≥12 months) without interval attacks. MRIs were compared between groups for key features. Results We included 43 patients with MOGAD (median age 31 years (range, 3–67); 63% female) and 49 patients with MS (median age 39 years (range, 17–65); 65% female). Resolution of at least one T2-lesion differentiated MOGAD from MS (sensitivity, (95% CI 77% to 100%), specificity, (95% CI 86% to 99%); Youden’s index (YI)=0.90). Resolution of at least two T2-lesions indicated MOGAD (sensitivity 62% (95% CI 41% to 79%); specificity, 100% (95% CI 94% to 100%); YI=0.62). MOGAD patients were more likely to have normal MRI scans at follow-up compared with MS (brain 14/44 (32%) vs 0/60 (0%), p<0.001; spine 21/27 (78%) vs 7/36 (19%), p<0.001). In addition, the presence of T1-hypointense, ovoid periventricular T2, and enhancing lesions were more common in MS versus MOGAD at attack and remission and in the spine, longitudinally extensive T2 lesions were more common in MOGAD attacks (8/27 (30%)). Conclusion Paired MRI at attack and remission revealed distinctive characteristics of MOGAD and MS, with greater diagnostic value at remission driven by the discriminating power of T2-lesion resolution. In MOGAD patients with initial parenchymal involvement, a 1-year follow-up MRI may aid diagnosis and serve as a new baseline.