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Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited and its efficacy remains controversial. In this study we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological, and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (GErman NEtwork for REsearch on AuToimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA, and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder (at least one symptom present in 38% [20/53]). At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About a third of patients (28% [15/53]) reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titer increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 (55% [24/44]) was associated with higher serum anti-IgLON5 IgG titers. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first six weeks was a predictor for therapy response. Sixty-eight percent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

Background and purpose Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (FLAIR-rSI) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial, intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of DWI-FLAIR mismatch, i.e., in those with no marked FLAIR hyperintensity in the region of the acute DWI lesion. In this post-hoc analysis, we investigated if quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analysed by binary logistic regression using different endpoints, i.e., favourable outcome defined as mRS 0-1, independent outcome defined as mRS 0-2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for NIHSS at symptom onset and stroke lesion volume. Results FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS 0-1 (p=0.169) and shift analysis (p=0.086), but 2 reached significance for mRS 0-2 (p=0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical endpoints with increasing FLAIR-rSI. Conclusion In patients in whom no marked parenchymal FLAIR hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of DWI lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset.

Cerebral vasospasm seems to be a frequent complication after ICH with IVH and might be associated with DCI. Larger studies are warranted to confirm this hypothesis.

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