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.

Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system (CNS), that predominantly affects the spinal cord and optic nerves. The neuropathologic hallmarks comprise deposits of antibodies and complement as well as loss of astrocytes, secondary degeneration of oligodendrocytes and neurons, and necrotic lesions with infiltration of neutrophilic and eosinophilic granulocytes. Pathognomonic serum autoantibodies against aquaporin-4 (AQP4-IgG, also termed NMO-IgG) are detectable in around 80 % of NMO patients and help to distinguish this rare entity from multiple sclerosis. The target antigen of NMO-IgG, the water channel protein AQP4, is ubiquitously expressed within the CNS and, as a component of the blood-brain barrier, highly concentrated in the endfeet of astrocytes. New international consensus criteria for NMO spectrum disorders, published in 2015, allow earlier diagnosis. Besides the two index manifestations, optic neuritis and transverse myelitis, involvement of the brainstem and diencephalon is relatively common in NMO. Inflammatory lesions of the area postrema typically cause intractable nausea and vomiting and/or hiccups. NMO mostly follows a relapsing course, especially in AQP4-IgG-positive cases. The treatment of acute exacerbations comprises intravenous methylprednisolone pulses and/or plasma exchange, and prevention of attacks requires long-term therapy with immunosuppressants and/or B-cell-depleting monoclonal antibodies.

Zusammenfassung Die Neuromyelitis optica (NMO, Devic-Syndrom) ist eine entz?ndliche Erkrankung des Zentralnervensystems mit den Indexereignissen Optikusneuritis und Querschnittsmyelitis. In der Mehrzahl der F?lle ist die NMO autoimmun bedingt und mit dem Vorliegen von Autoantik?rpern gegen den Wasserkanal Aquaporin-4 (AQP4) assoziiert. Mit der Entdeckung dieses hochspezifischen Serummarkers gelang erstmalig die Identifizierung eines definierten Zielautoantigens bei einer Erkrankung aus dem Formenkreis der Multiplen Sklerose. Neuere Beobachtungen weisen ?bereinstimmend darauf hin, dass AQP4-Antik?rper auch pathophysiologisch bedeutsam sind und bieten eine Rationale f?r den Einsatz von Plasmapherese und B-Zell-Depletion in der Therapie der AQP4-Ak-positiven NMO.