Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.

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 one 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 titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. 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 6 weeks was a predictor for therapy response. Sixty-eight per cent (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.

Targeted Temperature Management for Subarachnoid Hemorrhage: Excellent Outcome After Severe Vasospasm-A Case Series.

Targeted temperature management (TTM) might improve outcome of patients with severe subarachnoid hemorrhage (SAH) in which vasospasm, delayed cerebral ischemia (DCI), and increased intracranial pressure (ICP) are frequent and severe complications. A series of patients (n = 3) with severe aneurysmatic SAH were treated by TTM if they developed ICP crisis and/or severe vasospasm diagnosed by angiography. Once these complications were detected, body core temperature (BCT) was rapidly decreased to 35°C or 33°C, if necessary. BCT induced and maintained by surface cooling remained at the desired level for at least 72 hours. Rewarming was performed by 1°C, only if the target parameters ICP and velocities in the serial Doppler sonography indicating macrovascular vasospasm improved to regular levels. In case of increase of ICP or middle cerebral arteries velocities BCT was decreased again to the last effective level. The patients developed vasospasm between days 6 and 12 after SAH. All aneurysms were treated by coiling. BCT was reduced between days 6 and 12 after SAH. Total duration of BCT <36.5°C was between 5.5 and 8 days. It remained <35°C for 4-6 days, and at 33°C for 3 days on average. ICP could be sufficiently controlled in all patients, because no ICP crisis was observed during TTM and after rewarming. Two patients developed minor DCI. Side effects of prolonged ventilation of 7-18 days included pneumonia for two patients that could be treated sufficiently. Other complications were one case of ventriculitis and two temporary deliriums. Outcome of the patients was good because no focal neurological symptoms could be detected after rehabilitation. TTM represents a promising treatment approach for severe SAH in which standard treatment is often limited and experimental. It deserves further clinical investigation in a larger cohort.