Early Immunotherapy Research Articles

SARS-CoV-2-Related Acute Necrotizing Encephalopathy of Childhood With Good Response to Tocilizumab in an Adolescent

BackgroundAcute necrotizing encephalopathy of childhood (ANEC) is a rare parainfectious neurological disorder. ANEC is associated with a high mortality rate and poor neurological outcomes. ANEC is postulated to arise from immune-mediated or metabolic processes driven by viral infections. Although there have been some case reports of acute necrotizing encephalopathy with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coinfection in adults, paediatric cases are rare. MethodsA single case report of SARS-CoV-2-related ANEC in an 11-year-old boy is presented through retrospective chart review. Literature search was performed using PubMed, Embase, Cochrane database, and Google Scholar to compare and analyze similar cases of parainfectious immune-mediated encephalopathies related to SARS-CoV-2 in children. ResultsAn 11-year-old boy with acute SARS-CoV-2 infection presented with ophthalmoplegia, ataxia, and aphasia. Neuroimaging findings demonstrated significant swelling and signal changes in bilateral thalami, brainstem, and cerebellar hemispheres, consistent with ANEC. His high ANEC Severity Score indicated poor neurological prognosis. Treatment with a combination of early steroid therapy, intravenous immunoglobulin therapy, and targeted interleukin 6 (IL-6) blockade yielded good neurological improvements. Literature search identified 19 parainfectious immune-mediated neurological disorders related to SARS-CoV-2 in children. The only other pediatric ANEC case identified was postinfectious and thus not included. ConclusionsThis is the first report of a pediatric case of SARS-CoV-2-related ANEC, which responded well to early immunotherapy, including IL-6 blockade. Early immunotherapy with IL-6 blockade can be considered as an adjunct in managing severe ANEC.

Prognostic value of 18F-FDG PET/CT in patients with advanced or metastatic non-small-cell lung cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

This study aimed to investigate the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in predicting early immunotherapy response of immune checkpoint inhibitors (ICIs) in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). A comprehensive search of PubMed, Web of science, Embase and the Cochrane library was performed to examine the prognostic value of 18F-FDG PET/CT in predicting early immunotherapy response of ICIs in patients with NSCLC. The main outcomes for evaluation were overall survival (OS) and progression-free survival (PFS). Detailed data from each study were extracted and analyzed using STATA 14.0 software. 13 eligible articles were included in this systematic review. Compared to baseline 18F-FDG PET/CT imaging, the pooled hazard ratios (HR) of maximum and mean standardized uptake values SUVmax, SUVmean, MTV and TLG for OS were 0.88 (95% CI: 0.69-1.12), 0.79 (95% CI: 0.50-1.27), 2.10 (95% CI: 1.57-2.82) and 1.58 (95% CI: 1.03-2.44), respectively. The pooled HR of SUVmax, SUVmean, MTV and TLG for PFS were 1.06 (95% CI: 0.68-1.65), 0.66 (95% CI: 0.48-0.90), 1.50 (95% CI: 1.26-1.79), 1.27 (95% CI: 0.92-1.77), respectively. Subgroup analysis showed that high MTV group had shorter OS than low MTV group in both first line group (HR: 1.97, 95% CI: 1.39-2.79) and undefined line group (HR: 2.11, 95% CI: 1.61-2.77). High MTV group also showed a shorter PFS in first line group (HR: 1.85, 95% CI: 1.28-2.68), and low TLG group had a longer OS in undefined group (HR: 1.37, 95% CI: 1.00-1.86). No significant differences were in other subgroup analysis. Baseline MTV and TLG may have predictive value and should be prospectively studied in clinical trials. Baseline SUVmax and SUVmean may not be appropriate prognostic markers in advanced or metastatic NSCLC patients treated with ICIs. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=323906, identifier CRD42022323906.

Anti-NMDA Receptor Encephalitis in Children

Anti-NMDAR encephalitis is a type of neurological syndrome that can be paraneoplastic or non-paraneoplastic in nature. It is a recently discovered that is becoming much more recognized in children. The symptoms of anti-NMDAR encephalitis occur as a result of autoimmune antibody binding to the NMDA receptor on certain neuronal cell surfaces. Patients with anti-NMDAR encephalitis are described as having a change in mental status manifested by abrupt changes from calm behaviors to agitation, aggression or extreme irritability. In children, the first symptom to be recognized is often non-psychiatric: convulsion, status epilepticus, dystonia, verbal reduction or mutism .The diagnosis is clinical and confirmation is easy with demonstration of antibodies in serum and CSF; Early diagnosis and aggressive immunotherapy are imperative. Anti-NMDA receptor encephalitis can be reversible if diagnosed and treated early.

A retrospective cohort study of new-onset refractory status epilepticus (NORSE): clinical features, timing of immunotherapy and outcomes

To describe clinical characteristics associated with immunotherapy in patients with new-onset refractory status epilepticus (NORSE) and assess its timing and effect on outcomes at hospital discharge after six and 12 months of follow-up. Our secondary aim was to apply the cryptogenic NORSE (C-NORSE) score to subjects in order to evaluate its utility in identifying C-NORSE in our cohort. This was a retrospective single university hospital cohort study (2004-2021) of adults and children with NORSE. First-line immunotherapy was defined as corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis (PLEX). Early immunotherapy was defined as administration of a first-line agent within seven days of presentation. Twenty-one subjects with NORSE were identified between 2004 and 2021, which was cryptogenic in 18 and immune-mediated in three. All patients received immunotherapy. Seventeen patients received early immunotherapy (81%). There was no significant difference between early versus late immunotherapy regarding “good or favorable” outcomes (mRS 0-2) at hospital discharge or during follow-up. For cryptogenic NORSE patients, 7/11 (64%) achieved good outcomes at six months, 9/11 (82%) at 12 months, and 8/10 (80%) at the last follow-up visit at >13 months. For immune-mediated NORSE patients, 3/3 (100%) achieved good outcomes at six months and 2/2 (100%) at the last follow-up visit at >13 months. In our cohort, a C-NORSE score of ≥5 was obtained in 12/18 (67%) of cryptogenic cases and a score <5 in all three immunemediated cases. There is a paucity of published data on the timing of immunotherapy for NORSE. Although at our institution early administration of immunotherapy is feasible, more research is needed to determine which patients may benefit from immunotherapy and if the timing of immunotherapy affects short and long-term outcomes. Among the patients who survived hospitalization, long-term follow-up of our NORSE cohort demonstrated that a subset achieved good mRS (0-2) scores.

NOX4 has the potential to be a biomarker associated with colon cancer ferroptosis and immune infiltration based on bioinformatics analysis.

BackgroundColon cancer (CC) is a common tumor, but its pathogenesis is still not well understood. Competitive endogenous RNA (ceRNA) theory, ferroptosis and tumor immune infiltration may be the mechanisms of the development of cancer. The purpose of the study is to seek genes connected with both immunity and ferroptosis, and provide important molecular basis for early noninvasive diagnosis and immunotherapy of CC.MethodsWe extracted messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA) data of CC from The Cancer Genome Atlas database (TCGA), identified the differentially expressed mRNA (DEmRNA), miRNA (DEmiRNA) and lncRNA (DElncRNA), then constructed a ceRNA network. Venn overlap analysis was used to identify genes associated with immunity and ferroptosis in ceRNA network. The expression and prognosis of target genes were analyzed via Gene Expression Profiling Interactive Analysis (GEPIA) and PrognoScan database, and we analysed the related functions and signaling pathways of target genes by enrichment analysis. The correlation between target genes and tumor immune infiltrating was explored by CIBERSORT and spearman correlation analysis. Finally, the expression of target genes was detected via quantitative reverse transcription-PCR (qRT-PCR) in CC and normal colon tissues.ResultsResults showed that there were 4 DElncRNA, 4 DEmiRNA and 126 DEmRNA in ceRNA network. NADPH oxidase 4 protein (NOX4) was a DEmRNA associated with immunity and ferroptosis in ceRNA network. NOX4 was highly expressed in CC and connected with unfavourable prognosis. NOX4 was obviously enriched in pathways connected with carcinogenesis and significantly correlated with six kinds of immune cells. Immune checkpoints and NOX4 spearman correlation analysis showed that the expression of NOX4 was positively related to programmed cell death protein 1 (PD-1)-PDCD1, programmed cell death-Ligand 1 (PD-L1)-CD274 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4).ConclusionsTo conclude, our study suggests that NOX4 is associated with both ferroptosis and tumor immunity, and might be a biomarker associated with the carcinogenesis, prognosis of CC and a potential target of CC immunotherapy.

The validity of atypical psychosis diagnostic criteria to detect anti-NMDA receptor encephalitis with psychiatric symptoms

Anti-NMDAR encephalitis has a psychotic presentation that is difficult to distinguish from primary psychosis. An atypical psychosis that is similar to schizophrenia, mood disorder, and epilepsy is unique, and the original diagnostic criteria exist only in Japan. The clinical symptoms and courses of anti-NMDAR encephalitis and atypical psychosis are very similar. We investigated whether the diagnostic criteria of atypical psychosis are useful to increase the detection rate of anti-NMDAR encephalitis with psychiatric symptoms.The presence of anti-NR1/NR2B IgG antibodies in the cerebrospinal fluid of 218 newly admitted inpatients initially diagnosed with schizophrenia (n = 151), mood disorder (n = 47), or epilepsy with psychiatric symptoms (n = 20) was assessed by cell-based assay.Of 218 patients, 123 (36.3 years ± SD 17.2, 69.9 % females) fulfilled the diagnostic criteria of category B for atypical psychosis. All 12 patients (9.8 %, 12/123) with anti-NR1/NR2B IgG antibodies fulfilled category B of atypical psychosis statistically better than the patients without anti-NR1/NR2B IgG antibodies (P = 0.0009). Of the 12 patients with anti-NMDAR antibodies, two did not fulfill either criteria of catatonia (DSM-5) or Graus' diagnostic criteria of anti-NMDAR encephalitis during the time course, and 11 patients showed good prognosis with early immunotherapies. In ROC analysis, abnormal electroencephalogram findings showed the highest sensitivity (0.833) for detection of anti-NR1/NR2B IgG antibodies, and 31.3 % of patients with category B atypical psychosis and abnormal electroencephalogram findings had anti-NMDAR antibodies.Lumbar puncture and detection of anti-NMDAR antibodies should be considered for patients who fulfill atypical psychosis diagnosis criteria with an abnormal electroencephalogram.

Side effect profile of early immunotherapy after radiotherapy: a pooled analysis of studies in the US Food and Drug Administration database

Side effect profile of early immunotherapy after radiotherapy: a pooled analysis of studies in the US Food and Drug Administration database

Critical care management of meningitis and encephalitis: an update.

Meningitis and encephalitis represent severe neurological syndromes associated with encephalopathy, seizures, focal deficits, and neurological sequelae in survivors. We update on the critical care management of adult patients with severe meningitis and encephalitis. Large multicenter studies conducted in the adult population improved current knowledge on the epidemiology and outcomes of patients with severe meningitis and encephalitis. An early multimodal diagnostic workup (including CSF analysis, brain MRI, EEG, and serum studies) is mandatory for diagnosis and prognostication in those patients.New diagnostic methods, including multiplex PCR and next-generation sequencing techniques, allow for a faster differential diagnosis of infectious causes that may require specific antimicrobial therapy. Autoimmune causes of encephalitis, which may require urgent immunotherapy, are also increasingly recognized in the ICU setting. Although observational data suggest that early combined immunotherapy is associated with better neurological outcomes in patients with autoimmune encephalitis, randomized clinical trials have yet to be performed. Our review highlights the importance of an early multimodal approach for diagnosing severe meningitis and encephalitis. Randomized clinical trials are needed to identify pharmacological interventions that may improve patients' outcomes.

Value-Based, Cost-Effective Care: The Role of the Allergist-Immunologist

Asthma and allergic disease impact millions of patients and are associated with high costs. Up to 30% of all medical care involves wasted spending. Across the spectrum of care provided by the allergist-immunologist, there are opportunities to improve value and reduce medical waste. Several examples highlight this reality. Evidence suggests that most patients may receive cost-effective care in the management of chronic spontaneous urticaria without the need for laboratory testing. For patients with asthma, although a single maintenance and reliever therapy approach may be cost-effective, insurance-mandated therapy changes are not, and may harm patients. Biologics may be very effective in improving asthma control but are too expensive for this indication-as demonstrated by cost-effectiveness analyses and highlighted by the Institute of Clinical and Economic Review, which concluded that the value-based price for asthma biologics ranges between $6500 and 14,3000 per year. Early introduction may prevent food allergy, but screening before first introduction is neither necessary nor cost-effective, although early salvage food oral immunotherapy may result in improved quality of life and cost savings. Evidence does not support the presence of allergic disease as a risk factor for anaphylaxis to coronavirus disease 2019 vaccination, and risk-stratified vaccination approaches do not appear cost-effective. Allergen immunotherapy is a very cost-effective treatment option. The practice of allergy-immunology has continued to evolve in recent years and can provide a leading example of high-value practice.

Paediatric anti-NMDA-receptor encephalitis with ovarian teratoma

Herein, we report two paediatric cases of ovarian teratoma-associated anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. We performed surgical resection of the teratomas—enucleation in case 1 and salpingo-oophorectomy in case 2. The pathological diagnoses were immature teratomas with a small number of neuroglial elements, and cerebrospinal fluid (CSF) anti-NMDAR antibody test was positive in both cases. In case 1, the patient showed excellent recovery, and in case 2, neurological symptoms gradually improved. Paediatric cases of ovarian teratoma-associated anti-NMDAR encephalitis are rare, and early surgical resection and immunotherapy are important for good prognosis. We highlight the occurrence of paediatric cases of ovarian teratoma-associated anti-NMDAR encephalitis to create awareness and highlight the importance of surgical resection despite severe neurological symptoms.

Epileptic phenotypes in autoimmune encephalitis: from acute symptomatic seizures to autoimmune-associated epilepsy

ObjectiveTo describe the clinical and paraclinical findings, treatment options and long-term outcomes in autoimmune encephalitis (AE), with a close look to epilepsy.MethodsIn this retrospective observational cohort study, we enrolled patients...

Production and Quality Assurance of Human Polyclonal Hyperimmune Immunoglobulins Against SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the potential therapeutic value of early passive polyclonal immunotherapy using high-titer convalescent plasma (CCP). Human polyclonal hyperimmune immunoglobulin (HIG) has several advantages over CCP. Unlike CCP, HIG can provide standardized and controlled antibody content. It is also subjected to robust pathogen reduction rendering it virally safe and is purified by technologies demonstrated to preserve immunoglobulin neutralization capacity and Fc fragment integrity. This document provides an overview of current practices and guidance for the collection and testing of plasma rich in antibodies against Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) and its industrial fractionation for the manufacture of quality-assured and safe HIG. Considerations are also given to the production of HIG preparations in low- and middle-income countries.

Immunotherapy in autoimmune encephalitis.

Autoimmune encephalitis (AE) refers to immune-mediated neurological syndromes often characterised by the detection of pathogenic autoantibodies in serum and/or cerebrospinal fluid which target extracellular epitopes of neuroglial antigens. There is increasing evidence these autoantibodies directly modulate function of their antigens in vivo. Early treatment with immunotherapy improves outcomes. Yet, these patients commonly exhibit chronic disability. Importantly, optimal therapeutic strategies at onset and during escalation remain poorly understood. In this review of a rapidly emerging field, we evaluate recent studies on larger cohorts, registries, and meta-analyses to highlight existing evidence for contemporary therapeutic approaches in AE. We highlight acute and long-term treatments used in specific AE syndromes, exemplify how understanding disease pathogenesis can inform precision therapy and outline challenges of defining disability outcomes in AE. Early first-line immunotherapies, including corticosteroids and plasma exchange, improve outcomes, with emerging evidence showing second-line immunotherapies (especially rituximab) reduce relapse rates. Optimal timing of immunotherapy escalation remains unclear. Routine reporting of outcome measures which incorporate cognitive impairment, fatigue, pain, and mental health will permit more accurate quantification of residual disability and comprehensive comparisons between international multicentre cohorts, and enable future meta-analyses with the aim of developing evidence-based therapeutic guidelines.

P.014 Immunotherapy responses of patients with suspected autoimmune-associated epilepsy with negative neural antibody testing

Background: In refractory epilepsy patients with possible autoimmune-associated epilepsy (AAE) but negative antibody testing(-AB), immunotherapy trials (IMT) may still be pursued.The value of (IMT) in such patients remains unclear. For this reason, we reviewed their immunotherapy responses. Methods: Retrospective review of epilepsy patients admitted to the Epilepsy Unit between (2018-2021) who received (IMT). All had (-AB) and received immunotherapy (methylprednisolone (IVMP)-immune globulin (IVIg)-plasma exchange (PLEX)- rituximab).We considered responders when their seizure reduction was ≥ 50%. Results: 14 patients identified. Of them, 50%(n=7) females. Median age (43.5 year. IQR= 28.75-63.25). All refractory to ≥ 2 anti-seizure medications (ASM). Median epilepsy onset was (39.5 years. IQR=23.75-60.25).Median time from diagnosis until received immunotherapy was (15.5 months. IQR=12.75 -21.75). Patients received either IVIG+IVMP (35.7%, n=5) or IVIG alone (28.5%, n=4) or IVIG+IVMP+PLEX (21.4%, n=3) or IVMP alone (7.1%, n=1) or IVIG+IVMP+rituximab (7.1%, n=1). Median follow-up was 25 months.Although early immunotherapy responses were common, sustained response to immunotherapy at last follow-up was only in 21.4% (n=3). Factors confounding determination of immunotherapy efficacy were present in all responders (e.g:concurrent changes in ASM). Conclusions: Our findings suggest that (IMT) in patients with suspected (AAE) but with (-AB) are largely unsuccessful. This suggests an insufficient therapeutic effect after (IMT) or alternatively,non-immune-mediated mechanisms causing this type of epilepsy. Critical evaluations of (IMT)in such cases are needed.

Primary Central Nervous System Angiitis Mimicking a Space-Occupying Lesion

Abstract Background and Purpose Intracranial space-occupying lesions are a sine qua non for neoplastic lesions; however, occasionally non-neoplastic lesions mimic neoplastic lesions, leading to diagnostic dilemmas. We report our experience with three patients who presented with a progressive hemispheric syndrome and the diagnostic considerations involved in the cases. Materials and Methods In this retrospective study, we included three patients with primary angiitis of central nervous system (PACNS) who underwent craniotomy and biopsy, suspecting it to be mass lesions. Demographic features, clinical features, radiological features, histopathology, treatment, and clinical outcomes were studied. Results Majority were males. The male:female ratio was 2:1. Lobar involvement was common. MR brain with contrast showed features of high-grade glioma. Despite hemispheric involvement, there was no mass effect. Perilesional edema was seen in all cases. All underwent craniotomy and biopsy; histopathology was consistent with PACNS. All patients were treated with corticosteroids and cyclophosphamide. Rituximab was used in addition to cyclophosphamide in one patient. At 2 years follow-up, two patients were in disease remission and one patient died due to disease progression. Conclusion PACNS has a protean clinical manifestation. A high index of suspicion is required in cases with atypical clinical presentations, radiological features, and normal angiograms. Early histological diagnosis and aggressive immunotherapy with high-dose corticosteroids combined with intravenous cyclophosphamide yields favorable outcomes.

The Involvement of Long Non-Coding RNAs in Glioma: From Early Detection to Immunotherapy.

Glioma is a brain tumor that arises in the central nervous system and is categorized according to histology and molecular genetic characteristics. Long non-coding RNAs (lncRNAs) are RNAs longer than 200 nucleotides in length. They have been reported to influence significant events such as carcinogenesis, progression, and increased treatment resistance on glioma cells. Long non-coding RNAs promote cell proliferation, migration, epithelial-to-mesenchymal transition and invasion in glioma cells. Various significant advancements in transcriptomic profiling studies have enabled the identification of immune-related long non-coding RNAs as immune cell-specific gene expression regulators that mediates both stimulatory and suppressive immune responses, implying lncRNAs as potential candidates for improving immunotherapy efficacy against tumors and due to the lack of different diagnostic and treatments for glioma, lncRNAs are potential candidates to be used as future diagnostic, prognostic biomarker and treatment tools for glioma. This review’s primary purpose is to concentrate on the role of long non-coding RNAs in early glioma identification, treatment, and immunotherapy.

Anti-NMDAR Encephalitis with Poor Recovery on Steroid Pulse and IVIg: Practical Approach to Intensive Immunotherapy

Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a well-defined autoimmune encephalitis that is responsive to early intensive immunotherapy. Recent international consensus regarding treatment of NMDARE provides a practical treatment algorithm for immunotherapy escalation, while considering a patient's age, disease severity, and other background information. First-line immunotherapy, which includes an intravenous (IV) corticosteroid pulse with the addition of either intravenous immunoglobulins (IVIg) or plasma exchange, should be offered to all NMDARE-diagnosed patients as soon as possible. In cases where insufficient improvement follows a repeat of the first-line combination therapy (assessed on day 14 after the initial treatment), second-line immunotherapy comprising rituximab or an IV cyclophosphamide pulse (IVCPA) is considered. Per the recent expert consensus, rituximab is preferred to IVCPA as the second-line drug of choice, although the use of either drug in the treatment of NMDARE is off-label. Most patients show gradual improvement in the first few weeks following the introduction of second-line therapy, although repeated and alternating use of both drugs is often required. Some patients, whose NMDARE was refractory to the aforementioned therapies, have also been successfully treated with tocilizumab or bortezomib. Moreover, several international clinical trials involving rituximab, inebilizumab, bortezomib, and rozanolixizumab in the treatment of autoimmune encephalitis (AE, which includes NMDARE) are being conducted to establish high-grade evidence for the treatment of AE.

Five young investigators tackle big questions in oncology

Early-career researchers share their priorities for cancer research, from early screening and immunotherapy to nanotechnology and counseling.

Skin cutaneous melanoma properties of immune-related lncRNAs identifying potential prognostic biomarkers.

Skin cutaneous melanoma (SKCM) is one of the most aggressive and life-threatening cancers with high incidence rate, metastasis rate and mortality. Early detection and stratification of risk assessment are essential to treat SKCM and to improve survival rate. The aim of this study is to construct an immune-related lncRNAs (immlncRNAs) prognosis risk model to identify immune biomarkers for early diagnosis, prognosis assessment and target immunotherapy of SKCM. For this purpose, we identified 46 immlncRNAs significantly correlated with SKCM prognosis to construct the prognostic risk model and patients were stratified into the high- and low-risk subgroups according to the developed model. The predictive efficiency of this model has been proved by K-M survival analysis and receiver operating characteristic curve. Moreover, CIBERSORT algorithms confirmed that there were differences in immune cell infiltration between the high- and low-risk groups. Functional enrichment analysis further indicated that immlncRNAs were related to a variety of immune response process signaling pathways, suggesting that relevant immlncRNAs could play an important role in the immune regulation of SKCM. Finally, subgroup analysis and multiple Cox regression analysis further proved the stability of the model. In summary, we successfully constructed a 46 immlncRNA-related prognostic risk score model with excellent predictive efficacy and provided more possibilities to investigate the immune regulation mechanisms and to develop immunotherapy of SKCM.

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.