Frederik Bartels

All Publications

• Memory Deficits in Cancer Patients With Serum NMDA Receptor Autoantibodies. Neurology Bartels, F., Tapuc, A., Rentzsch, K., Duong, S. L., Pruss, H., Finke, C. 2026; 106 (2): e214490

  Abstract

  OBJECTIVES: Neuronal autoantibodies are linked to cognitive impairment in neurologic diseases and can be associated with tumors. In patients with cancer, IgA/IgM N-Methyl-D-Aspartate receptor (NMDAR) autoantibodies are most common, yet their clinical relevance is unclear. We assessed cognitive function in cancer patients with serum NMDAR autoantibodies and compared the results with matched controls.METHODS: For this cross-sectional case-control study in Germany, we recruited 1,055 patients with cancer and tested for neuronal serum autoantibodies. Cognitive assessment was performed blinded to antibody status and after excluding patients with potential confounders of cognitive dysfunction. The tests included verbal memory (Rey Auditory Verbal Learning Test), visuospatial memory (Rey-Osterrieth Complex Figure), and working memory.RESULTS: Fifty-six patients with IgA/IgM NMDAR autoantibodies (median age 61.0 years [28.0-86.0], 35.7% female) were matched 1:1 to autoantibody-negative patients by age, sex, cancer type, and stage. Autoantibody-positive patients showed impairments in verbal memory (mean score ± SD: 9.7 ± 3.6 vs 11.4 ± 3.2; p = 0.01; Cohen d = 0.49), visuospatial memory (19.4 ± 7.0 vs 22.6 ± 5.6; p = 0.01; d = 0.50), and working memory (6.2 ± 1.9 vs 7.0 ± 2.1; p = 0.04; d = 0.40). Memory function decreased with increasing IgA NMDAR autoantibody levels. Both groups performed similarly on measures of attention, executive function, and verbal fluency.DISCUSSION: Serum NMDAR autoantibodies are associated with isolated memory deficits in patients with cancer and might serve as a potential biomarker for cancer-related cognitive impairment.

  View details for DOI 10.1212/WNL.0000000000214490

  View details for PubMedID 41453122

• Neurofilament light chain as a surrogate candidate for disease activity in multiple sclerosis (LUMINOUS)-A meta-regression of randomized controlled trials. Multiple sclerosis (Houndmills, Basingstoke, England) Pretzsch, R., El Mahdaoui, S., Johnson, P., Soares, M. D., Koerbel, K., Held, F., Bajrami, A., Pozzilli, V., Lucchini, M., Barbuti, E., Bartels, F., Barket, R., Cordano, C., Hemmer, B., Cagol, A., Schiavetti, I., Sormani, M. P., ECTRIMS Winter School 2024 study group 2026: 13524585251407973

  Abstract

  BACKGROUND/OBJECTIVES: Neurofilament light chain (NfL) is a promising biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). This meta-regression assesses the relationship between treatment effects on serum/plasma NfL (s/pNfL) and clinical and radiological endpoints in randomized controlled trials (RCTs).METHODS: A systematic PubMed search identified RCTs in MS (1999-2023) with ⩾24months' duration and s/pNfL data. Extracted outcomes included treatment effects on s/pNfL, annualized relapse rate (ARR), confirmed disability worsening (CDW), magnetic resonance imaging (MRI) new/enlarging T2 lesions, and percentage brain volume change (PBVC). We evaluated the association of treatment effect on the selected outcomes at the trial level by a meta-regression, weighted by trial size and duration.RESULTS: Fifteen RCTs (n=6814) were included, nine in relapsing MS (RMS, n=5221), and six in progressive MS (PMS, n=1593). Treatment effects on s/pNfL showed a moderate association with treatment effects on MRI new/enlarging T2 lesions (R2=0.42, p=0.01), ARR (R2=0.33, p=0.03) and CDW (R2=0.30, p=0.04), but not with PBVC. In RMS-only trials, association with ARR (R2=0.45, p=0.05) and CDW (R2=0.50, p=0.03) was more pronounced.CONCLUSION: In MS, treatment effects on s/pNfL are moderately associated with therapeutic effects on ARR, MRI new/enlarging T2 lesions, and CDW, whereas no consistent association was observed with PBVC.

  View details for DOI 10.1177/13524585251407973

  View details for PubMedID 41574448

• Distinct Reactivity Patterns to EBV Nuclear Proteins and CNS Antigens Distinguish CNS Demyelinating Disorders from Systemic Autoimmunity Sattarnezhad, N., Held, F., Babaei, M., Gawde, S., Ho, P., Barrett, A., Wijerante, T., Comanescu, A., Parsafar, S., Bartels, F., McDonald, J., Kipp, L., Van Haren, K., Chaichian, Y., Lock, C., Han, M., Baker, M., Dunn, J., Steinman, L., Lanz, T., Robinson, W. SAGE PUBLICATIONS LTD. 2025: 309-310

  View details for Web of Science ID 001603659901013

• Reduced brain volumes in children with radiologically isolated syndrome. Multiple sclerosis (Houndmills, Basingstoke, England) Koukou, G., Bartels, F., Aigner, A., Cleaveland, R., Tuncer, A., Wendel, E. M., Bertolini, A., Wassmer, E., Kornek, B., Schimmel, M., Panzer, A., Finke, C., Rostásy, K. 2025: 13524585251359066

  Abstract

  Pediatric multiple sclerosis (MS) is associated with reduced brain volumes at first episode compared to healthy controls.To assess brain volumes in children fulfilling the criteria of radiologically isolated syndrome (RIS) at onset and over time.Clinical course, laboratory findings, MR-imaging in pediatric RIS were compared to controls from the NIH Pediatric MRI Data Repository and a cohort of patients with pediatric MS.20 RIS and 37 MS patients were included in the study. Median age at RIS diagnosis was 13.1 years (IQR: 10.3, 14.8) and whole brain volume was reduced by 77 cm3, compared to matched healthy controls (1673 cm3 (1637, 1728) vs 1750 cm3 (1699, 1802)). Nine RIS patients developed MS (RIS-to-MS) at a median age of 15.8 years (12.7,17.0). Longitudinal volumetry revealed lower brain volume in both non-converting and converting RIS patients compared to controls, similar to the trajectory in pediatric MS (RIS -4.7% (-6.5, -2.9), RIS-to-MS -5.1% (-6.9, -3.4), MS -6.6 % (-7.6, -5.5)). Oligoclonal bands, cerebrospinal fluid (CSF) pleocytosis, and reduced brain volume in RIS at diagnosis increased hazards of conversion to MS.Reduced whole brain volume is already present in pediatric radiologically isolated syndrome (RIS). Longitudinal analysis of RIS patients revealed reduced brain volume over time, similar to MS.

  View details for DOI 10.1177/13524585251359066

  View details for PubMedID 40737451

• Brain atrophy patterns in anti-IgLON5 disease. Brain : a journal of neurology Yogeshwar, S. M., Bartels, F., Grüter, T., Muñiz-Castrillo, S., Picard, G., Crijnen, Y. S., Bernard, E., Heidbreder, A., Zekeridou, A., Ringelstein, M., Kraft, A., Kovac, S., Wandinger, K. P., de Vries, J. M., Boon, A. J., Veenbergen, S., Geis, C., Penner, L., Melzer, N., Leypoldt, F., Blaabjerg, M., Pittock, S. J., Gaig, C., Sabater, L., Santamaria, J., Graus, F., Dalmau, J., Prüss, H., Höftberger, R., Schreiner, B., McKeon, A., Lewerenz, J., Irani, S., Mignot, E., Titulaer, M. J., Ayzenberg, I., Honnorat, J., Finke, C. 2025

  Abstract

  Anti-IgLON5 disease is an autoimmune encephalitis that presents with a heterogenous clinical phenotype, including sleep disorders, movement abnormalities and bulbar involvement. It is characterised by autoantibodies against IgLON5, 85% association with HLA-DQB1*05:∼ and a brainstem-dominant tauopathy. Cellular and murine models report pathogenic effects of the autoantibodies, and neurodegenerative factors suggest progressive atrophy as a common sequela. However, evidence from in vivo patient data and long-term follow up are limited. Further, the degree of progression remains elusive. In this multi-centre study, clinical and brain MRI data were collected from 127 patients across twelve countries to investigate the relationships between clinical presentations and the development of distinct brain atrophy patterns. Our data show that most patients develop a complex multi-system phenotype as the disease progresses, however, neuromuscular manifestations rarely emerge at later disease stages. By comparison to healthy controls, this disease presents with severe sub-structure specific atrophy, especially affecting the hypothalamus, brainstem, accumbens and basal ganglia which, in age-independent analyses, show significant ventricular enlargement and also suggest progression of brainstem atrophy over the disease course. Moreover, the focality of atrophy was functionally linked to specific symptoms, with more severe involvement of the basal ganglia in patients with movement disorders, and greater atrophy in the hippocampus and thalamus in patients with cognitive impairment. Taken together, our results provide evidence of distinct atrophy patterns in anti-IgLON5 disease, which closely mirror sites of pathophysiologic processes, including autoantibody binding and tau deposition. Our data emphasize the brainstem as the pathophysiological hub of the disease and provide normative data for the incorporation of atrophy measurements into routine clinical assessments and future treatment studies to monitor disease trajectory and evaluate future treatment strategies.

  View details for DOI 10.1093/brain/awaf256

  View details for PubMedID 40650880

• Distinguishing Transient From Persistent Brain Structural Changes in Pediatric Patients With Acute Disseminated Encephalomyelitis NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Millward, J., Pilgrim, E., Baumann, M., Wendel, E., El Naggar, I., Bertolini, A., Bartels, F., Finke, C., Paul, F., Niendorf, T., Rostasy, K., Waiczies, S. 2025; 12 (1): e200337

  Abstract

  Pediatric patients with acute disseminated encephalomyelitis (ADEM) are at risk of impaired brain growth, with long-term neuropsychiatric consequences. We previously reported transient expansions of cerebral ventricle volume (VV) in experimental autoimmune encephalomyelitis, which subsequently normalized. In this study, we investigated changes in VV in ADEM in relation to other brain structures and clinical outcomes.We investigated brain MRI scans acquired in routine clinical practice from a multicenter cohort of 61 pediatric patients with ADEM, of whom 39 were myelin oligodendrocyte glycoprotein (MOG) antibody-positive. Patients were compared with 1,219 pediatric healthy controls (HCs). Volumes of multiple brain structures were computed using a contrast-agnostic machine learning-based tool and analyzed with mixed-effect models regarding other clinical parameters.Patients with ADEM had larger VV than HCs at initial clinical presentation, before immune therapy. Most of the patients showed further VV increases within 2 months after disease onset. Patients had smaller brain volumes than HCs, with specific reductions in deep gray matter structures. These changes were more pronounced in MOG antibody-negative patients.Of the patients with more than 2 MRI scans, 12 of 22 resolved their VV expansion back to within 15% of baseline values while 10 of 22 had persistently increased VV at the last available MRI within 1 year from onset. Patients with persistent VV expansion had greater reductions in volumes of other brain structures at the last MRI than patients whose VV resolved and were more likely to have residual neurologic signs. The VV resolving and nonresolving patients did not differ regarding age, sex, elevated CSF cell counts at baseline, or occurrence of relapses. However, patients with a larger magnitude of VV expansion-≥90% of baseline volume-were more likely to be in the nonresolving group.We could distinguish between 2 outcomes of VV changes in ADEM: one in which the VV expanded but ultimately returned to normal and one in which the expansions continued after disease onset and treatment but failed to resolve. The latter was associated with reduced brain volume, particularly in deep gray matter structures. This highlights the necessity for patients with ADEM to undergo regular MRI scans to assess whether developing VV expansions indicate a greater risk of permanent brain atrophy.

  View details for DOI 10.1212/NXI.0000000000200337

  View details for Web of Science ID 001383869300001

  View details for PubMedID 39715470

  View details for PubMedCentralID PMC11676258

• MRI findings in autoimmune encephalitis REVUE NEUROLOGIQUE Hartung, T. J., Bartels, F., Kuchling, J., Krohn, S., Leidel, J., Mantwill, M., Wurdack, K., Yogeshwar, S., Scheel, M., Finke, C. 2024; 180 (9): 895-907

  Abstract

  Autoimmune encephalitis encompasses a spectrum of conditions characterized by distinct clinical features and magnetic resonance imaging (MRI) findings. Here, we review the literature on acute MRI changes in the most common autoimmune encephalitis variants. In N-methyl-D-aspartate (NMDA) receptor encephalitis, most patients have a normal MRI in the acute stage. When lesions are present in the acute stage, they are typically subtle and non-specific white matter lesions that do not correspond with the clinical syndrome. In some NMDA receptor encephalitis cases, these T2-hyperintense lesions may be indicative of an NMDA receptor encephalitis overlap syndrome with simultaneous co-existence of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Encephalitis with leucine-rich glioma-inactivated 1 (LGI1)-, contactin-associated protein-like 2 (CASPR2)- or glutamic acid decarboxylase (GAD)- antibodies typically presents as limbic encephalitis (LE) with unilateral or bilateral T2/fluid attenuated inversion recovery (FLAIR) hyperintensities in the medial temporal lobe that can progress to hippocampal atrophy. Gamma aminobutyric acid-B (GABA-B) receptor encephalitis also often shows such medial temporal hyperintensities but may additionally involve cerebellar lesions and atrophy. Gamma aminobutyric acid-A (GABA-A) receptor encephalitis features multifocal, confluent lesions in cortical and subcortical areas, sometimes leading to generalized atrophy. MRI is unremarkable in most patients with immunoglobulin-like cell adhesion molecule 5 (IgLON5)-disease, while individual case reports identified T2/FLAIR hyperintense lesions, diffusion restriction and atrophy in the brainstem, hippocampus and cerebellum. These findings highlight the need for MRI studies in patients with suspected autoimmune encephalitis to capture disease-specific changes and to exclude alternative diagnoses. Ideally, MRI investigations should be performed using dedicated autoimmune encephalitis imaging protocols. Longitudinal MRI studies play an important role to evaluate potential relapses and to manage long-term complications. Advanced MRI techniques and current research into imaging biomarkers will help to enhance the diagnostic accuracy of MRI investigations and individual patient outcome prediction. This will eventually enable better treatment decisions with improved clinical outcomes.

  View details for DOI 10.1016/j.neurol.2024.08.006

  View details for Web of Science ID 001348452800001

  View details for PubMedID 39358087

• Computerized cognitive training improves cognitive function in primary breast cancer survivors NPJ BREAST CANCER Kleinknecht, K. R., Bierend, M., Keim, L., Bartels, F., Lampit, A., Finke, C. 2024; 10 (1): 85

  Abstract

  Cancer-related cognitive impairment has a significant impact on the quality of life and perceived cognitive ability of breast cancer patients and frequently affects attention, working memory, and executive function. Several interventional approaches to treat these deficits have been studied, including web-based cognitive training, but methods and timing in relation to cancer treatment are heterogeneous. Only few interventions start early after primary breast cancer treatment, a time when many patients report the greatest impairments in quality of life and cognition. In this randomized controlled pilot study, 31 breast cancer survivors with subjective cognitive deficits and a mean post-treatment duration of 6.6 months (SD = 9.3) were assigned to either 14 weeks of a web-based cognitive training program (training group, n = 16) or a control group (n = 15). All patients underwent detailed neuropsychological assessment, evaluation of patient-reported outcomes (PROMs), and neurological examination before (baseline, T1) and after (follow-up, T2) the intervention. Longitudinal (T1 vs. T2) and cross-sectional (T2) cognitive performance was assessed for both groups. Overall cognitive impairment significantly improved in the training group following training (56% vs 25%; p = 0.03, Phi = 0.51), but not in the control group (73% vs. 73%; p = 1) in the longitudinal analysis (T1 vs. T2). Specifically, the training group showed statistically significant improvement of executive functions (p = 0.004, Phi = 0.32). No effects of training on subjective cognitive deficits or PROMs were observed. Comparing cross-sectional cognitive performance at follow-up (T2), the training group showed a significantly lower rate of cognitive impairment overall (p = 0.007, Phi = 0.48) and a better cognitive performance for executive function (p = 0.04, Phi = 0.32) compared to the control group. In this prospective pilot study, web-based cognitive training was efficacious in improving overall cognitive performance and executive function. Importantly, this study investigated a web-based cognitive training for the immediate post-treatment phase, when up to 75% of breast cancer patients experience cognitive decline. These results indicate that cognitive training may improve neuropsychological outcomes for patients with breast cancer.

  View details for DOI 10.1038/s41523-024-00694-8

  View details for Web of Science ID 001325726000002

  View details for PubMedID 39349493

  View details for PubMedCentralID PMC11443049

• Dataset for: Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune-related adverse events DATA IN BRIEF Mueller-Jensen, L., Knauss, S., Roque, L., Schinke, C., Maierhof, S. K., Bartels, F., Finke, C., Rentzsch, K., Ulrich, C., Mohr, R., Stenzel, W., Endres, M., Boehmerle, W., Huehnchen, P. 2024; 53: 110062

  Abstract

  The rise of cancer immunotherapy has been a milestone in clinical oncology. Above all, immune checkpoint inhibitor treatment (ICI) with monoclonal antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has improved survival rates for an increasing number of malignancies. However, despite the clinical benefits, ICI-related autoimmunity has become a significant cause of non-relapse-related morbidity and mortality. Neurological immune-related adverse events (irAE-n) are particularly severe toxicities with a high risk for chronic illness, long-term steroid dependency, and early ICI treatment termination. While the clinical characteristics of irAE-n are well described, little is known about underlying immune mechanisms and potential biomarkers. Recently, high frequencies of neuronal autoantibodies in patients with irAE-n have been reported, however, their clinical relevance is unclear. Here, we present a dataset on neuronal autoantibody profiles in ICI-treated cancer patients with and without irAE-n, which was generated to investigate the potential role of neuronal autoantibodies in ICI-induced autoimmunity. Between September 2017 and January 2022 serum samples of 29 cancer patients with irAE-n post-ICI treatment) and 44 cancer control patients without high-grade immune-related adverse events (irAEs, n = 44 pre- and post-ICI treatment) were collected and tested for a large panel of brain-reactive and neuromuscular autoantibodies using indirect immunofluorescence and immunoblot assays. Prevalence of autoantibodies was compared between the groups and correlated with clinical characteristics such as outcome and irAE-n manifestation. These data represent the first systematic comparison of neuronal autoantibody profiles between ICI-treated cancer patients with and without irAE-n, providing valuable information for both researchers and clinicians. In the future, this dataset may be valuable for meta-analyses on the prevalence of neuronal autoantibodies in cancer patients.

  View details for DOI 10.1016/j.dib.2024.110062

  View details for Web of Science ID 001175282800001

  View details for PubMedID 38317734

  View details for PubMedCentralID PMC10838681

• Retrospective Pediatric Cohort Study Validates NEOS Score and Demonstrates Applicability in Children With Anti-NMDAR Encephalitis NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Nikolaus, M., Rausch, P., Rostasy, K., Bertolini, A., Wickstroem, R., Johannsen, J., Denecke, J., Breu, M., Schimmel, M., Diepold, K., Haeusler, M., Quade, A., Berger, A., Rosewich, H., Steen, C., von Au, K., Dreesmann, M., Finke, C., Bartels, F., Kaindl, A. M., Schuelke, M., Knierim, E. 2023; 10 (3)

  Abstract

  Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is the most common form of autoimmune encephalitis in children and adults. Although our understanding of the disease mechanisms has progressed, little is known about estimating patient outcomes. Therefore, the NEOS (anti-NMDAR Encephalitis One-Year Functional Status) score was introduced as a tool to predict disease progression in NMDARE. Developed in a mixed-age cohort, it currently remains unclear whether NEOS can be optimized for pediatric NMDARE.This retrospective observational study aimed to validate NEOS in a large pediatric-only cohort of 59 patients (median age of 8 years). We reconstructed the original score, adapted it, evaluated additional variables, and assessed its predictive power (median follow-up of 20 months). Generalized linear regression models were used to examine predictability of binary outcomes based on the modified Rankin Scale (mRS). In addition, neuropsychological test results were investigated as alternative cognitive outcome.The NEOS score reliably predicted poor clinical outcome (mRS ≥3) in children in the first year after diagnosis (p = 0.0014) and beyond (p = 0.036, 16 months after diagnosis). A score adapted to the pediatric cohort by adjusting the cutoffs of the 5 NEOS components did not improve predictive power. In addition to these 5 variables, further patient characteristics such as the "Herpes simplex virus encephalitis (HSE) status" and "age at disease onset" influenced predictability and could potentially be useful to define risk groups. NEOS also predicted cognitive outcome with higher scores associated with deficits of executive function (p = 0.048) and memory (p = 0.043).Our data support the applicability of the NEOS score in children with NMDARE. Although not yet validated in prospective studies, NEOS also predicted cognitive impairment in our cohort. Consequently, the score could help identify patients at risk of poor overall clinical outcome and poor cognitive outcome and thus aid in selecting not only optimized initial therapies for these patients but also cognitive rehabilitation to improve long-term outcomes.

  View details for DOI 10.1212/NXI.0000000000200102

  View details for Web of Science ID 001157626000013

  View details for PubMedID 36948591

  View details for PubMedCentralID PMC10032577

• Severe Hippocampal Atrophy in a Patient With Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy JAMA NEUROLOGY Bartels, F., Heine, J., Finke, C. 2023; 80 (6): 642-643

  View details for DOI 10.1001/jamaneurol.2023.0606

  View details for Web of Science ID 000989785800003

  View details for PubMedID 37036726

• Impaired Brain Growth in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Acute Disseminated Encephalomyelitis NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION Bartels, F., Baumgartner, B., Aigner, A., Cooper, G., Blaschek, A., Wendel, E., Bertolini, A., Karenfort, M., Baumann, M., Cleaveland, R., Wegener-Panzer, A., Leiz, S., Salandin, M., Krieg, P., Reindl, T., Reindl, M., Finke, C., Rostasy, K. 2023; 10 (2)

  Abstract

  Acute disseminated encephalomyelitis (ADEM) is the most common phenotype in pediatric myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease. A previous study demonstrated impaired brain growth in ADEM. However, the effect of MOG antibodies on brain growth remains unknown. Here, we performed brain volume analyses in MOG-positive and MOG-negative ADEM at onset and over time.In this observational cohort study, we included a total of 62 MRI scans from 24 patients with ADEM (54.2% female; median age 5 years), of which 16 (66.7%) were MOG positive. Patients were compared with healthy controls from the NIH pediatric MRI data repository and a matched local cohort. Mixed-effect models were applied to assess group differences and other relevant factors, including relapses.At baseline and before any steroid treatment, patients with ADEM, irrespective of MOG antibody status, showed reduced brain volume compared with matched controls (median [interquartile range] 1,741.9 cm3 [1,645.1-1,805.2] vs 1,810.4 cm3 [1,786.5-1,836.2]). Longitudinal analysis revealed reduced brain growth for both MOG-positive and MOG-negative patients with ADEM. However, MOG-negative patients showed a stronger reduction (-138.3 cm3 [95% CI -193.6 to -82.9]) than MOG-positive patients (-50.0 cm3 [-126.5 to -5.2]), independent of age, sex, and treatment. Relapsing patients (all MOG positive) showed additional brain volume loss (-15.8 cm3 [-68.9 to 37.3]).Patients with ADEM exhibit brain volume loss and failure of age-expected brain growth. Importantly, MOG-negative status was associated with a more pronounced brain volume loss compared with MOG-positive patients.

  View details for DOI 10.1212/NXI.0000000000200066

  View details for Web of Science ID 000943280600014

  View details for PubMedID 36754833

  View details for PubMedCentralID PMC9909582

• Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune related adverse events FRONTIERS IN IMMUNOLOGY Mueller-Jensen, L., Knauss, S., Ginesta Roque, L., Schinke, C., Maierhof, S. K., Bartels, F., Finke, C., Rentzsch, K., Ulrich, C., Mohr, R., Stenzel, W., Endres, M., Boehmerle, W., Huehnchen, P. 2023; 14: 1108116

  Abstract

  Neurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n.In this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies.IrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis.Neuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.

  View details for DOI 10.3389/fimmu.2023.1108116

  View details for Web of Science ID 000934668800001

  View details for PubMedID 36845122

  View details for PubMedCentralID PMC9945255

• Clinical and neuroimaging findings in MOGAD-MRI and OCT CLINICAL AND EXPERIMENTAL IMMUNOLOGY Bartels, F., Lu, A., Oertel, F., Finke, C., Paul, F., Chien, C. 2021; 206 (3): 266-281

  Abstract

  Myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group of disorders that are different from aquaporin-4 autoantibody-associated neuromyelitis optica spectrum disorder and from classic multiple sclerosis. In-vivo imaging of the MOGAD patient central nervous system has shown some distinguishing features when evaluating magnetic resonance imaging of the brain, spinal cord and optic nerves, as well as retinal imaging using optical coherence tomography. In this review, we discuss key clinical and neuroimaging characteristics of paediatric and adult MOGAD. We describe how these imaging techniques may be used to study this group of disorders and discuss how image analysis methods have led to recent insights for consideration in future studies.

  View details for DOI 10.1111/cei.13641

  View details for Web of Science ID 000674185200001

  View details for PubMedID 34152000

  View details for PubMedCentralID PMC8561692

• Association Between Neuronal Autoantibodies and Cognitive Impairment in Patients With Lung Cancer JAMA ONCOLOGY Bartels, F., Wandrey, M., Aigner, A., Stroenisch, T., Farmer, K., Rentzsch, K., Tessmer, A., Grohe, C., Finke, C. 2021; 7 (9): 1302-1310

  Abstract

  Paraneoplastic neurological syndromes are associated with neuronal autoantibodies, and some of these autoantibodies are associated with neuropsychological symptoms. The most common underlying tumor is lung cancer. The association of neuronal autoantibodies with cognitive deficits has not been systematically investigated in patients with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).To assess the frequency of neuronal autoantibodies in patients with lung cancer and analyze their association with cognitive function.This prospective, cross-sectional study included 167 patients with lung cancer (both SCLC and NSCLC) recruited at a single lung cancer center in Berlin, Germany, between June 2015 and April 2016. Detailed neuropsychological testing was performed in a carefully selected subgroup of 97 patients (from which patients with potential confounding factors were excluded). Investigators were blinded to patients' autoantibody status and cognitive test results. Data were analyzed from May 2016 to December 2019.Prevalence of neuronal autoantibodies and their association with cognitive impairment. The evaluation of autoantibodies as potential risk factors for cognitive impairment was performed using bayesian logistic regression models.Among 167 patients with lung cancer (median age, 66.0 years [interquartile range, 59.0-72.0 years]; 105 men [62.9%]), 127 had NSCLC, and 40 had SCLC. Brain-directed autoantibodies were detected in 61 of 167 patients (36.5%); 33 patients (19.8%) had known autoantibodies and 28 patients (16.8%) had autoantibodies against currently unknown antigens that were detected through immunohistochemical analysis. Cognitive impairment was found in 65 of 97 patients (67.0%). Among patients with SCLC, the odds of cognitive impairment for those with any autoantibodies was 11-fold higher (odds ratio [OR], 11.0; 95% credible interval [CrI], 1.2-103.6) than that of autoantibody-negative patients, and the increased odds were independent of age, sex, and neurological deficit. Among patients with NSCLC, those with immunoglobin A autoantibodies targeting the N-methyl-d-aspartate receptor had a relevantly increased odds of verbal memory deficits (OR, 182.8; 95% CrI, 3.1-10 852.4). Autoantibodies against currently unknown antigens were also associated with increased odds of cognitive impairment (OR, 2.8; 95% CrI, 0.6-12.1).In this prospective, cross-sectional study, more than one-third of patients with lung cancer had neuronal autoantibodies that were found to be associated with cognitive impairment. These autoantibodies might represent a potentially treatable mechanism of immune-mediated cognitive impairment among patients with lung cancer.

  View details for DOI 10.1001/jamaoncol.2021.2049

  View details for Web of Science ID 000669020200004

  View details for PubMedID 34196651

  View details for PubMedCentralID PMC8251651

• EU paediatric MOG consortium consensus: Part 2-Neuroimaging features of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY Baumann, M., Bartels, F., Finke, C., Adamsbaum, C., Hacohen, Y., Rostasy, K., Eu Paediat Mog Consortium 2020; 29: 14-21

  Abstract

  Imaging plays a crucial role in differentiating the spectrum of paediatric acquired demyelinating syndromes (ADS), which apart from myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) includes paediatric multiple sclerosis (MS), aquaporin-4 antibody neuromyelitis optica spectrum disorders (NMOSD) and unclassified patients with both monophasic and relapsing ADS. In contrast to the imaging characteristics of children with MS, children with MOGAD present with diverse imaging patterns which correlate with the main demyelinating phenotypes as well as age at presentation. In this review we describe the common neuroradiological features of children with MOGAD such as acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, AQP4 negative NMOSD. In addition, we report newly recognized presentations also associated with MOG-ab such as the 'leukodystophy-like' phenotype and autoimmune encephalitis with predominant involvement of cortical and deep grey matter structures. We further delineate the features, which may help to distinguish MOGAD from other ADS and discuss the future role of MR-imaging in regards to treatment decisions and prognosis in children with MOGAD. Finally, we propose an MRI protocol for routine examination and discuss new imaging techniques, which may help to better understand the neurobiology of MOGAD.

  View details for DOI 10.1016/j.ejpn.2020.10.002

  View details for Web of Science ID 000602702900003

  View details for PubMedID 33158737

• EU paediatric MOG consortium consensus: Part 5-Treatment of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY Bruijstens, A. L., Wendel, E., Lechner, C., Bartels, F., Finke, C., Breu, M., Flet-Berliac, L., de Chalus, A., Adamsbaum, C., Capobianco, M., Laetitia, G., Hacohen, Y., Hemingway, C., Wassmer, E., Lim, M., Baumann, M., Wickstrom, R., Armangue, T., Rostasy, K., Deiva, K., Neuteboom, R. F. 2020; 29: 41-53

  Abstract

  In recent years, the understanding about the different clinical phenotypes, diagnostic and prognostic factors of myelin oligodendrocyte glycoprotein-antibody-associated disorders (MOGAD) has significantly increased. However, there is still lack of evidence-based treatment protocols for acute attacks and children with a relapsing course of the disease. Currently used acute and maintenance treatment regimens are derived from other demyelinating central nervous system diseases and are mostly centre-specific. Therefore, this part of the Paediatric European Collaborative Consensus attempts to provide recommendations for acute and maintenance therapy based on clinical experience and evidence available from mainly retrospective studies. In the acute attack, intravenous methylprednisolone (IVMP) leads to a favourable outcome in the majority of patients and can be followed by tapering of oral steroids up to a maximum of three months to maintain the benefit of acute treatment by suppressing disease activity. Intravenous immunoglobulins (IVIG) and plasmapheresis constitute second-line therapies in case of insufficient response to IVMP. After a first relapse, maintenance treatment should be started in order to prevent further relapses and the possibility of permanent sequelae. Four first-line therapies consisting of rituximab (RTX), azathioprine, mycophenolate mofetil or monthly IVIG have been identified by the consensus group. In case of further relapses despite maintenance treatment, the consensus group recommends treatment escalation with RTX or IVIG, followed by combining those two, and ultimately adding maintenance oral steroids. Many open questions remain which need to be addressed in further international prospective evaluation of MOGAD treatment. This international collaboration is essential to expand the state of current knowledge.

  View details for DOI 10.1016/j.ejpn.2020.10.005

  View details for Web of Science ID 000602702900006

  View details for PubMedID 33176999

• EU paediatric MOG consortium consensus: Part 3-Biomarkers of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY Armangue, T., Capobianco, M., de Chalus, A., Laetitia, G., Deiva, K., EU Paediat MOG Consortium 2020; 29: 22-31

  Abstract

  A first episode of acquired demyelinating disorder (ADS) in children is a diagnostic challenge as different diseases can express similar clinical features. Recently, antibodies against myelin oligodendrocyte glycoprotein (MOG) have emerged as a new ADS biomarker, which clearly allow the identification of monophasic and relapsing ADS forms different from MS predominantly in children. Due to the novelty of this antibody there are still challenges and controversies about its pathogenicity and best technique to detect it. In this manuscript we will discuss the recommendations and caveats on MOG antibody assays, role in the pathogenesis, and additionally discuss the usefulness of other potential new biomarkers in MOG-antibody associated disorders (MOGAD).

  View details for DOI 10.1016/j.ejpn.2020.11.001

  View details for Web of Science ID 000602702900004

  View details for PubMedID 33191096

• <i>LAPTM5</i>-CD40 Crosstalk in Glioblastoma Invasion and Temozolomide Resistance FRONTIERS IN ONCOLOGY Berberich, A., Bartels, F., Tang, Z., Knoll, M., Pusch, S., Hucke, N., Kessler, T., Dong, Z., Wiestler, B., Winkler, F., Platten, M., Wick, W., Abdollahi, A., Lemke, D. 2020; 10: 747

  Abstract

  Background: Glioma therapy is challenged by the diffuse and invasive growth of glioma. Lysosomal protein transmembrane 5 (LAPTM5) was identified as an invasion inhibitor by an in vivo screen for invasion-associated genes. The aim of this study was to decipher the function of LAPTM5 in glioblastoma and its interaction with the CD40 receptor which is intensively evaluated as a target in the therapy of diverse cancers including glioma. Methods: Knockdown of LAPTM5 was performed in different glioma cell lines to analyze the impact on clonogenicity, invasiveness, sensitivity to temozolomide chemotherapy, and tumorigenicity in vitro and in vivo. An expression array was used to elucidate the underlying pathways. CD40 knockdown and overexpression were induced to investigate a potential crosstalk of LAPTM5 and CD40. LAPTM5 and CD40 were correlated with the clinical outcome of glioma patients. Results: Knockdown of LAPTM5 unleashed CD40-mediated NFκB activation, resulting in enhanced invasiveness, clonogenicity, and temozolomide resistance that was overcome by NFκB inhibition. LAPTM5 expression correlated with better overall survival in glioblastoma patients depending on CD40 expression status. Conclusion: We conclude that LAPTM5 conveyed tumor suppression and temozolomide sensitation in CD40-positive glioblastoma through the inhibition of CD40-mediated NFκB activation. Hence, LAPTM5 may provide a potential biomarker for sensitivity to temozolomide in CD40-positive glioblastoma.

  View details for DOI 10.3389/fonc.2020.00747

  View details for Web of Science ID 000543190800001

  View details for PubMedID 32582531

  View details for PubMedCentralID PMC7289993

• Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis ANNALS OF NEUROLOGY Bartels, F., Krohn, S., Nikolaus, M., Johannsen, J., Wickstrom, R., Schimmel, M., Haeusler, M., Berger, A., Breu, M., Blankenburg, M., Stoffels, J., Hendricks, O., Bernert, G., Kurlemann, G., Knierim, E., Kaindl, A., Rostasy, K., Finke, C. 2020; 88 (1): 148-159

  Abstract

  To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients.We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity.Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome.Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

  View details for DOI 10.1002/ana.25754

  View details for Web of Science ID 000536039800001

  View details for PubMedID 32314416

• Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure MULTIPLE SCLEROSIS JOURNAL Bartels, F., Nobis, K., Cooper, G., Wendel, E., Cleaveland, R., Bajer-kornek, B., Blaschek, A., Schimmel, M., Blankenburg, M., Baumann, M., Karenfort, M., Finke, C., Rostasy, K. 2019; 25 (7): 927-936

  Abstract

  Paediatric multiple sclerosis (pedMS) patients at a single site were shown to have reduced brain volumes and failure of age-expected brain growth compared to healthy controls. However, the precise time of onset of brain volume loss remains unclear.To longitudinally study brain volumes in a multi-centre European cohort at first presentation and after 2 years.Brain volumes of high-resolution magnetic resonance imaging (MRI) data from 37 pedMS patients at first presentation prior to steroid therapy and at 2-year follow-up ( n = 21) were compared to matched longitudinal MRI data from the NIH Paediatric MRI Data Repository.Patients showed significantly reduced whole brain, grey and white matter and increased ventricular volumes at initial presentation and at follow-up compared to controls. Over 2 years, patients exhibited significant reduction of whole brain and white matter volumes, accompanied by increased ventricular volume. Brain volume loss at follow-up correlated with a higher number of infratentorial lesions, relapses and an increased Expanded Disability Status Scale (EDSS) score.In pedMS patients, brain volume loss is present already at first clinical presentation and accelerated over 2 years. Increased disease activity is associated with more severe brain volume loss. MRI brain volume change might serve as an outcome parameter in future prospective pedMS studies.

  View details for DOI 10.1177/1352458519829698

  View details for Web of Science ID 000469855700009

  View details for PubMedID 30945587

• Neuronal autoantibodies associated with cognitive impairment in melanoma patients ANNALS OF ONCOLOGY Bartels, F., Stroenisch, T., Farmer, K., Rentzsch, K., Kiecker, F., Finke, C. 2019; 30 (5): 823-829

  View details for DOI 10.1093/annonc/mdz083

  View details for Web of Science ID 000482490300019

• Anti-ARHGAP26 Autoantibodies Are Associated With Isolated Cognitive Impairment FRONTIERS IN NEUROLOGY Bartels, F., Pruess, H., Finke, C. 2018; 9: 656

  Abstract

  Autoantibodies against the RhoGTPase-activating protein 26 (ARHGAP26) were originally identified in the context of subacute autoimmune cerebellar ataxia. Further studies identified a wider clinical spectrum including psychotic, affective, and cognitive symptoms. Only a few patients reported so far had evidence of a tumor association. A prospective analysis between January 2015 and December 2017 at the Dept. of Neurology at Charité-Universitätsmedizin Berlin identified 14 patients with ARHGAP26 autoantibodies on a cell-based assay, of which three patients had additional brain immunohistochemistry staining of cerebellar molecular layer and Purkinje cells, who were therefore considered antibody-positive. In all three patients, ARHGAP26 autoantibodies were associated with tumors. In two patients, an isolated cognitive impairment without additional neurological deficits was observed. These cases thus further extend the clinical spectrum associated with ARHGAP26 autoantibodies and strengthen a potential paraneoplastic context.

  View details for DOI 10.3389/fneur.2018.00656

  View details for Web of Science ID 000441320700001

  View details for PubMedID 30158896

  View details for PubMedCentralID PMC6104436

• High prevalence of neuronal surface autoantibodies associated with cognitive deficits in cancer patients JOURNAL OF NEUROLOGY Finke, C., Bartels, F., Luett, A., Pruess, H., Harms, L. 2017; 264 (9): 1968-1977

  Abstract

  The recent discovery of neuronal cell-surface antibodies profoundly expanded the clinical spectrum of paraneoplastic neurological syndromes. Many of these syndromes are associated with impaired cognitive function, a clinical symptom that is of increasing concern in cancer patients. However, the frequency of these antibodies in cancer patients and their relation to clinical syndromes is currently unknown. Here, we investigated the prevalence of neuronal cell-surface antibodies and associated paraneoplastic neurological syndromes in 323 patients with different cancer types and in 105 controls. Cerebrospinal fluid and serum samples were analysed for a large panel of anti-neuronal antibodies and all patients were screened for cognitive deficits. Blood-brain barrier integrity was assessed using the age-normalized albumin cerebrospinal fluid/serum ratio. Anti-neuronal autoantibodies were observed in 24.5% of cancer patients (in contrast to 3.1% in neurological control patients without cancer and 2.5% in healthy controls) and were almost exclusively detected in serum. The majority of antibodies were directed against cell-surface antigens (75.9%), most frequently IgA/IgM isotypes targeting the N-methyl-D-aspartate (NMDA) receptor. Cognitive deficits and cerebellar syndromes were significantly more prevalent in antibody-positive in comparison with antibody-negative patients (21 vs. 7%, p = 2.7 × 10-4; 11 vs. 2%, p = 3.0 × 10-3). Antibody-positive patients with cognitive deficits had a significantly increased albumin cerebrospinal fluid/serum ratio in comparison with antibody-positive patients with other neurological deficits, indicating blood-brain barrier dysfunction (49.1 × 10-3 vs. 12.0 × 10-3; p = 0.036). Our results show that anti-neuronal antibodies have a high prevalence in a wide range of different tumour types and are associated with distinct neurological deficits. Specifically, the results suggest a so far undefined cognitive paraneoplastic syndrome in patients with antibodies targeting neuronal surface antigens and concurrent blood-brain barrier dysfunction. Anti-neuronal antibodies might thus serve as a biomarker for potentially treatment-responsive cognitive impairments in cancer patients.

  View details for DOI 10.1007/s00415-017-8582-0

  View details for Web of Science ID 000409831400015

  View details for PubMedID 28785798