Publications by authors named "Nico Melzer"

68 Publications

Determinants of cognition in autoimmune limbic encephalitis-A retrospective cohort study.

Hippocampus 2021 Jul 16. Epub 2021 Jul 16.

Department of Neurology with Institute of Translational Neurology, Westfälische Wilhelms-University of Münster, Münster, Germany.

Autoimmune limbic encephalitis (ALE) is the most common type of autoimmune encephalitis (AIE). Subacute memory disturbance, temporal lobe seizures, and psychiatric symptoms are clinical hallmarks of the disease. However, little is known on the factors contributing to cognitive functioning in ALE. Hence, we here investigate major determinants of cognitive functioning in ALE. In a retrospective analysis of 102 patients with ALE, we first compared verbal learning capacity, nonverbal learning capacity, and attentional and executive functioning by absence or presence of different types of neural autoantibodies (AABs). Subsequently we established three linear regression models including 63, 38, and 61 patients, respectively to investigate how cognitive functioning in these domains may depend on common markers of ALE such as intrathecal inflammation, blood-cerebrospinal fluid (CSF)-barrier function, mesiotemporal epileptiform discharges and slowing, determined by electroencephalography (EEG) and structural mesiotemporal changes, measured with magnetic resonance imaging (MRI). We also accounted for possible effects of cancer- and immunotherapy and other centrally effective medication. There was no effect of AAB status on cognitive functioning. Although the regression models could not predict verbal and nonverbal learning capacity, structural mesiotemporal neural network alterations on T2-/fluid attenuated inversion recovery (FLAIR)-signal-weighted MRI and mesiotemporal epileptiform discharges or slowing on EEG exerted a significant impact on memory functions. In contrast, the regression model significantly predicted attentional and executive functioning with CSF white blood cell count and centrally effective medication being significant determinants. In this cohort, cognitive functioning in ALE does not depend on the AAB status. Common markers of ALE cannot predict memory functioning that only partially depends on structural and functional alterations of mesiotemporal neural networks. Common markers of ALE significantly predict attentional and executive functioning that is significantly related to centrally effective medication and CSF white blood cell count, which may point toward inflammation affecting brain regions beyond the limbic system.
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http://dx.doi.org/10.1002/hipo.23375DOI Listing
July 2021

Classification of neurological diseases using multi-dimensional cerebrospinal fluid analysis.

Brain 2021 Apr 12. Epub 2021 Apr 12.

Department of Neurology with Institute of Translational Neurology, University and University Hospital Münster, Münster, Germany.

Although cerebrospinal fluid (CSF) analysis routinely enables diagnosis of neurological diseases, it is mainly used for gross distinction between infectious, autoimmune inflammatory, and degenerative central nervous system (CNS) disorders. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analyzed 546 patients with autoimmune neuro-inflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters altered across all autoimmune neuro-inflammatory CNS-diseases and differentiating them from other neurological conditions and inter-autoimmunity classifiers sub-differentiating variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist classification of neurological patients. Overall, we show that an integrated analysis of blood and CSF parameters improves differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.
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http://dx.doi.org/10.1093/brain/awab147DOI Listing
April 2021

Cross-reactivity of a pathogenic autoantibody to a tumor antigen in GABA receptor encephalitis.

Proc Natl Acad Sci U S A 2021 Mar;118(9)

Institute of Clinical Neuroimmunology, Biomedical Center and Hospital of the Ludwig-Maximilians-Universität München, D-82152 Martinsried, Germany;

Encephalitis associated with antibodies against the neuronal gamma-aminobutyric acid A receptor (GABA-R) is a rare form of autoimmune encephalitis. The pathogenesis is still unknown but autoimmune mechanisms were surmised. Here we identified a strongly expanded B cell clone in the cerebrospinal fluid of a patient with GABA-R encephalitis. We expressed the antibody produced by it and showed by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry that it recognizes the GABA-R. Patch-clamp recordings revealed that it tones down inhibitory synaptic transmission and causes increased excitability of hippocampal CA1 pyramidal neurons. Thus, the antibody likely contributed to clinical disease symptoms. Hybridization to a protein array revealed the cross-reactive protein LIM-domain-only protein 5 (LMO5), which is related to cell-cycle regulation and tumor growth. We confirmed LMO5 recognition by immunoprecipitation and ELISA and showed that cerebrospinal fluid samples from two other patients with GABA-R encephalitis also recognized LMO5. This suggests that cross-reactivity between GABA-R and LMO5 is frequent in GABA-R encephalitis and supports the hypothesis of a paraneoplastic etiology.
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http://dx.doi.org/10.1073/pnas.1916337118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936355PMC
March 2021

CD8 T-Lymphocyte-Driven Limbic Encephalitis Results in Temporal Lobe Epilepsy.

Ann Neurol 2021 04 15;89(4):666-685. Epub 2021 Jan 15.

Section for Translational Epilepsy Research, Department of Neuropathology, University Hospital Bonn, Bonn, Germany.

Objective: Limbic encephalitis (LE) comprises a spectrum of inflammatory changes in affected brain structures including the presence of autoantibodies and lymphoid cells. However, the potential of distinct lymphocyte subsets alone to elicit key clinicopathological sequelae of LE potentially inducing temporal lobe epilepsy (TLE) with chronic spontaneous seizures and hippocampal sclerosis (HS) is unresolved.

Methods: Here, we scrutinized pathogenic consequences emerging from CD8 T cells targeting hippocampal neurons by recombinant adeno-associated virus-mediated expression of the model-autoantigen ovalbumin (OVA) in CA1 neurons of OT-I/RAG1 mice (termed "OVA-CD8 LE model").

Results: Viral-mediated antigen transfer caused dense CD8 T cell infiltrates confined to the hippocampal formation starting on day 5 after virus transduction. Flow cytometry indicated priming of CD8 T cells in brain-draining lymph nodes preceding hippocampal invasion. At the acute model stage, the inflammatory process was accompanied by frequent seizure activity and impairment of hippocampal memory skills. Magnetic resonance imaging scans at day 7 of the OVA-CD8 LE model revealed hippocampal edema and blood-brain barrier disruption that converted into atrophy until day 40. CD8 T cells specifically targeted OVA-expressing, SIINFEKL-H-2K -positive CA1 neurons and caused segmental apoptotic neurodegeneration, astrogliosis, and microglial activation. At the chronic model stage, mice exhibited spontaneous recurrent seizures and persisting memory deficits, and the sclerotic hippocampus was populated with CD8 T cells escorted by NK cells.

Interpretation: These data indicate that a CD8 T-cell-initiated attack of distinct hippocampal neurons is sufficient to induce LE converting into TLE-HS. Intriguingly, the role of CD8 T cells exceeds neurotoxic effects and points to their major pathogenic role in TLE following LE. ANN NEUROL 2021;89:666-685.
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http://dx.doi.org/10.1002/ana.26000DOI Listing
April 2021

Blood and cerebrospinal fluid immune cell profiles in patients with temporal lobe epilepsy of different etiologies.

Epilepsia 2020 10 7;61(10):e153-e158. Epub 2020 Sep 7.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Inflammation plays a role in the pathogenesis of immune-mediated epilepsy, but also in epilepsy of other etiology such as hippocampal sclerosis. This study aimed to characterize immune cell signatures in the peripheral blood (PB) and cerebrospinal fluid (CSF) in temporal lobe epilepsy (TLE) of different etiologies. We retrospectively evaluated CSF routine parameters and immune cell profiles using flow cytometry in a cohort of 51 patients and 45 age-matched controls with functional disorders. Groups were comprised of patients with nonlesional TLE (n = 26), TLE due to hippocampal sclerosis (n = 14), or limbic encephalitis with antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65-LE; n = 11). TLE patients showed increased proportions of human leukocyte antigen-DR isotype (HLA-DR)-expressing CD4 T lymphocytes in the CSF. Furthermore, they were characterized by a shift in monocyte subsets toward immature CD14 CD16 cells in the PB and blood/CSF-barrier dysfunction. Whereas TLE patients in general showed similar immune cell profiles, patients with GAD65-LE differed from other TLE patients by increased proportions of HLA-DR-expressing CD8 T lymphocytes and type 2/3 oligoclonal bands. These findings point to a role of innate and adaptive immunity in TLE. CSF parameters may help to discriminate epilepsy patients from controls and different forms of TLE from each other.
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http://dx.doi.org/10.1111/epi.16688DOI Listing
October 2020

Lateralized Deficits of Disgust Processing After Insula-Basal Ganglia Damage.

Front Psychol 2020 30;11:1429. Epub 2020 Jun 30.

Institute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.

A growing body of evidence suggests a role of the insular cortex (IC) and the basal ganglia (BG) in the experience, expression, and recognition of disgust. However, human lesion research, probing this structure-function link, has yielded rather disparate findings in single cases of unilateral and bilateral damage to these areas. Comparative group approaches are needed to elucidate whether disgust-related deficits specifically follow damage to the IC-BG system, or whether there might be a differential hemispheric contribution to disgust processing. We examined emotional processing by means of a comprehensive emotional test battery in four patients with left- and four patients with right-hemispheric lesions to the IC-BG system as well as in 19 healthy controls. While single tests did not provide clear-cut separations of patient groups, composite scores indicated selective group effects for disgust. Importantly, left-lesioned patients presented attenuated disgust composites, while right-lesioned patients showed increased disgust composites, as compared to each other and controls. These findings propose a left-hemispheric basis of disgust, potentially due to asymmetrical representations of autonomic information in the human forebrain. The present study provides the first behavioral evidence of hemispheric lateralization of a specific emotion in the human brain, and contributes to neurobiological models of disgust.
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http://dx.doi.org/10.3389/fpsyg.2020.01429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347022PMC
June 2020

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome.

J Neurol 2020 Jul 3;267(7):2101-2114. Epub 2020 Apr 3.

Society of Epilepsy Research, Bielefeld, Germany.

Objective: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions.

Methods: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters.

Results: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention.

Conclusions: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.
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http://dx.doi.org/10.1007/s00415-020-09814-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213550PMC
July 2020

An expanded parenchymal CD8+ T cell clone in GABA receptor encephalitis.

Ann Clin Transl Neurol 2020 02 14;7(2):239-244. Epub 2020 Jan 14.

Institute of Clinical Neuroimmunology, Biomedical Center and Hospital of the Ludwig-Maximilians Universität München, Munich, Germany.

The role of T cells in autoimmune encephalitis syndromes with autoantibodies against cell surface antigens is still enigmatic. Here we analyzed the T cell receptor repertoires of CD8+ and CD4+ T cells in a patient with "idiopathic" gamma-aminobutyric-acid-A receptor (GABA -R) encephalitis by next-generation sequencing and single-cell analyses. We identified a CD8+ T cell clone that was strongly expanded in the cerebrospinal fluid and in the hippocampus but not in the operculo-insular cortex. By contrast, CD4+ T cells were polyclonal in these tissues. Such a strong clonal expansion suggests that CD8+ T cells may play a significant role in the pathogenesis.
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http://dx.doi.org/10.1002/acn3.50974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034500PMC
February 2020

Comparing Plasma Exchange to Escalated Methyl Prednisolone in Refractory Multiple Sclerosis Relapses.

J Clin Med 2019 Dec 22;9(1). Epub 2019 Dec 22.

Neurology Clinic and Institute for Translational Neurology, University of Muenster, 48149 Münster, Germany.

Intravenous methyl prednisolone (IVMPS) represents the standard of care for multiple sclerosis (MS) relapses, but fail to improve symptoms in one quarter of patients. In this regard, apart from extending steroid treatment to a higher dose, therapeutic plasma exchange (TPE) has been recognized as a treatment option. The aim of this retrospective, monocentric study was to investigate the efficacy of TPE versus escalated dosages of IVMPS in refractory MS relapses. An in-depth medical chart review was performed to identify patients from local databases. Relapse recovery was stratified as "good/full", "average" and "worst/no" according to function score development. In total, 145 patients were analyzed. Good/average/worst recovery at discharge was observed in 60.9%/32.6%/6.5% of TPE versus 15.2%/14.1%/70.7% of IVMPS patients, respectively. A total of 53.5% of IVMPS patients received TPE as rescue treatment and 54.8% then responded satisfactorily. The multivariable odds ratio (OR) for worst/no recovery was 39.01 (95%-CI: 10.41-146.18; ≤ 0.001), favoring administration of TPE as first escalation treatment. The effects were sustained at three-month follow-ups, as OR for further deterioration was 6.48 (95%-CI: 2.48-16.89; ≤ 0.001), favoring TPE. In conclusion, TPE was superior over IVMPS in the amelioration of relapse symptoms at discharge and follow-up. This study provides class IV evidence supporting the administration of TPE as the first escalation treatment to steroid-refractory MS relapses.
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http://dx.doi.org/10.3390/jcm9010035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027010PMC
December 2019

Low CSF CD4/CD8+ T-cell proportions are associated with blood-CSF barrier dysfunction in limbic encephalitis.

Epilepsy Behav 2020 01 14;102:106682. Epub 2019 Dec 14.

Department of Epileptology, University of Bonn Medical Center, Venusberg - Campus 1, 53127 Bonn, Germany.

Purpose: Investigating immune cells in autoimmune limbic encephalitis (LE) will contribute to our understanding of its pathophysiology and may help to develop appropriate therapies. The aim of the present study was to analyze immune cells to reveal underlying immune signatures in patients with temporal lobe epilepsy (TLE) with LE.

Methods: We investigated 68 patients with TLE with LE compared with 7 control patients with TLE with no signs of LE screened from 154 patients with suspected LE. From the patients with TLE-LE, we differentiated early seizure onset (<20 years, n = 9) and late seizure onset group (≥20 years, n = 59) of patients. Patients underwent neuropsychological assessment, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and peripheral blood (PB) and cerebrospinal fluid (CSF) analysis including flow cytometry.

Results: We identified a higher CD4/8+ T-cell ratio in the PB in all patients with TLE-LE and in patients with late-onset TLE-LE each compared with controls (Kruskal-Wallis one-way ANOVA (analysis of variance) with Dunn's test, p < 0.05). Moreover, a lower CD4/CD8+ T-cell ratio is detected in all patients with TLE-LE with blood-CSF barrier dysfunction, unlike in those with none (Kruskal-Wallis one-way ANOVA with Dunn's test, p < 0.05).

Conclusions: These findings suggest that the proportion of CD4+ and CD8+ T-cells in the CSF of patients with LE associated with blood-CSF barrier dysfunction plays a potential role in CNS (central nervous system) inflammation in these patients. Thus, flow cytometry as a methodology reveals novel insights into LE's genesis and symptomatology. The CD4/8+ T-cell ratio in PB as a biomarker for LE requires further investigation.
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http://dx.doi.org/10.1016/j.yebeh.2019.106682DOI Listing
January 2020

Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis.

Ann Clin Transl Neurol 2019 12 4;6(12):2586-2594. Epub 2019 Nov 4.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.

Allelic variants of genes encoding for the Fc gamma receptors IIIA and IIA have been associated with the clinical response to cell-depleting antibodies in lymphoma patients. Here, we tested the hypothesis that FCGR3A and FCGR2A high-affinity polymorphisms predict clinical outcomes to alemtuzumab therapy in 85 patients with relapsing-remitting multiple sclerosis. No differences in clinical and MRI-based efficacy parameters, the development of severe infusion-associated reactions and secondary autoimmune diseases during a 2 year follow-up was observed based on FCGR3A or FCGR2A polymorphisms. This study does not support the use of FCGR genetic variants to predict clinical outcomes to alemtuzumab.
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http://dx.doi.org/10.1002/acn3.50935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917309PMC
December 2019

Therapeutic Apheresis in Acute Relapsing Multiple Sclerosis: Current Evidence and Unmet Needs-A Systematic Review.

J Clin Med 2019 Oct 4;8(10). Epub 2019 Oct 4.

Department of Neurology with Institute of Translational Neurology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.

Multiple sclerosis (MS) is the most abundant inflammatory demyelinating disorder of the central nervous system. Despite recent advances in its long-term immunomodulatory treatment, MS patients still suffer from relapses, significantly contributing to disability accrual. In recent years, apheresis procedures such as therapeutic plasma exchange (TPE) and immunoadsorption (IA) have been recognized as two options for treating MS relapses, that do not respond to standard treatment with corticosteroids. TPE is already incorporated in most international guidelines, although evidence for its use resulted mostly from either case series or small unblinded and/or non-randomized trials. Data on IA are still sparse, but several studies indicate comparable efficacy between both apheresis procedures. This article gives an overview of the published evidence on TPE and IA in the treatment of acute relapses in MS. Further, we outline current evidence regarding individual outcome predictors, describe technical details of apheresis procedures, and discuss apheresis treatment in children and during pregnancy.
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http://dx.doi.org/10.3390/jcm8101623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832170PMC
October 2019

Seizures and epilepsy in multiple sclerosis: epidemiology and prognosis in a large tertiary referral center.

J Neurol 2019 Jul 8;266(7):1789-1795. Epub 2019 May 8.

Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany.

Background: Seizures and epilepsy may substantially add to the burden of disease in multiple sclerosis (MS), whereas the exact prevalence and prognosis of seizures and epilepsy in patients with MS remains largely unknown.

Objectives: We aimed to investigate the epidemiology and prognosis of seizures and epilepsy in MS.

Methods: We retrospectively analyzed a cohort of 4078 MS patients from a single tertiary referral clinic.

Results: After excluding 37 patients with unconfirmed MS and alternative seizure etiologies, we found seizures attributable to MS in 1.5% and epilepsy in 0.9% of patients. 40.4% of patients with a follow-up of at least twelve months experienced only a single seizure and 59.6% had recurring seizures. 39% of patients with recurrent seizures were considered drug-resistant, with 9.7% experiencing status epilepticus. Seizure recurrence after a first seizure depended significantly on the MS subtype and was seen more often if the first seizure occurred simultaneously with a MS relapse than in the absence of a relapse.

Conclusion: Our study shows a lower number of seizures and epilepsy in MS than previously reported. While a single seizure in MS usually has a good prognosis, relapse-associated seizures and established epilepsy in MS may not be as benign as previously assumed.
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http://dx.doi.org/10.1007/s00415-019-09332-xDOI Listing
July 2019

An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephalitis.

Front Neurol 2019 1;10:178. Epub 2019 Mar 1.

Department of Neurology, University of Muenster, Muenster, Germany.

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This has been deemed to represent the predominant antibody effector mechanism depleting the NMDAR from the synaptic and extra-synaptic neuronal cell membrane. To assess in detail the molecular mechanisms of autoantibody-induced NMDAR endocytosis, vesicular trafficking, and exocytosis we transiently co-expressed rat GluN1-1a-EGFP and GluN2B-ECFP alone or together with scaffolding postsynaptic density protein 95 (PSD-95), wild-type (WT), or dominant-negative (DN) mutant Ras-related in brain (RAB) proteins (RAB5WT, RAB5DN, RAB11WT, RAB11DN) in HEK 293T cells. The cells were incubated with a pH-rhodamine-labeled human recombinant monoclonal GluN1 IgG1 autoantibody (GluN1-aAb) genetically engineered from clonally expanded intrathecal plasma cells from a patient with anti-NMDAR encephalitis, and the pH-rhodamine fluorescence was tracked over time. We show that due to the acidic luminal pH, internalization of the NMDAR-autoantibody complex into endosomes and lysosomes increases the pH-rhodamine fluorescence. The increase in fluorescence allows for mechanistic assessment of endocytosis, vesicular trafficking in these vesicular compartments, and exocytosis of the NMDAR-autoantibody complex under steady state conditions. Using this method, we demonstrate a role for PSD-95 in stabilization of NMDARs in the cell membrane in the presence of GluN1-aAb, while RAB proteins did not exert a significant effect on vertical trafficking of the internalized NMDAR autoantibody complex in this heterologous expression system. This novel assay allows to unravel molecular mechanisms of autoantibody-induced receptor internalization and to study novel small-scale specific molecular-based therapies for autoimmune encephalitis syndromes.
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http://dx.doi.org/10.3389/fneur.2019.00178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405626PMC
March 2019

Understanding the burden of refractory myasthenia gravis.

Ther Adv Neurol Disord 2019 1;12:1756286419832242. Epub 2019 Mar 1.

University of Münster, Münster, Germany.

Myasthenia gravis (MG) is an autoantibody-mediated disease that compromises the acetylcholine receptors or associated structures of the postsynaptic membrane of the neuromuscular junction. This leads to impaired neuromuscular transmission and subsequent fluctuating fatigability and weakness of ocular, bulbar, and limb skeletal muscles. Over the past few decades, there have been significant advances in our understanding of the disease pathophysiology and improvements in prognosis due to intensive care medicine and immunomodulation. Despite this, an estimated 10-20% of patients with MG do not achieve an adequate response, are intolerant to conventional treatment, or require chronic treatment with intravenous immunoglobulins or plasma separation procedures. Such patients are regarded as having MG that is 'refractory' to treatment and may represent a distinct clinical subgroup. Because the majority of patients with MG have well-controlled disease, the burden of illness in the minority with refractory disease is poorly understood and may be underestimated. However, clinically these patients are liable to experience extreme fatigue, considerable disability owing to uncontrolled symptoms, and frequent myasthenic crises and hospitalizations. Both acute adverse effects and an increased risk of comorbidity from treatment regimens may contribute to reduced quality of life. As yet, little is known concerning the impact of refractory MG on mental health and health-related quality of life. This review aims to highlight the burden of disease and unmet needs in patients with refractory MG.
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http://dx.doi.org/10.1177/1756286419832242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399761PMC
March 2019

Management and prognostic markers in patients with autoimmune encephalitis requiring ICU treatment.

Neurol Neuroimmunol Neuroinflamm 2019 01 30;6(1):e514. Epub 2018 Oct 30.

Hans-Berger-Department of Neurology (J.S., D.B., C.G., O.W.W., A.G.), Jena University Hospital; Department of Neurology (H.B.H., S.T.G.), University Hospital Erlangen; Department of Neurology and Neurophysiology (H.F), University Hospital Freiburg; Department of Neurology (N.M., A.D.), University Hospital Münster; Department of Neurology (H.P., L.-T.L), Charité University Medicine Berlin; Department of Neurology (K.F.), Bezirksklinikum Regensburg; Neuroimmunology Section (F.L., G.N.), Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig-Holstein, Kiel; Department of Neurology (I.S.), University Hospital Giessen; Center for Neurology and Psychiatrics (C.D.), University Hospital Köln; Department of Neurology (J.B.), University Hospital Heidelberg; Department of Neurology (J.B.), Klinikum Kassel; Department of Neurology (J.L.), University Hospital Ulm; Institute of Clinical Neuroimmunology (F.T.), Ludwig-Maximillians-University München; Department of Neurology (A.K.), Martha Maria Hospital Halle; Department of Neurology (A.J.), Dortmund Hospital; Department of Neurology (M.R.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (K.-W.S.), University Hospital Hannover; Department of Neurology (C.U.), Hospital Ludwigshafen; Institute of Medical Statistics, Computer and Data Sciences (A.S), Jena University Hospital; and Center for Sepsis Control and Care (A.S., C.G.), Jena University Hospital, Germany.

Objective: To assess intensive care unit (ICU) complications, their management, and prognostic factors associated with outcomes in a cohort of patients with autoimmune encephalitis (AE).

Methods: This study was an observational multicenter registry of consecutively included patients diagnosed with AE requiring Neuro-ICU treatment between 2004 and 2016 from 18 tertiary hospitals. Logistic regression models explored the influence of complications, their management, and diagnostic findings on the dichotomized (0-3 vs 4-6) modified Rankin Scale score at hospital discharge.

Results: Of 120 patients with AE (median age 43 years [interquartile range 24-62]; 70 females), 101 developed disorders of consciousness, 54 autonomic disturbances, 42 status epilepticus, and 39 severe sepsis. Sixty-eight patients were mechanically ventilated, 85 patients had detectable neuronal autoantibodies, and 35 patients were seronegative. Worse neurologic outcome at hospital discharge was associated with necessity of mechanical ventilation (sex- and age-adjusted OR 6.28; 95% CI, 2.71-15.61) tracheostomy (adjusted OR 6.26; 95% CI, 2.68-15.73), tumor (adjusted OR 3.73; 95% CI, 1.35-11.57), sepsis (adjusted OR 4.54; 95% CI, 1.99-10.43), or autonomic dysfunction (adjusted OR 2.91; 95% CI, 1.24-7.3). No significant association was observed with autoantibody type, inflammatory changes in CSF, or pathologic MRI.

Conclusion: In patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.
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http://dx.doi.org/10.1212/NXI.0000000000000514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278855PMC
January 2019

Primary B Cell Lymphoma of the CNS Mimicking Anti-LGI1 Limbic Encephalitis.

Front Neurol 2018 10;9:658. Epub 2018 Aug 10.

Clinic of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Limbic encephalitis is a potentially paraneoplastic type of encephalitis mainly involving the limbic system. Recently, diagnostic criteria comprising clinical presentation as well as imaging, laboratory and electrophysiological findings have been established. Here, we show that incipient primary central nervous system lymphoma can closely resemble limbic encephalitis including positive testing for anti-LGI1 antibodies illustrating the need for thorough interpretation of initial laboratory and radiologic findings and tight follow-up examinations.
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http://dx.doi.org/10.3389/fneur.2018.00658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095976PMC
August 2018

Onconeural antigen spreading in paraneoplastic neurological disease due to small cell lung cancer.

Oxf Med Case Reports 2018 Jul 9;2018(7):omy034. Epub 2018 Jul 9.

Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, Münster, Germany.

Cellular and humoral immunity towards distinct onconeural antigens is the hallmark of paraneoplastic neurological diseases (PNDs). Stable formation of immunoglobulin (Ig) G antibodies to particular onconeural antigens occurs in the majority of cases, whereas persistent coexistence of antibodies specific for multiple onconeural antigens is a relatively rare phenomenon of certain malignant tumors like small cell lung cancer (SCLC). We here describe onconeural antigen spreading in a 70-year-old Caucasian male with PND due to SCLC. Onconeural antigen spreading may be promoted by two mutually non-exclusive mechanisms: (i) a switch of antigen expression pattern of the underlying tumor tissue as a result of a mutagenic process caused by the cancer itself and (ii) a self-propagated paraneoplastic immune response with persistent neuronal destruction, liberation, processing and presentation of intracellular neural antigens. This illustrates a potential dissociation between peripheral anti-tumoral immunity and central anti-neural immunity during the course of PND.
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http://dx.doi.org/10.1093/omcr/omy034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037119PMC
July 2018

Immune cell profiling in the cerebrospinal fluid of patients with primary angiitis of the central nervous system reflects the heterogeneity of the disease.

J Neuroimmunol 2018 08 7;321:109-116. Epub 2018 Jun 7.

Clinic of Neurology with Institute of Translational Neurology, University Hospital Münster, University Münster, 48149 Münster, Germany. Electronic address:

Primary angiitis of the central nervous system (PACNS) is a rare and heterogeneous inflammatory disease of the CNS vasculature with poorly understood pathophysiology. Comprehensive immune-cell phenotyping revealed increased frequencies of leukocytes in the cerebrospinal fluid (CSF) of PACNS patients compared to patients with multiple sclerosis, ischemic stroke, and somatoform disorders (n = 18 per group). Changes in the intrathecal immune-cell profile were heterogeneous in PACNS. While proportions of T-cell subsets remained unaltered, some PACNS patients showed a shift toward NK- or B cells. Intrathecal immunoglobulin synthesis was observed in a subgroup of PACNS patients with an increased frequency of antibody producing plasma cells.
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http://dx.doi.org/10.1016/j.jneuroim.2018.06.004DOI Listing
August 2018

Amygdala enlargement and emotional responses in (autoimmune) temporal lobe epilepsy.

Sci Rep 2018 06 22;8(1):9561. Epub 2018 Jun 22.

Institute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.

Temporal lobe epilepsy with amygdala enlargement (TLE-AE) is increasingly recognized as a distinct adult electroclinical syndrome. However, functional consequences of morphological alterations of the amygdala in TLE-AE are poorly understood. Here, two emotional stimulation designs were employed to investigate subjective emotional rating and skin conductance responses in a sample of treatment-naïve patients with suspected or confirmed autoimmune TLE-AE (n = 12) in comparison to a healthy control group (n = 16). A subgroup of patients completed follow-up measurements after treatment. As compared to healthy controls, patients with suspected or confirmed autoimmune TLE-AE showed markedly attenuated skin conductance responses and arousal ratings, especially pronounced for anxiety-inducing stimuli. The degree of right amygdala enlargement was significantly correlated with the degree of autonomic arousal attenuation. Furthermore, a decline of amygdala enlargement following prompt aggressive immunotherapy in one patient suffering from severe confirmed autoimmune TLE-AE with a very recent clinical onset was accompanied by a significant improvement of autonomic responses. Findings suggest dual impairments of autonomic and cognitive discrimination of stimulus arousal as hallmarks of emotional processing in TLE-AE. Emotional responses might, at least partially, recover after successful treatment, as implied by first single case data.
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http://dx.doi.org/10.1038/s41598-018-27914-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015084PMC
June 2018

Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.

Ann Neurol 2018 04;83(4):863-869

Department of Neurology, Christian-Albrechts-University Kiel, Germany.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.
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http://dx.doi.org/10.1002/ana.25216DOI Listing
April 2018

Accelerated long-term forgetting in focal epilepsies with special consideration given to patients with diagnosed and suspected limbic encephalitis.

Cortex 2019 01 31;110:58-68. Epub 2018 Jan 31.

Department of Epileptology, University of Bonn Medical Center, Bonn, Germany.

Rationale: Accelerated long-term forgetting (ALF) is a phenomenon found in late onset epilepsy and in transient epileptic amnesia (TEA). Here we evaluated ALF in patients with focal epilepsies and limbic encephalitis (LE) in particular.

Methods: ALF was assessed in 36 patients with focal epilepsy and 154 healthy subjects using an extended version of the Verbal Learning and Memory Test (VLMT), with free recall after 30 min and again after one week. From these patients, 89% had temporal lobe epilepsy; 42% left-lateralized; 39% right; 19% bilateral; 17% were diagnosed with hippocampal sclerosis; 64% displayed features indicating LE; 52% with amygdala pathology, and 61% were antibody positive. ALF was defined as either having unimpaired free recall after 30 min and impaired recall after a week (A) or as a loss in recall exceeding the absolute (B) and percentage loss (C) in the interval of the 30 min and one week recall seen in controls by more than one standard deviation.

Results: Repeated measures analysis revealed an association between LE and ALF. Depending on its definition (A, B, or C), ALF was evident in 31%, 42%, or 67% of the patients. Poor verbal memory and ALF (C) were prominent in left-lateralized epilepsies. ALF (A) appeared more frequently in auto-antibody negative patients with LE, ALF (B) less frequently with hippocampal sclerosis. Seizures during the interval did not explain ALF.

Conclusion: Depending on its definition, ALF is seen in patients with normal or impaired memory at ½ h. ALF seems related to LE but might as well be the first sign of memory impairment in patients with milder epilepsies and not yet definite structural temporal lobe pathology. Longitudinal assessment would be essential for discerning when ALF becomes evident, whether conditions exist in which ALF precedes short-term forgetting, and whether ALF responds to treatment.
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http://dx.doi.org/10.1016/j.cortex.2018.01.003DOI Listing
January 2019

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody.

Ann Clin Transl Neurol 2017 11 3;4(11):768-783. Epub 2017 Oct 3.

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany.

Objective: Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form.

Methods: Patients with recent onset typical anti-NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light-chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.

Results: Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.

Interpretation: A CNS-specific humoral immune response is present in anti-NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti-NMDAR encephalitis as a humorally mediated autoimmune disease.
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http://dx.doi.org/10.1002/acn3.444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682115PMC
November 2017

Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy-Mitochondria, Calcium Dynamics and Reactive Oxygen Species.

Int J Mol Sci 2017 Sep 8;18(9). Epub 2017 Sep 8.

Department of Neurology, University of Münster, 48149 Münster, Germany.

Acquired epilepsies can arise as a consequence of brain injury and result in unprovoked seizures that emerge after a latent period of epileptogenesis. These epilepsies pose a major challenge to clinicians as they are present in the majority of patients seen in a common outpatient epilepsy clinic and are prone to pharmacoresistance, highlighting an unmet need for new treatment strategies. Metabolic and homeostatic changes are closely linked to seizures and epilepsy, although, surprisingly, no potential treatment targets to date have been translated into clinical practice. We summarize here the current knowledge about metabolic and homeostatic changes in seizures and acquired epilepsy, maintaining a particular focus on mitochondria, calcium dynamics, reactive oxygen species and key regulators of cellular metabolism such as the Nrf2 pathway. Finally, we highlight research gaps that will need to be addressed in the future which may help to translate these findings into clinical practice.
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http://dx.doi.org/10.3390/ijms18091935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618584PMC
September 2017

Treating refractory post-herpetic anti--methyl-d-aspartate receptor encephalitis with rituximab.

Oxf Med Case Reports 2017 Jul 3;2017(7):omx034. Epub 2017 Jul 3.

Department of Neurology, University of Münster, Münster, Germany.

Herpes simplex virus-1 has been identified as the trigger factor in certain cases of NMDA-receptor autoimmune encephalitis. We report on a 67-year-old female patient, who was severely affected by post-herpetic NMDA-receptor autoimmune encephalitis. Her symptoms did not improve under methylprednisolone pulse therapy and plasma exchange under acyclovir prophylaxis. She received protein A immunoadsorption and a long-term immunosuppression with rituximab. Under treatment, activated T-cells as well as B- and plasma cells decreased in peripheral blood and cerebrospinal fluid, and anti-NMDA-R IgG titers in serum and cerebrospinal fluid declined with near complete cessation of intrathecal autoantibody synthesis. The patient regained near complete independence and profoundly improved on formal neuropsychological assessment. Despite reduction of antiviral defense through of lowered activated T cells and concomitantly decreasing HSV-specific IgG antibodies, no evidence of viral reactivation was detected.
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http://dx.doi.org/10.1093/omcr/omx034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495011PMC
July 2017

Natalizumab-associated PML: Challenges with incidence, resulting risk, and risk stratification.

Neurology 2017 Mar 22;88(12):1197-1205. Epub 2017 Feb 22.

From the Department of Neurology (N.S., T.S.-H., N.M., H.W.), University of Münster, Germany; and University of Alabama School of Public Health (G.C.), Birmingham.

Progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment continues to be a severe problem of clinically successful therapy. This is an update of risk stratification developments and discusses the current approach to depict and calculate PML incidence and PML risk. (1) PML incidence and resulting risk used in today's clinical practice are potentially outdated and the risk for patients with prior immunosuppression might have been underestimated. (2) Risk stratification according to treatment duration epochs likely suggests lower risk due to patients stopping treatment within a given epoch. PML incidence within the complete treatment epoch is statistically lowered due to the fact that patients at the beginning of an epoch presumably have a lower PML risk than the patients at the end. Periodic risk is not accurate in assessing risk for long treatment durations. (3) The JC virus (JCV) serostatus risk factor has low specificity concerning PML prediction and anti-JCV seroconversion during treatment with natalizumab further lowers its specificity over time. Specificity of the risk factor treatment duration varies depending on the average treatment duration and the number of short-term patients. These short-term patients reduce overall average treatment duration and thus enhance the specificity of the risk factor and reduce overall PML incidence. It is also suggested that short-term natalizumab patients are exclusively non-PML, even though they might still develop PML. Clinicians have to consider the cumulative risk of patients to stratify efficiently.
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http://dx.doi.org/10.1212/WNL.0000000000003739DOI Listing
March 2017

Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.

Neurol Neuroimmunol Neuroinflamm 2017 Jan 5;4(1):e307. Epub 2016 Dec 5.

Institute of Experimental Immunology (R.M., M. Scharf, I.M.D., S.M., Y.D., B.T., C.P., S.B., W.S., L.K.), Euroimmun AG, Lübeck; Department of Neurology (C.C.G., K.S.G., M.H., U.B., A.S.-M., K.B., C.S., H.L., M.D., T.W., H.W., S.G.M., N.M.), University of Münster; Centre for Neurology and Hertie-Institute for Clinical Brain Research (L.S., M. Synofzik), Tübingen; German Center for Neurodegenerative Diseases (DZNE) (L.S., M. Synofzik), Tübingen; and Institute of Clinical Chemistry and Department of Neurology (K.-P.W.), University Hospital of Schleswig-Holstein, Lübeck, Germany.

Objective: To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration.

Methods: Three patients with subacute to chronic cerebellar ataxia and controls underwent detailed clinical and neuropsychological assessment together with quantitative high-resolution structural MRI. Sera and CSF were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IFA) and immunoblot. Immunoprecipitation with lysates of hippocampus and cerebellum combined with mass spectrometric analysis was used to identify the autoantigen, which was verified by recombinant expression in HEK293 cells and use in several immunoassays. Multiparameter flow cytometry was performed on peripheral blood and CSF, and peripheral blood was subjected to T-cell receptor spectratyping.

Results: Patients presented with a subacute to chronic cerebellar and brainstem syndrome. MRI was consistent with cortical and cerebellar gray matter atrophy associated with subsequent neuroaxonal degeneration. IFA screening revealed strong immunoglobulin G1 reactivity in sera and CSF with hippocampal and cerebellar molecular and granular layers, but not with a panel of 30 recombinantly expressed established neural autoantigens. Neurochondrin was subsequently identified as the target antigen, verified by IFA and immunoblot with HEK293 cells expressing human neurochondrin as well as the ability of recombinant neurochondrin to neutralize the autoantibodies' tissue reaction. Immune phenotyping revealed intrathecal accumulation and activation of B and T cells during the acute but not chronic phase of the disease. T-cell receptor spectratyping suggested an antigen-specific T-cell response accompanying the formation of antineurochondrin autoantibodies. No such neurochondrin reactivity was found in control cohorts of various neural autoantibody-associated neurologic syndromes, relapsing-remitting multiple sclerosis, cerebellar type of multiple system atrophy, hereditary cerebellar ataxias, other neurologic disorders, or healthy donors.

Conclusion: Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration.
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http://dx.doi.org/10.1212/NXI.0000000000000307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141526PMC
January 2017

Isolated dysphagia as initial sign of anti-IgLON5 syndrome.

Neurol Neuroimmunol Neuroinflamm 2017 Jan 22;4(1):e302. Epub 2016 Nov 22.

Division of Sleep Medicine and Neuromuscular Disorders (A.H.), Department of Neurology (J.B.S., N.M., T.R., A.H., I.K., R.D., P.M., T.W., R.D.), University of Münster, Germany.

Objective: To report on dysphagia as initial sign in a case of anti-IgLON5 syndrome and provide an overview of the current literature.

Methods: The diagnostic workup included cerebral MRI, fiber optic endoscopic evaluation of swallowing (FEES) with the FEES tensilon test, a videofluoroscopic swallowing study, evoked potentials and peripheral nerve conduction studies, polysomnography, lumbar puncture, and screening for neural autoantibodies. A systematic review of all published cases of IgLON5 syndrome is provided.

Results: We report a case of anti-IgLON5 syndrome presenting with slowly progressive neurogenic dysphagia. FEES revealed severe neurogenic dysphagia and bilateral palsy of the vocal cords. Autoantibody screening was positive for IgLON5 IgG (+++, 1:1,000) serum levels but no other known neural autoantibody. Polysomnography was highly suggestive of non-REM parasomnia. Symptoms were partially responsive to immunotherapy.

Conclusions: Slowly progressive neurogenic dysphagia may occur as initial sign of anti-IgLON5 syndrome highlighting another clinical presentation of this rare disease.
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http://dx.doi.org/10.1212/NXI.0000000000000302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120591PMC
January 2017