Publications by authors named "Andreas Lutterotti"

52 Publications

Antigen-Specific Immune Tolerance in Multiple Sclerosis-Promising Approaches and How to Bring Them to Patients.

Front Immunol 2021 22;12:640935. Epub 2021 Mar 22.

Neuroimmunology and MS Research Section, Neurology Clinic, University Hospital Zurich & University of Zurich, Zurich, Switzerland.

Antigen-specific tolerance induction aims at treating multiple sclerosis (MS) at the root of its pathogenesis and has the prospect of personalization. Several promising tolerization approaches using different technologies and modes of action have already advanced to clinical testing. The prerequisites for successful tolerance induction include the knowledge of target antigens, core pathomechanisms, and how to pursue a clinical development path that is distinct from conventional drug development. Key aspects including patient selection, outcome measures, demonstrating the mechanisms of action as well as the positioning in the rapidly growing spectrum of MS treatments have to be considered to bring this therapy to patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.640935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019937PMC
March 2021

Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS.

Neurol Neuroimmunol Neuroinflamm 2021 03 1;8(2). Epub 2021 Mar 1.

From Neuroimmunology and MS Research (nims) (M.P., P.T.-O., A.L., I.J., M.Z., C.C., W.F., R.M., M.S.), Department of Neurology, University Hospital and University Zurich, Switzerland; Department of Neuroscience DNS (M.P.), University Hospital of Padova, Italy; and Institute for Clinical Chemistry (T.H., A.H.), University Hospital and University Zurich, Switzerland.

Objective: CNS damage can increase the susceptibility of the blood-brain barrier (BBB) to changes induced by systemic inflammation. The aim of this study is to better understand BBB permeability in patients with MS and to examine whether compromised BBB integrity in some of these patients is associated with CNS damage and systemic inflammation.

Methods: Routine CSF measurements of 121 patients with MS were analyzed including number and type of infiltrating cells, total protein, lactate, and oligoclonal bands, as well as intrathecal production of immunoglobulins and CSF/serum quotients for albumin, immunoglobulins, and glucose. In addition, in a subcohort of these patients, we performed ex vivo immunophenotyping of CSF-infiltrating and paired circulating lymphocytes using a panel of 13 monoclonal antibodies, we quantified intrathecal neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1), and we performed intrathecal lipidomic analysis.

Results: Patients with MS with abnormal high levels of albumin in the CSF showed a distinct CSF cell infiltrate and markers of CNS damage such as increased intrathecal levels of NF-L and CHI3L1 as well as a distinct CSF lipidomic profile. In addition, these patients showed higher numbers of circulating proinflammatory Th1 and Th1* cells compatible with systemic inflammation. Of interest, the abnormally high levels of albumin in the CSF of those patients were preserved over time.

Conclusions: Our results support the hypothesis that CNS damage may increase BBB vulnerability to systemic inflammation in a subset of patients and thus contribute to disease heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963437PMC
March 2021

Anti-IgLON5 Disease: A New Bulbar-Onset Motor Neuron Mimic Syndrome.

Neurol Neuroimmunol Neuroinflamm 2021 03 2;8(2). Epub 2021 Feb 2.

From the Department of Neurology (J.W., I.J., A.L., H.-H.J.), Department of Respiratory Medicine and Sleep Disorders Center (E.I.S., K.E.B.), Department of Immunology (E.P.-M., J.N.), University Hospital Zurich; Lindenhofspital (B. Schwizer), Bern; and Department of Neurology and University Zurich Institute of Experimental Immunology (B. Schreiner), University Hospital Zurich, Switzerland.

Objective: To expand the spectrum of anti-IgLON5 disease by adding 5 novel anti-IgLON5-seropositive cases with bulbar motor neuron disease-like phenotype.

Methods: We characterized the clinical course, brain MRI and laboratory findings, and therapy response in these 5 patients.

Results: Patients were severely affected by bulbar impairment and its respiratory consequences. Sleep-related breathing disorders and parasomnias were common. All patients showed clinical or electrophysiologic signs of motor neuron disease without fulfilling the diagnostic criteria for amyotrophic lateral sclerosis. One patient regained autonomy in swallowing and eating, possibly related to immunotherapy.

Conclusion: IgLON5 disease is an important differential diagnosis to evaluate in patients with bulbar motor neuron disease-like phenotype and sleep disorders. There is need for a deeper understanding of the underlying pathobiology to determine whether IgLON5 disease is an immunotherapy-responsive condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000962DOI Listing
March 2021

HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.

Cell 2020 Nov 21;183(5):1264-1281.e20. Epub 2020 Oct 21.

Neuroimmunology and MS Research, Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich 8091, Switzerland. Electronic address:

The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4 T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4 T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4 T cells in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2020.09.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707104PMC
November 2020

Large and Small Cerebral Vessel Involvement in Severe COVID-19: Detailed Clinical Workup of a Case Series.

Stroke 2020 12 15;51(12):3719-3722. Epub 2020 Oct 15.

Neuroimmunology and Multiple Sclerosis Research Section (A.L., I.J.), University Hospital and University of Zurich, Switzerland.

Background And Purpose: Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms.

Methods: We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death.

Results: Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable.

Conclusions: Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.120.031224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678671PMC
December 2020

Benralizumab in eosinophilic granulomatosis with polyangiitis complicated by Staphylococcus aureus sepsis.

Clin Immunol 2021 Jan 15;222:108574. Epub 2020 Aug 15.

Department of Immunology, University Hospital Zurich, Zurich, Switzerland. Electronic address:

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is an ANCA-associated small-vessels vasculitis characterized by hypereosinophilia and eosinophilic asthma. EGPA with life-threatening organ involvement, particularly cardiac and central nervous system (CNS), is a medical emergency requiring immediate immunosuppression. We describe a 58-year-old patient with a history of chronic rhinosinusitis and eosinophilic asthma, who presented with fever, hypereosinophilia and systemic inflammation. Diagnostic workup identified a cardiac mass, CNS vasculitis, CNS embolization and Staphylococcus aureus in blood cultures. Due to rapid normalization of blood cultures, the intracardiac mass was not considered as primarily infective. Active EGPA with cardiac and CNS involvement complicated by a secondary S. aureus sepsis was diagnosed. In order to not negatively impact antibacterial immunity in active EGPA, antibiotic therapy was combined with Benralizumab, which was well tolerated and EGPA resolved rapidly. Benralizumab could serve as a therapeutic option for eosinophil-mediated pathologies in severely ill patients where immunosuppressives are initially contraindicated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2020.108574DOI Listing
January 2021

Treatment of MOG-IgG-associated disorder with rituximab: An international study of 121 patients.

Mult Scler Relat Disord 2020 Sep 2;44:102251. Epub 2020 Jun 2.

Department of Neurology, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom; Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; Department of Neurology, The Cleveland Clinic Abu Dhabi, United Arab Emirates. Electronic address:

Objective: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD).

Methods: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model).

Results: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3-14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3-24.9) months. In this 'relapsing group', relapse rate declined by 37% (95%CI=19-52%, p<0.001) overall, 63% (95%CI=35-79%, p = 0.001) when RTX was used first line (n = 47), and 26% (95%CI=2-44%, p = 0.038) when used after other steroid-sparing immunotherapies (n = 54). Predicted 1-year and 2-year relapse-free survival was 79% and 55% for first-line RTX therapy, and 38% and 18% for second-/third-line therapy. Circulating CD19B-cells were suppressed to <1% of total circulating lymphocyte population at the time of 45/57 (78.9%) relapses.

Conclusion: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2020.102251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895306PMC
September 2020

Comparative Analysis of T-Cell Responses to Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein in Inflammatory Demyelinating Central Nervous System Diseases.

Front Immunol 2020 17;11:1188. Epub 2020 Jun 17.

Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Autoantibodies against aquaporin-4 (AQP4-Ab) and myelin oligodendrocyte glycoprotein (MOG-Ab) are associated with rare central nervous system inflammatory demyelinating diseases like neuromyelitis optica spectrum disorders (NMOSD). Previous studies have shown that not only antibodies, but also autoreactive T-cell responses against AQP4 are present in NMOSD. However, no study has yet analyzed the presence of MOG reactive T-cells in patients with MOG antibodies. Therefore, we compared AQP4 and MOG specific peripheral T-cell response in individuals with AQP4-Ab ( = 8), MOG-Ab ( = 10), multiple sclerosis (MS, = 8), and healthy controls (HC, = 14). Peripheral blood mononuclear cell cultures were stimulated with eight AQP4 and nine MOG peptides selected from previous studies and a tetanus toxoid peptide mix as a positive control. Antigen-specific T-cell responses were assessed using the carboxyfluorescein diacetate succinimidyl ester proliferation assay and the detection of granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-ɤ and interleukin (IL)-4, IL-6, and IL-17A in cell culture supernatants. Additionally, human leukocyte antigen (HLA)-DQ and HLA-DR genotyping of all participants was performed. We classified a T-cell response as positive if proliferation (measured by a cell division index ≥3) was confirmed by the secretion of at least one cytokine. Reactivity against AQP4 peptides was observed in many groups, but the T-cell response against AQP4 p156-170 was present only in patients with AQP4-Ab (4/8, 50%) and absent in patients with MOG-Ab, MS and HC (corrected = 0.02). This AQP4 p156-170 peptide specific T-cell response was significantly increased in participants with AQP4-Ab compared to those without [Odds ratio (OR) = 59.00, 95% confidence interval-CI 2.70-1,290.86]. Moreover, T-cell responses against at least one AQP4 peptide were also more frequent in participants with AQP4-Ab (OR = 11.45, 95% CI 1.24-106.05). We did not observe any significant differences for the other AQP4 peptides or any MOG peptide. AQP4-Ab were associated with HLA DQB102 (OR = 5.71, 95% CI 1.09-30.07), DRB101 (OR = 9.33, 95% CI 1.50-58.02) and DRB103 (OR = 6.75, 95% CI = 1.19-38.41). Furthermore, HLA DRB101 was also associated with the presence of AQP4 p156-170 reactive T-cells (OR = 31.67, 95% CI 1.30-772.98). To summarize, our findings suggest a role of AQP4-specific, but not MOG-specific T-cells, in NMOSD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311656PMC
April 2021

Digitalisation of the Brief Visuospatial Memory Test-Revised and Evaluation with a Machine Learning Algorithm.

Stud Health Technol Inform 2020 Jun;270:168-172

Bern University of Applied Sciences, Biel, Switzerland.

The disease multiple sclerosis (MS) is characterized by various neurological symptoms. This paper deals with a novel tool to assess cognitive dysfunction. The Brief Visuospatial Memory Test-Revised (BVMT-R) is a recognized method to measure optical recognition deficits and their progression. Typically, the test is carried out on paper. We present a way to make this process more efficient, without losing quality by having the patients using a tablet App and having the drawings rated with the use of a machine learning (ML) algorithm. A dataset of 1'525 drawings were digitalized and then randomly split in a training dataset and in a test dataset. In addition to the training dataset the already trained drawings from a preliminary paper were added to the training dataset. The ratings done by two neuropsychologists matched for 81% of the test dataset. The ratings done automatically with the ML algorithm matched 72% with the ones of the first neuropsychologist and 79% of the ones of the second neuropsychologist. For a semi-automated rating we defined a threshold value for the reliability of the rating of 78.8%, under which the drawing is routed for manual rating. With this threshold value the ML algorithm matched 80.3% and 86.6% of the ratings of the first and second neuropsychologists. The neuropsychologists have in that case to manually check 17.4% of the drawings. With our results is it possible to execute the BVMT-R Test in a digital way. We found out, that our ML algorithms have with the semi-automated method the similar matching as the two professional raters.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/SHTI200144DOI Listing
June 2020

Autoantibodies against the prion protein in individuals with mutations.

Neurology 2020 10 25;95(14):e2028-e2037. Epub 2020 Feb 25.

From the Institute of Neuropathology (K.F., M.C., M.L., M.E., S. Hornemann, A.A.), Institute of Surgical Pathology (U.C.), and Department of Neurology, Neuroimmunology and MS Research (NIMS) (A.L.), University of Zurich, Switzerland; Department of Chemistry (G.M., T.K.), University of Cambridge, UK; CJD Foundation Israel (A.A.), Pardes Hanna; ICM (J.-P.B.), Salpêtrière Hospital, Sorbonne University, Paris, France; CIC bioGUNE and IKERBASQUE (J.C.), Basque Foundation for Science, Bizkaia, Spain; Sorbonne University (S. Haïk), ICM, Salpêtrière Hospital, Paris, France; Ophthalmology Division (E.L.), University of Graz, Austria; Broad Institute (E.V.M.), Cambridge, MA; Treviso Hospital (I.R.), Italy; Department of Pathology, Neurology, and National Prion Disease Pathology Surveillance Center (J.G.S.), Case Western Reserve University, Cleveland, OH; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Hospital Clinic, IDIBAPS, University of Barcelona, Spain; and Department of Prion Diseases (D.Ž.), Slovak Medical University, Bratislava, Slovakia.

Objective: To determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease.

Methods: In this case-control study, we collected 124 blood samples from individuals with a variety of pathogenic mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human immunoglobulin G antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between (1) mutation carriers vs controls and (2) asymptomatic vs symptomatic mutation carriers. Robustness of results was examined in matched cohorts.

Results: We found that antibody reactivity was present in a subset of both mutation carriers and controls. Autoantibody levels were not influenced by mutation status or clinical manifestation of prion disease. Post hoc analyses showed anti-PrP autoantibody titers to be independent of personal history of autoimmune disease and other immunologic disorders, as well as codon 129 polymorphism.

Conclusions: Pathogenic variants do not notably stimulate antibody-mediated anti-PrP immunity. Anti-PrP immunoglobulin G autoantibodies are not associated with the onset of prion disease. The presence of anti-PrP autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well-tolerated.

Clinicaltrialsgov Identifier: NCT02837705.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682844PMC
October 2020

Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis.

J Neurol Neurosurg Psychiatry 2019 06 25;90(6):642-651. Epub 2019 Jan 25.

Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zurich, Switzerland.

Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients' quality of life. Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms. Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients. This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2018-320050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581095PMC
June 2019

GDP-l-fucose synthase is a CD4 T cell-specific autoantigen in DRB3*02:02 patients with multiple sclerosis.

Sci Transl Med 2018 10;10(462)

Neuroimmunology and MS Research (nims), Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091 Zürich, Switzerland.

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4 T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)-l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid-infiltrating CD4 T cells from HLA-DRB3*-positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aat4301DOI Listing
October 2018

Memory B Cells Activate Brain-Homing, Autoreactive CD4 T Cells in Multiple Sclerosis.

Cell 2018 09 30;175(1):85-100.e23. Epub 2018 Aug 30.

Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address:

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4 T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as "autoproliferation" of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2018.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191934PMC
September 2018

Unfavorable Structural and Functional Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis.

J Neuroophthalmol 2019 Mar;39(1):3-7

Neuroimmunology and Multiple Sclerosis Research (IJ, JVMH, SL, RM, AL, and SS), Neurology Clinic, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Ophthalmology (JVMH, KPW, and KL), University Hospital Zurich, Zurich, Switzerland; Department of Ophthalmology (MP), Luzerner Kantonsspital, Lucerne, Switzerland; Clinical Department of Neurology (MR), Medical University of Innsbruck, Innsbruck, Austria; and Neurology Clinic (MW, KPW), University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Recurrent optic neuritis (rON) associated with myelin oligodendrocyte glycoprotein (MOG)-specific antibodies has been initially reported to show a better clinical outcome than aquaporin-4 (AQP4)-seropositive ON in neuromyelitis optica spectrum disorder (NMOSD). Here, we characterize clinical and neuroimaging findings in severe cases of MOG antibody-positive and AQP4 antibody-negative bilateral rON.

Methods: Three male adults with rON (ages 18, 44, and 63 years) were evaluated with optical coherence tomography (OCT), MRI, cerebrospinal fluid (CSF), and serological studies.

Results: All patients experienced >7 relapses of ON with severe reduction of visual acuity and partial response to steroid treatment. Optic nerves were affected bilaterally, although unilateral relapses were more frequent than simultaneous bilateral recurrences. Patients were MOG-seropositive but repeatedly tested negative for AQP4 antibodies. OCT showed severe thinning of the peripapillary retinal nerve fiber layer. On MRI, contrast-enhancing lesions extended over more than half the length of the optic nerve. CSF analyses during ON episodes were normal. Severe visual deficits accumulated over time in 2 of 3 patients, despite immunosuppressive therapy.

Conclusions: MOG-seropositive and AQP4-seronegative rON may be associated with an aggressive disease course and poor functional and structural outcomes. In contrast to previous reports, the severity and pattern of retinal and optic nerve damage closely resembled phenotypes commonly observed in AQP4-seropositive rON without fulfilling current diagnostic criteria for NMOSD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WNO.0000000000000669DOI Listing
March 2019

Transient impairment of olfactory threshold in acute multiple sclerosis relapse.

Mult Scler Relat Disord 2018 Jul 26;23:74-77. Epub 2018 May 26.

Department of Neurology, Medical University of Innsbruck, Austria.

Background: Impairment of olfactory threshold is a feature of early and active relapsing remitting multiple sclerosis (RRMS). It predicts inflammatory disease activity and was reported to be transient. However, the timing of onset and resolve of olfactory threshold impairment remains unclear.

Objective: To prospectively assess the development of olfactory threshold in acute MS relapse over time in comparison to stable MS patients.

Methods: In a prospective observational design, we measured olfactory threshold by performing the Sniffin' Sticks test (minimum score 0, maximum score 16 reflecting optimal olfactory function) at baseline and after 4, 12 and 24 weeks. We included 30 RRMS patients with acute MS relapse and 30 clinically stable RRMS patients (defined as no relapse within the last 12 months) as a control group.

Results: Olfactory threshold was impaired in patients with acute MS relapse at baseline (median difference = -3.5; inter-quartile range [IQR] -4.5- - 2.5; p < 0.001), week 4 (-2.5; IQR -3.0 - -2.0; p < 0.001), week 12 (-1.5; IQR -2.0 - -0.5; p = 0.002) and week 24 (-0.5; IQR -1.0 - 0.0; p = 0.159) compared to stable MS patients. Of note, in relapsing patients in whom disease-modifying treatment was initiated or escalated after relapse, threshold did not differ anymore from stable patients at week 12 (-0.5; IQR -1.0 - 0.5; p = 0.247) and week 24 (0.0; IQR -1.0 - 1.0; p = 0.753).

Conclusions: Olfactory threshold impairment seems to be a transient bystander feature of MS relapse. It may be correlated to the level of inflammation within the CNS and might be a useful biomarker in this regard.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2018.05.006DOI Listing
July 2018

Challenges and needs in experimental therapies for multiple sclerosis.

Curr Opin Neurol 2018 06;31(3):263-267

Andreas Lutterotti, Neurology Clinic, University Hospital Zurich & University of Zurich, Frauenklinikstrasse, Zurich, Switzerland.

Purpose Of Review: Despite dramatic advances in the treatment of people with multiple sclerosis over the last decade, several unmet medical needs still remain and should be approached with new compounds in experimental clinical trials. The prerequisites for successful clinical trials in multiple sclerosis have changed considerably over time and activities have started to improve clinical development of new drugs in several aspects including trial designs, patient selection and outcome parameters. This review will address some of the challenges in early experimental trials in multiple sclerosis and recent approaches in the field.

Recent Findings: Highly intensive treatment regimens like autologous hematopoietic stem cell transplantation provide evidence for sustained long-term treatment effects in multiple sclerosis patients. Several different approaches towards neuroprotection and remyelination have entered the clinical phase and demonstrated that stabilization, even improvement of disability is achievable in short-term studies.

Summary: New therapeutic strategies have entered the clinic with the prospects of long-term efficacy and enduring effects on disability progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WCO.0000000000000560DOI Listing
June 2018

Change of olfactory function as a marker of inflammatory activity and disability progression in MS.

Mult Scler 2019 02 29;25(2):267-274. Epub 2017 Nov 29.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria/Department of Neurology, University Hospital Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland.

Background: Impaired olfactory threshold has been reported in early inflammatory phases of MS, while impaired odor identification was associated with more widespread disability.

Objective: To prospectively assess the development of olfactory function and its correlation with relapse and disability progression.

Methods: In this prospective, 3-year longitudinal study on 151 MS patients and 30 healthy controls, three different qualities of olfactory function (threshold, discrimination, and identification) were quantified using the Sniffin' Sticks test. The influence of relapses and disability on olfactory function was analyzed at different time points and in a multivariate model.

Results: Discrimination and identification capability significantly worsened over 3 years, while threshold did not. Threshold was markedly impaired in patients with relapse activity within 12 months, recovered in the absence of relapse, and was associated with a 2.5-fold increased risk of relapse. Deterioration of discrimination and identification was irreversible and both strongly associated with and predictive of EDSS progression.

Conclusion: Olfactory function changes over time in MS. Threshold impairment is transient and predicts inflammatory disease activity, while odor identification and discrimination are associated with disability progression. Olfactory dysfunction might be a useful and easily obtainable parameter to monitor patients with regard to inflammation and neurodegeneration in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458517745724DOI Listing
February 2019

Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination.

J Neuroinflammation 2017 Oct 25;14(1):208. Epub 2017 Oct 25.

Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Antibodies to the myelin oligodendrocyte glycoprotein (MOG) are associated with a subset of inflammatory demyelinating diseases of the central nervous system such as acute disseminated encephalomyelitis and neuromyelitis optica spectrum disorders. However, whether human MOG antibodies are pathogenic or an epiphenomenon is still not completely clear. Although MOG is highly conserved within mammals, previous findings showed that not all human MOG antibodies bind to rodent MOG. We therefore hypothesized that human MOG antibody-mediated pathology in animal models may only be evident using species-specific MOG antibodies.

Methods: We screened 80 human MOG antibody-positive samples for their reactivity to mouse and rat MOG using either a live cell-based assay or immunohistochemistry on murine, rat, and human brain tissue. Selected samples reactive to either human MOG or rodent MOG were subsequently tested for their ability to induce complement-mediated damage in murine organotypic brain slices or enhance demyelination in an experimental autoimmune encephalitis (EAE) model in Lewis rats. The MOG monoclonal antibody 8-18-C5 was used as a positive control.

Results: Overall, we found that only a subset of human MOG antibodies are reactive to mouse (48/80, 60%) or rat (14/80, 18%) MOG. Purified serum antibodies from 10 human MOG antibody-positive patients (8/10 reactive to mouse MOG, 6/10 reactive to rat MOG), 3 human MOG-negative patients, and 3 healthy controls were tested on murine organotypic brain slices. Purified IgG from one patient with high titers of anti-human, mouse, and rat MOG antibodies and robust binding to myelin tissue produced significant, complement-mediated myelin loss in organotypic brain slices, but not in the EAE model. Monoclonal 8-18-C5 MOG antibody caused complement-mediated demyelination in both the organotypic brain slice model and in EAE.

Conclusion: This study shows that a subset of human MOG antibodies can induce complement-dependent pathogenic effects in a murine ex vivo animal model. Moreover, a high titer of species-specific MOG antibodies may be critical for demyelinating effects in mouse and rat animal models. Therefore, both the reactivity and titer of human MOG antibodies must be considered for future pathogenicity studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-017-0984-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657084PMC
October 2017

CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1.

Sleep 2017 Mar;40(3)

Clinical Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.

Introduction: Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease.

Methods: We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools.

Results: Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope.

Conclusions: A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsw070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806576PMC
March 2017

Is it Time for Immunotherapy Trials in Narcolepsy?

J Clin Sleep Med 2017 03 15;13(3):363-364. Epub 2017 Mar 15.

Department of Neurology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5664/jcsm.6478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337581PMC
March 2017

Restoring immune tolerance in neuromyelitis optica: Part II.

Neurol Neuroimmunol Neuroinflamm 2016 Oct 7;3(5):e277. Epub 2016 Sep 7.

Neuroimmunology Unit and Experimental Therapeutics Program (A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; Department of Neurology (L.S.), Stanford University School of Medicine, Palo Alto; The Guthy-Jackson Charitable Foundation (J.M.B.), San Diego, CA; Department of Gastroenterology (D.B.-R., P.V.), Hospital Clínic, CIBERehd and Center of Neuroimmunology & Inflammatory Bowel Disease, Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona, Spain; Genentech, Inc. (P.S.C.), South San Francisco, CA; Department of Pathology (M.C.-S.), University of Florida School of Medicine, Gainesville; Opexa Therapeutics (D.H.), The Woodlands, TX; Department of Surgery (J.I.K.), Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Department of Biochemistry (D.M.K.), University of Illinois, Urbana; Neuroimmunology and MS Research (A.L., R.M., S.S.), Department of Neurology, University Hospital Zurich, University Zurich, Switzerland; Ann Romney Center for Neurologic Diseases (H.L.W.), Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neurology and Program in Immunology (S.S.Z.), University of California, San Francisco School of Medicine; Department of Ophthalmology and Visual Sciences (T.J.S.), Kellogg Eye Center, and Division of Metabolism, Endocrine and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor; Department of Medicine (M.R.Y.), Divisions of Molecular Medicine & Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles; and Harbor-UCLA Medical Center & LABioMed at Harbor-UCLA Medical Center (M.R.Y.), Torrance, CA.

Neuromyelitis optica spectrum disorder (NMO/SD) and its clinical variants have at their core the loss of immune tolerance to aquaporin-4 and perhaps other autoantigens. The characteristic phenotype is disruption of astrocyte function and demyelination of spinal cord, optic nerves, and particular brain regions. In this second of a 2-part article, we present further perspectives regarding the pathogenesis of NMO/SD and how this disease might be amenable to emerging technologies aimed at restoring immune tolerance to disease-implicated self-antigens. NMO/SD appears to be particularly well-suited for these strategies since aquaporin-4 has already been identified as the dominant autoantigen. The recent technical advances in reintroducing immune tolerance in experimental models of disease as well as in humans should encourage quantum leaps in this area that may prove productive for novel therapy. In this part of the article series, the potential for regulatory T and B cells is brought into focus, as are new approaches to oral tolerization. Finally, a roadmap is provided to help identify potential issues in clinical development and guide applications in tolerization therapy to solving NMO/SD through the use of emerging technologies. Each of these perspectives is intended to shine new light on potential cures for NMO/SD and other autoimmune diseases, while sparing normal host defense mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015540PMC
October 2016

Restoring immune tolerance in neuromyelitis optica: Part I.

Neurol Neuroimmunol Neuroinflamm 2016 Oct 7;3(5):e276. Epub 2016 Sep 7.

Department of Neurology (L.S.), Stanford University School of Medicine, Palo Alto, CA; Neuroimmunology Unit and Experimental Therapeutics Program (A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada; The Guthy-Jackson Charitable Foundation (J.M.B.), San Diego, CA; Department of Gastroenterology (D.B.-R., P.V.), Hospital Clínic, CIBERehd and Center of Neuroimmunology & Inflammatory Bowel Disease, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain; Genentech, Inc. (P.S.C.), South San Francisco, CA; Department of Pathology (M.C.-S.), University of Florida School of Medicine, Gainesville; Opexa Therapeutics (D.H.), The Woodlands, TX; Department of Surgery (J.I.K.), Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA; Department of Biochemistry (D.M.K.), University of Illinois, Urbana; Neuroimmunology and MS Research (A.L., R.M., S.S.), Department of Neurology, University Hospital Zurich, University Zurich, Switzerland; Forest Landing Court (H.L.W.), Rockville, MD; Ann Romney Center for Neurologic Diseases (S.S.Z.), Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Neurology and Program in Immunology (H.L.W.), University of California, San Francisco School of Medicine; Department of Medicine (S.S.Z.), Divisions of Molecular Medicine & Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles; Harbor-UCLA Medical Center & LABioMed at Harbor-UCLA Medical Center (M.R.Y.), Torrance, CA; Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, and Division of Metabolism and Endocrine Diseases, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor (T.J.S.).

Neuromyelitis optica (NMO) and spectrum disorder (NMO/SD) represent a vexing process and its clinical variants appear to have at their pathogenic core the loss of immune tolerance to the aquaporin-4 water channel protein. This process results in a characteristic pattern of astrocyte dysfunction, loss, and demyelination that predominantly affects the spinal cord and optic nerves. Although several empirical therapies are currently used in the treatment of NMO/SD, none has been proven effective in prospective, adequately powered, randomized trials. Furthermore, most of the current therapies subject patients to long-term immunologic suppression that can cause serious infections and development of cancers. The following is the first of a 2-part description of several key immune mechanisms in NMO/SD that might be amenable to therapeutic restoration of immune tolerance. It is intended to provide a roadmap for how potential immune tolerance restorative techniques might be applied to patients with NMO/SD. This initial installment provides a background rationale underlying attempts at immune tolerization. It provides specific examples of innovative approaches that have emerged recently as a consequence of technical advances. In several autoimmune diseases, these strategies have been reduced to practice. Therefore, in theory, the identification of aquaporin-4 as the dominant autoantigen makes NMO/SD an ideal candidate for the development of tolerizing therapies or cures for this increasingly recognized disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015539PMC
October 2016

Orbital Pseudotumor as a Rare Extrahepatic Manifestation of Hepatitis C Infection.

Case Rep Gastroenterol 2016 Jan-Apr;10(1):108-14. Epub 2016 May 19.

Division of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Hepatitis C is frequently accompanied by immune-related extrahepatic manifestations affecting the skin, kidneys, central and peripheral nervous system and exocrine glands. We present the case of a 40-year-old man with left-sided ptosis, exophthalmos and headache. MRI demonstrated left-sided orbital pseudotumor with lacrimal and retro-orbital contrast enhancement extending to the cavernous sinus and the vestibulocochlear nerve. Immunological tests of serum and cerebrospinal fluid identified hepatitis C virus (HCV) as a potential causative agent but did not indicate any additional infectious, malignant or immunological disorder. Hepatological evaluation revealed no signs of advanced liver disease. After initial spontaneous improvement, the patient subsequently developed vestibulocochlear failure with gait disorder, tinnitus and transient left-parietal sensory loss. Lacrimal biopsy demonstrated lymphocytic infiltrate, prompting steroid treatment. After initial improvement, steroids could not be tapered below 40 mg daily for several months due to recurrent symptoms. Twelve months after the initial presentation, the patient's chronic HCV infection was successfully treated with sofosbuvir, simeprevir and ribavirin and he remains now free of symptoms without steroids. In patients with chronic hepatitis C, lymphocytic infiltrate of the salivary and lacrimal glands is a frequent phenomenon. However, the extent of the lymphocytic infiltrate beyond the lacrimal gland to the tip of the orbit, cavernous sinus and vestibulocochlear nerve as in our patient is highly unusual. For all symptomatic extrahepatic manifestations of hepatitis C infection, treatment of HCV as the underlying immune stimulus is recommended, and it helped to control the symptoms in our patient. In addition, long-term follow-up for recurrent lymphocyte infiltrate and development of lymphoma is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000444011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929361PMC
July 2016

Long Term Clinical Prognostic Factors in Relapsing-Remitting Multiple Sclerosis: Insights from a 10-Year Observational Study.

PLoS One 2016 8;11(7):e0158978. Epub 2016 Jul 8.

Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

Background: Multiple sclerosis (MS) has a highly heterogenic course making prediction of long term outcome very difficult.

Objective: The objective was to evaluate current and identify additional clinical factors that are linked to long term outcome of relapsing-remitting MS assessed by disability status 10 years after disease onset.

Methods: This observational study included 793 patients with relapsing-remitting MS. Clinical factors hypothesized to influence long term outcome measured by EDSS scores 10 years after disease onset were analysed by Kaplan-Meier-estimates. Multinomial logistic regression models regarding mild (EDSS ≤2.5), moderate (EDSS 3.0-5.5) or severe (EDSS ≥6.0) disability were calculated to correct for confounders.

Results: Secondary progression was the strongest predictor of severe disability (Hazard ratio [HR] 503.8, 95% confidence interval [CI] 160.0-1580.1); p<0.001). Complete remission of neurological symptoms at onset reduced the risk of moderate disability (HR 0.42; CI 0.23-0.77; p = 0.005), while depression (HR 3.59; CI 1.14-11.24; p = 0.028) and cognitive dysfunction (HR 4.64; CI 1.11-19.50; p = 0.036) 10 years after disease onset were associated with severe disability. Oligoclonal bands and pregnancy were not correlated with disability.

Conclusion: We were able to identify clinically apparent chronic depression and cognitive dysfunction to be associated with adverse long term outcome in MS and to confirm that pregnancy has no negative impact. Additionally, we emphasize the positive predictive value of complete remission of initial symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158978PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938610PMC
July 2017

Rituximab induces clonal expansion of IgG memory B-cells in patients with inflammatory central nervous system demyelination.

J Neuroimmunol 2016 Jan 19;290:49-53. Epub 2015 Nov 19.

Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Rituximab, a monoclonal B-cell cytolytic antibody, has beneficial effects in patients with inflammatory demyelinating diseases. So far, little data exists on B-cell subset recovery after rituximab treatment in inflammatory demyelinating diseases of the central nervous system (CNS). To elucidate whether rituximab promotes qualitative changes in the IgG memory B-cell repertoire we performed a single cell analysis in three patients with CNS demyelination. We did not observe any qualitative changes but detected an increased clonal expansion in the IgG memory B-cell compartment after treatment, indicating that a single course of rituximab does not eliminate specific IgG memory B-cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneuroim.2015.11.006DOI Listing
January 2016

Impact of glatiramer acetate on paraclinical markers of neuroprotection in multiple sclerosis: A prospective observational clinical trial.

J Neuroimmunol 2015 Oct 10;287:98-105. Epub 2015 Aug 10.

Clinical Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria; Clinics for Neurological Rehabilitation Münster, Groeben 700, 6232 Münster, Austria; Department of Radiology, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address:

Data from in vitro and animal studies support a neuroprotective role of glatiramer acetate (GA) in multiple sclerosis (MS). We investigated prospectively whether treatment with GA leads to clinical and paraclinical changes associated with neuroprotection in patients with relapsing-remitting (RR) MS. Primary aim of this clinical study was to determine serum BDNF levels in RR-MS patients who were started on GA as compared to patients who remained therapy-naive throughout 24 months. Secondary outcomes included relapses and EDSS, cognition, quality of life, fatigue and depression, BDNF expression levels on peripheral immune cells (FACS, RT-PCR), serum anti-myelin basic peptide (MBP) antibody status, evoked potential and cerebral MRI studies. While GA treatment did not alter serum levels or expression levels on peripheral immune cells of BDNF over time it resulted in a transient increase of serum IgG antibody response to MBP, mainly due to subtype IgG1 (p<0.05), after 3 months. However, no significant differences were found between GA treated and therapy-naive patients with regard to serum BDNF and intracellular BDNF expression levels, nerve conduction (including median and tibial nerve somatosensory, pattern-shift visual and upper and lower limb motor evoked potentials) or MRI (including volume of hyperintense lesions, volume of hypointense lesions after CE, mean diffusivity and fractional anisotropy) outcome parameters. In conclusion, our findings do not support a major impact of GA treatment on paraclinical markers of neuroprotection in human RR-MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneuroim.2015.08.004DOI Listing
October 2015

NMDA receptor antibodies: A rare association in inflammatory demyelinating diseases.

Neurol Neuroimmunol Neuroinflamm 2015 Oct 13;2(5):e141. Epub 2015 Aug 13.

Clinical Department of Neurology (M. Ramberger, G.B., K.S., A.L., F.D., T.B., M. Reindl) and Department of Pediatrics I (K.R., M.B.), Medical University of Innsbruck, Austria; Institute of Neurology (R.H.), Medical University of Vienna, Austria; Pediatric Neurology (K.R.), Witten/Herdecke University, Children's Hospital Datteln, Datteln, Germany; Department of Neurology (F.A.-D.), Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Sozialmedizinisches Zentrum Ost Donauspital, Vienna, Austria; and Neuroimmunology and Multiple Sclerosis Research (A.L.), Department of Neurology, University Hospital Zurich and University of Zurich, Switzerland.

Objectives: To analyze the frequency of NMDA receptor (NMDAR) antibodies in patients with various inflammatory demyelinating diseases of the CNS and to determine their clinical correlates.

Methods: Retrospective case-control study from 2005 to 2014 with the detection of serum IgG antibodies to NMDAR, aquaporin-4, and myelin oligodendrocyte glycoprotein by recombinant live cell-based immunofluorescence assays. Fifty-one patients with acute disseminated encephalomyelitis, 41 with neuromyelitis optica spectrum disorders, 34 with clinically isolated syndrome, and 89 with multiple sclerosis (MS) were included. Due to a known association of NMDAR antibodies with seizures and behavioral symptoms, patients with those clinical manifestations were preferentially included and are therefore overrepresented in our cohort. Nine patients with NMDAR encephalitis, 94 patients with other neurologic diseases, and 48 healthy individuals were used as controls.

Results: NMDAR antibodies were found in all 9 patients with NMDAR encephalitis but in only 1 of 215 (0.5%) patients with inflammatory demyelination and in none of the controls. This patient had relapsing-remitting MS with NMDAR antibodies present at disease onset, with an increase in NMDAR antibody titer with the onset of psychiatric symptoms and cognitive deficits.

Conclusion: In demyelinating disorders, NMDAR antibodies are uncommon, even in those with symptoms seen in NMDAR encephalitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537309PMC
October 2015

Antibody responses following induction of antigen-specific tolerance with antigen-coupled cells.

Mult Scler 2015 Apr 8;21(5):651-5. Epub 2014 Sep 8.

Clinical Department of Neurology, Innsbruck Medical University, Austria/Neuroimmunology and Multiple Sclerosis Research, Department of Neurology, University Hospital Zurich, Switzerland

We have recently demonstrated the safety and tolerability of a novel therapeutic regimen employing autologous blood cells chemically coupled with seven myelin peptides to induce antigen-specific tolerance in MS (ETIMS study). The aim of the current study was an extended safety analysis to assess the effect of the ETIMS approach on antibodies to common autoantigens, the myelin peptides used and common recall antigens. None of the patients showed induction of autoantibody responses. One patient had a measurable myelin peptide-specific response at baseline, which was reduced after treatment. Total immunoglobulins and recall antibody responses showed no significant change.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458514549405DOI Listing
April 2015

Neuromyelitis optica in Austria in 2011: to bridge the gap between neuroepidemiological research and practice in a study population of 8.4 million people.

PLoS One 2013 5;8(11):e79649. Epub 2013 Nov 5.

Department of Neurology, Sozialmedizinisches Zentrum Ost Donauspital, Vienna, Austria ; Department of Neurology, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Vienna, Austria.

Background: In 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration. Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment.

Methods: (1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%). All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University). (2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008. All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses. The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span. Failure and response to treatment are made visible at one glance. Database closure was 31 December 2011. All co-operators were offered co-authorship.

Results: All 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail. Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results. All identified patients were Caucasians.

Conclusions: A nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD. This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079649PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818238PMC
August 2014