Publications by authors named "Jette Lautrup Frederiksen"

36 Publications

Anti-myelin oligodendrocyte glycoprotein antibodies in a girl with good recovery after five episodes of prior idiopathic optic neuritis.

Am J Ophthalmol Case Rep 2021 Jun 24;22:101060. Epub 2021 Mar 24.

Clinic of Optic Neuritis, The Danish Multiple Sclerosis Center (DMSC), Department of Neurology, Rigshospitalet - Glostrup, University of Copenhagen, Valdemar Hansens Vej 13, 2600, Glostrup, Denmark.

Purpose: To describe the clinical, radiological, immunological and electrophysiological features of a myelin oligodendrocyte glycoprotein (MOG)-IgG positive girl with five prior episodes of idiopathic bilateral optic neuritis (ON).

Observations: We report a Danish girl who has been followed by pediatricians and pediatric neurologists since the age of 10 with recurrent episodes of idiopathic bilateral ON. Since the age of 15 there has been no recurrence of ON, and the patient has been thoroughly investigated for Multiple Sclerosis (MS) several times, but with negative findings. At the age of 19 the patient was referred to the Clinic of Optic Neuritis where she was tested seropositive for antibodies against MOG (MOG- IgG) on a conventionally cell-based assay. Despite 5 previous episodes of ON, the latency and amplitude signals of pattern-reversal visual evoked potentials (pVEP) including multifocal VEP were detected within the normal range.

Conclusion: The clinical implications of MOG- IgG are not yet clear, but in cases where the diagnosis of MS is less likely and where ON is the main symptom, testing for both IgG antibodies against AQP4 and MOG while having atypical optic neuropathies in mind is important. MOG-IgG positive patients may have a good prognosis with regards to visual function.
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http://dx.doi.org/10.1016/j.ajoc.2021.101060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100534PMC
June 2021

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

Neurology 2021 07 28;97(2):68-79. Epub 2021 Apr 28.

From the Department of Neurology, Medical Faculty (A.A., O.A., H.-P.H., O.M., S.M., M.R., P.A.), Heinrich-Heine University Düsseldorf, Germany; Department of Neurology (A.C.-H., A.J.G.), University of California San Francisco; Departments of Neurology, Population Health, and Ophthalmology (L.J.B., R.K.), NYU Grossman School of Medicine, New York, NY; Mulier Institute (L.B.), Centre for Research on Sports in Society, Utrecht, the Netherlands; Scientific Institute San Raffaele (P.B.), Milan, Italy; Centre for Public Health (A.A.B.), Queen's University Belfast, Northern Ireland, UK; Division of Neuroimmunology (P.A.C., S. Saidha), Johns Hopkins University, Baltimore, MD; Departments of Clinical Neurosciences and Surgery (F.C.), University of Calgary, Alberta, Canada; Institut d'Investigacións Biomediques August Pi iSunyer (IDIBAPS) and Hospital Clinic (B.S.-D., E.H.M.-L., P.V.), University of Barcelona, Spain; Bascom Palmer Eye Institute (D.C.D.), University of Miami Miller School of Medicine, FL; Department of Ophthalmology (N.F.), University Medical Center, Göttingen; Department of Ophthalmology (R.P.F., F.G.H.), University of Bonn, Germany; Department of Neurology (J.L.F., G.P.-J.), Rigshospitalet Glostrup and University of Copenhagen, Denmark; Laboratory of Neuroimmunology (E.F., T.F.), Stanford University School of Medicine, CA; Institute of Ophthalmology (D.G.-H.), National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (D.G.-H.), London, UK; Biocruces Bizkaia Health Research Institute (I.G.), Barakaldo, Spain; Department of Neurosciences (J.S.G.), University of California, San Diego; Brain and Mind Centre (H.-P.H.), University of Sydney, Australia; Department of Neurology (H.-P.H.), Medical University of Vienna, Austria; Institute of Clinical Neuroimmunology (J.H.), LMU Hospital, Ludwig-Maximilians Universität München, Germany; UConn Health Comprehensive MS Center, Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology (J.I.), University of Connecticut School of Medicine, Farmington; Faculty of Medicine and Health Sciences (A.K.), Macquarie University, Sydney, Australia; Department of Neurology (B.K., T.K.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Germany; Department of Medicine and Radiology (S.K.), University of Melbourne, Australia; Department of Neurology with Institute of Translational Neurology (J.K.), University of Münster; Eye Center, Medical Center, Faculty of Medicine (W.A.L.), University of Freiburg, Germany; Experimental Neurophysiology Unit (L.L.), Institute of Experimental Neurology (INSPE), IRCCS San Raffaele, University Vita-Salute San Raffaele, Milan, Italy; Lille Neurosciences & Cognition (O.O.), Univ Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC), France; Experimental and Clinical Research Center (F.P., H.G.Z., A.U.B.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Moorfields Eye Hospital (A.P.), The National Hospital for Neurology and Neurosurgery, Queen Square, UCL Institute of Neurology, London, UK; Neuro-ophthalmology Expert Center (A.P.), Amsterdam UMC, the Netherlands; Department of Neurology, First Faculty of Medicine (J.L.P.), Charles University and General University Hospital in Prague, Czech Republic; Department of Ophthalmology (G.R.), Ramon y Cajal Hospital, Medicine University of Alcalá, Madrid, Spain; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Düsseldorf, Germany; Department of Neurology (S. Schippling), University Hospital Zurich, Switzerland; Departments of Ophthalmology, Neuroscience, and Physiology (J.S.S.), NYU Langone Health, NYU Grossman School of Medicine, New York; Departments of Biomedical Engineering, Electrical and Computer Engineering (J.S.S.), NYU Tandon School of Engineering, Brooklyn, NY; Thomas Jefferson University Medical College (R.C.S.), Philadelphia, PA; Queen Square MS Centre, Department of Neuroinflammation (A.T.), UCL Institute of Neurology, University College London, UK; Departments of Ophthalmology and Clinical Research (S.W.), Bern University Hospital, University of Bern, Switzerland; Division of Neurology, Department of Pediatrics (E.A.Y.), Hospital for Sick Children, Division of Neurosciences and Mental Health SickKids Research Institute, University of Toronto, Canada; Department of Clinical Neurosciences (P.Y.-W.-M.), University of Cambridge; Moorfields Eye Hospital (P.Y.-W.-M.), London, UK; University of California (A.U.B.), Irvine; and IMSVISUAL (A.A., A.C.-H., O.A., L.J.B., L.B., P.A.C., F.C., J.L.F., E.F., T.F., I.G., J.S.G., A.J.G., H.-P.H., J.H., J.I., R.K., A.K., B.K., T.K., J.K., L.L., E.H.M.-L., S.M., O.O., F.P., A.P., G.P.-J., J.L.P., M.R., S. Saidha, S. Schippling, R.C.S., P.V., E.A.Y., H.G.Z., A.U.B., P.A.), International Multiple Sclerosis Visual System Consortium, Middleton, WI.

Objective: To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.

Methods: To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.

Results: A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.

Conclusions: The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.
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http://dx.doi.org/10.1212/WNL.0000000000012125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279566PMC
July 2021

The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis.

J Neurol 2021 Mar 4. Epub 2021 Mar 4.

Department of Molecular Medicine- Neurobiology Research, University of Southern Denmark, J.B. Winsløws Vej 21, 5000, Odense, Denmark.

Background: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease.

Objective: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue.

Methods: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map.

Results: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons.

Conclusion: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.
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http://dx.doi.org/10.1007/s00415-021-10489-7DOI Listing
March 2021

Epstein-Barr Virus and Multiple Sclerosis.

Front Immunol 2020 17;11:587078. Epub 2020 Dec 17.

Department of Neurology, Rigshospitalet, Glostrup, Denmark.

Multiple sclerosis (MS) is a neurologic disease affecting myelinated nerves in the central nervous system (CNS). The disease often debuts as a clinically isolated syndrome, e.g., optic neuritis (ON), which later develops into relapsing-remitting (RR) MS, with temporal attacks or primary progressive (PP) MS. Characteristic features of MS are inflammatory foci in the CNS and intrathecal synthesis of immunoglobulins (Igs), measured as an IgG index, oligoclonal bands (OCBs), or specific antibody indexes. Major predisposing factors for MS are certain tissue types (e.g., HLA DRB1*15:01), vitamin D deficiency, smoking, obesity, and infection with Epstein-Barr virus (EBV). Many of the clinical signs of MS described above can be explained by chronic/recurrent EBV infection and current models of EBV involvement suggest that RRMS may be caused by repeated entry of EBV-transformed B cells to the CNS in connection with attacks, while PPMS may be caused by more chronic activity of EBV-transformed B cells in the CNS. In line with the model of EBV's role in MS, new treatments based on monoclonal antibodies (MAbs) targeting B cells have shown good efficacy in clinical trials both for RRMS and PPMS, while MAbs inhibiting B cell mobilization and entry to the CNS have shown efficacy in RRMS. Thus, these agents, which are now first line therapy in many patients, may be hypothesized to function by counteracting a chronic EBV infection.
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http://dx.doi.org/10.3389/fimmu.2020.587078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773893PMC
June 2021

Neurovascular contact plays no role in trigeminal neuralgia secondary to multiple sclerosis.

Cephalalgia 2021 Apr 28;41(5):593-603. Epub 2020 Nov 28.

Danish Headache Center, Department of Neurology, Rigshospitalet - Glostrup, Glostrup, Denmark.

Introduction: A demyelinating plaque and neurovascular contact with morphological changes have both been suggested to contribute to the etiology of trigeminal neuralgia secondary to multiple sclerosis (TN-MS). The aim of this study was to confirm or refute whether neurovascular contact with morphological changes is involved in the etiology of TN-MS.

Methods: We prospectively enrolled consecutive TN-MS patients from the Danish Headache Center. Clinical characteristics were collected systematically. MRI scans were done using a 3.0 Tesla imager and were evaluated by the same experienced blinded neuroradiologist.

Results: Sixty-three patients were included. Fifty-four patients were included in the MRI analysis. There was a low prevalence of neurovascular contact with morphological changes on both the symptomatic side (6 (14%)) and the asymptomatic side (4 (9%)),  = 0.157. Demyelinating brainstem plaques along the trigeminal afferents were more prevalent on the symptomatic side compared to the asymptomatic side (31 (58%) vs. 12 (22%),  < 0.001). A demyelinating plaque was highly associated with the symptomatic side (odds ratio = 10.6,  = 0.002).

Conclusion: The primary cause of TN-MS is demyelination along the intrapontine trigeminal afferents. As opposed to classical trigeminal neuralgia, neurovascular contact does not play a role in the etiology of TN-MS. Microvascular decompression should generally not be offered to patients with TN-MS.The study was registered at ClinicalTrials.gov (number NCT04371575).
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http://dx.doi.org/10.1177/0333102420974356DOI Listing
April 2021

Fibrinogen: A potential biomarker for predicting disease severity in multiple sclerosis.

Mult Scler Relat Disord 2020 Nov 18;46:102509. Epub 2020 Sep 18.

University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.

Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The exact pathogenesis behind the development of MS is unknown. This study aims to elucidate the role of fibrinogen in MS pathology and discuss candidacy as a biomarker for disease management.

Method: The method applied is a systematic literature review on the bio-medical database PubMed.

Results: This study found that even though the role of fibrinogen in disease development has been studied considerably, clinical application as a viable biomarker has not yet been achieved conclusively in human studies.

Conclusion: Recent evidence points toward fibrinogen and its degradation products playing a possible role in the disease pathogenesis Further research is needed to convincingly evaluate fibrinogen as a practical biomarker for diagnostic use or for assessing disease severity.
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http://dx.doi.org/10.1016/j.msard.2020.102509DOI Listing
November 2020

Current Evidence on the Efficacy of Gluten-Free Diets in Multiple Sclerosis, Psoriasis, Type 1 Diabetes and Autoimmune Thyroid Diseases.

Nutrients 2020 Aug 1;12(8). Epub 2020 Aug 1.

The Bartholin Institute, Rigshospitalet, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.

In this review, we summarize the clinical data addressing a potential role for gluten in multiple sclerosis (MS), psoriasis, type 1 diabetes (T1D) and autoimmune thyroid diseases (ATDs). Furthermore, data on the prevalence of celiac disease (CD) and gluten-related antibodies in the above patient groups are presented. Adequately powered and properly controlled intervention trials investigating the effects of a gluten-free diet (GFD) in non-celiac patients with MS, psoriasis, T1D or ATDs are lacking. Only one clinical trial has studied the effects of a GFD among patients with MS. The trial found significant results, but it is subject to major methodological limitations. A few publications have found beneficial effects of a GFD in a subgroup of patients with psoriasis that were seropositive for anti-gliadin or deamidated gliadin antibodies, but no effects were seen among seronegative patients. Studies on the role of gluten in T1D are contradictive, however, it seems likely that a GFD may contribute to normalizing metabolic control without affecting levels of islet autoantibodies. Lastly, the effects of a GFD in non-celiac patients with ATDs have not been studied yet, but some publications report that thyroid-related antibodies respond to a GFD in patients with concomitant CD and ATDs. Overall, there is currently not enough evidence to recommend a GFD to non-celiac patients with MS, psoriasis, ATDs or T1D.
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http://dx.doi.org/10.3390/nu12082316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468712PMC
August 2020

Predictive value of optical coherence tomography, multifocal visual evoked potentials, and full-field visual evoked potentials of the fellow, non-symptomatic eye for subsequent multiple sclerosis development in patients with acute optic neuritis.

Mult Scler 2021 03 8;27(3):391-400. Epub 2020 Jun 8.

Department of Clinical Neurophysiology, Rigshospitalet-Glostrup, Glostrup, Denmark/Department of Neurology, Slagelse Hospital, Slagelse, Denmark.

Background: Diagnosis of multiple sclerosis (MS) may sometimes be ascertained at the time of optic neuritis (ON) but other times require the advent of new disease activity.

Objectives: The aim of this study was to examine the predictive value of optical coherence tomography (OCT) and visual evoked potential (VEP) measurements of the non-symptomatic, fellow eye of ON patients, for conversion to MS.

Methods: This is a prospective cohort study in patients with acute ON. OCT thickness measurements of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer-inner plexiform layer (GCLIPL), and multifocal (mf) VEP and full-field (ff) VEP, were performed. Univariate and multivariate Cox regression examined the value of predictors for the conversion to MS.

Results: A total of 79 unilateral, acute ON patients, with no MS diagnosis or prior demyelination, were included. Of which, 28 patients developed MS during follow-up. Inferonasal GCLIPL, mean GCLIPL, and pRNFL thickness significantly predicted MS development in multivariate analysis (hazard ratio (HR) = 0.922-0.939, = 0.0172-0.021). MfVEP mean latency (HR = 1.052,  = 0.006) only predicted MS conversion in univariate analysis. No significant predictive value was shown for the other parameters ( > 0.2).

Conclusion: While both mfVEP and OCT are useful tools in the evaluation of acute ON patients, only OCT measurements of fellow eyes may serve as an independent predictor of MS development.
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http://dx.doi.org/10.1177/1352458520917924DOI Listing
March 2021

Intrathecal IgM as a Prognostic Marker in Multiple Sclerosis.

Mol Diagn Ther 2020 06;24(3):263-277

Department of Neurology, University of Copenhagen, Rigshospitalet Glostrup, Glostrup, Denmark.

One of the great challenges related to multiple sclerosis (MS) research is the identification of markers of prognosis and treatment response. In the last couple of decades, an association between intrathecally produced immunoglobulin M (IgM) and a more severe course of the disease has been suggested. Therefore, the objective of this literature review was to gather and review evidence from studies on intrathecally produced IgM as a prognostic marker of clinically isolated syndrome (CIS) converting to clinically definite MS (CDMS), the prognosis of MS and treatment response in patients with MS. This was accomplished through a systematic literature search of the PubMed database, which resulted in 719 hits that were then systematically assessed with well-defined inclusion and exclusion criteria. This process resulted in 29 relevant research articles. The combined evidence from the current literature suggests that intrathecal IgM is a negative prognostic marker that identifies patients with CIS who have a higher risk of converting to CDMS and patients with relapsing-remitting MS (RRMS) with a higher risk of a more aggressive disease course. However, a few studies, some with large studied populations, have reported conflicting results regarding MS prognosis. Further research is needed to establish a more accurate estimate of the effect of intrathecal IgM on the disease course of MS. Further research is also necessary to evaluate the potential prognostic value of intrathecal IgM in treatment response.
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http://dx.doi.org/10.1007/s40291-020-00455-wDOI Listing
June 2020

Sensitive Assessment of Acute Optic Neuritis by a New, Digital Flicker Test.

Ophthalmic Res 2020 25;63(3):332-340. Epub 2019 Oct 25.

Clinic of Optic Neuritis and Clinic of Multiple Sclerosis, Department of Neurology, Rigshospitalet - Glostrup, University of Copenhagen, Glostrup, Denmark.

Background: The Aulhorn flicker test (AFT) previously showed promise in diagnosing acute optic neuritis (ON) albeit with suboptimal sensitivity. A new, digitalized version of the AFT (the DFT) has not previously been examined in acute ON.

Objectives: To examine the sensitivity, specificity and reproducibility of the DFT in acute ON.

Method: The DFT assesses the subjective brightness of a flickering field (1-60 Hz). In normal subjects, brightness enhancement occurs at intermediate frequencies, whereas in acute ON darkness enhancement (DE) is hypothesized. AFT and DFT measurements were obtained in acute ON patients (≤31 days from first symptom) with DE as a quantitative covariate. Reproducibility of the DFT end point was assessed in the form of an intraclass correlation.

Results: 30 untreated first-time acute ON patients and 55 healthy controls were examined. AFT and DFT were performed 12.7 days (range: 4-30) following ON onset. The DFT showed a sensitivity of 0.93 (95% CI = 0.78-0.99) to a specificity of 0.96 (95% CI = 0.87-1.00). The AFT showed a sensitivity of 0.76 (95% CI = 0.56-0.90) to a specificity of 1.00 (95% CI = 0.93-1.00). No significant correlation was shown between DFT and visual acuity. The intraclass correlation of the DFT end point in healthy subjects was 0.84.

Conclusions: We present a new DFT in acute ON displaying a high specificity of 0.96 and a sensitivity of 0.93. Our study indicates the DFT to be an accurate and easy-to-use tool in diagnosing acute ON, which may be especially helpful in atypical cases.
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http://dx.doi.org/10.1159/000503304DOI Listing
March 2021

Functional-structural assessment of the optic pathways in patients with optic neuritis.

Doc Ophthalmol 2020 04 17;140(2):159-168. Epub 2019 Oct 17.

Clinic of Optic Neuritis and Clinic of Multiple Sclerosis, Department of Neurology, Rigshospitalet - Glostrup, University of Copenhagen, Valdemar Hansens Vej 13, 2600, Glostrup, Denmark.

Background: The pattern-reversal visual evoked potential (pVEP) is widely used for the diagnosis of Optic Neuritis (ON), but this method has some limitations. The aim of this study was to examine the added value of multifocal visual evoked potentials (mfVEP) and spectral-domain optical coherence tomography (SD-OCT) in the diagnosis of ON in patients that exhibit a normal pVEP.

Method: Thirty-three patients with a history of having ON and 30 sex- and age-matched healthy controls (HC) were investigated. We included patients who were suspected of having a first-time ON and in whom pVEP showed normal results. Both eyes of the patients and HC were systematically investigated with SD-OCT, visual acuity, pVEP and mfVEP. The ON-affected eyes of the patients were compared with only one randomly selected eye per person in the HC group. The fellow "non-affected" eye of patients was held as a separate group. Statistical analyses were performed (including t test, Spearman's rank-order correlation test) using SPSS Statistics, Version 24.0.

Results: A significant difference was found in OCT mean retinal nerve fibre layer thickness (RNFLt) between patients and HC (p = 0.013) (i.e. 84.24 (± 17.00) μm versus 93.48(± 6.44) μm). An association was detected in patients between mean inter-eye asymmetry of the RNFLt and global (averaged) mfVEP amplitude (r = 0.565, p = 0.002). When analysing mfVEP signals from sectors in the upper hemifield, a significant difference was found in mean mfVEP amplitude between patients and HC (p = 0.005).

Conclusions: Abnormality is potentially measurable (via reduced RNFLt and focal analyses with mfVEP amplitude) in patients suspected of having a first episode of ON where pVEP reports no abnormality. The mfVEP and SD-OCT may together be of value as supplementary tools in diagnosing ON in this patient group.
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http://dx.doi.org/10.1007/s10633-019-09728-0DOI Listing
April 2020

A free and simple computerized screening test for visual field defects.

Scand J Psychol 2019 Aug 26;60(4):289-294. Epub 2019 May 26.

Department of Psychology, University of Copenhagen, Copenhagen, Denmark.

About 30-40% of stroke patients suffer from visual field defects following injury. These can interfere with the standard neuropsychological assessment and complicate the interpretation of tests that use visual materials. However, information about the integrity of a patient's central visual field is often unavailable. We, therefore, designed a screening tool, the computerized visual field test (c-VFT), specifically targeted at providing easily available, but rough, information about patients' central visual field. c-VFT was tested in two samples of stroke patients. Eleven patients were tested on c-VFT and on the Esterman test. Five patients were tested on c-VFT and the Humphrey Visual Field Analyzer (HFA), central 10-2. Criterion validity of the c-VFT was investigated by calculating quadrantwise intraclass correlation for both comparisons. For the HFA comparison, we also calculated point-to-point intraclass correlation, sensitivity, and specificity. Analyses revealed moderately good correspondence between c-VFT and the Esterman test, and between c-VFT and HFA 10-2, respectively. When looking specifically at test points within one degree of visual angle apart in the two tests, intraclass correlation increased. For these points, the sensitivity of c-VFT was 0.89 and specificity was 0.97. While the c-VFT is not designed to be diagnostic nor to replace the detailed visual field analysis, this study shows that it provides a reasonable screening of the central visual field. The test can easily be used and will be made freely available to neuropsychological clinicians and researchers.
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http://dx.doi.org/10.1111/sjop.12546DOI Listing
August 2019

Nationwide prevalence and incidence study of neuromyelitis optica spectrum disorder in Denmark.

Neurology 2018 12 9;91(24):e2265-e2275. Epub 2018 Nov 9.

From the Department of Neurology (V.P., K.S., T.P.), Aarhus University Hospital; Department of Neurology (Z.I., H.H.N.), Odense University Hospital; Institute of Clinical Research (Z.I., H.H.N.), Institute of Molecular Biology (H.H.N.), and Department of Regional Health Research, Faculty of Health Sciences (E.S.), University of Southern Denmark, Odense; The Danish Multiple Sclerosis Center (M.M., P.E.H.J., F.S.), Department of Neurology, Rigshospitalet, University of Copenhagen; The Danish Multiple Sclerosis Registry (M.M., N.K.-H.), Department of Neurology, Rigshospitalet, Copenhagen University Hospital; Department of Clinical Epidemiology, Clinical Institute (N.K.-H.), and Department of Biomedicine (T.C.), Aarhus University; MS-Clinic of Southern Jutland (Sønderborg, Esbjerg, Kolding) (M.K., E.S.), Department of Neurology, Hospital of Southern Jutland, Sønderborg; Department of Neurology (C.C.P., Z.M.), Aalborg University Hospital; Multiple Sclerosis Unit (S.F.R.), Department of Neurology, Herlev Hospital, Copenhagen; Department of Neurology (M.B.J.), Nordsjællands Hospital, Hillerød; Department of Neurology (A.E.P.), Hospital of Southwest Jutland, Esbjerg; Department of Neurology (L.R.), Hospital of Central Denmark Region, Viborg; Department of Autoimmunology and Biomarkers (M.C.L., N.H.), Statens Serum Institut, Copenhagen; and Department of Neurology (J.L.F.), Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Objectives: To estimate the nationwide population-based incidence, prevalence, and geographical distribution of neuromyelitis optica (NMO) spectrum disorder (NMOSD) in Denmark based on the 2015 International Panel for NMO Diagnosis (IPND) criteria.

Methods: We conducted a multicentre, historically prospective study. Data were sourced from the Danish National Patient Registry, the Danish Multiple Sclerosis Registry, departments of neurology, and laboratories providing aquaporin-4 antibody test. Cases were selected based on the 2006 Wingerchuk and the 2015 IPND criteria and were individually validated by an expert panel.

Results: We confirmed NMO in 30 cases (2006 criteria) and NMOSD in 56 cases (2015 IPND criteria) between 2007 and 2014. Defined by the 2006 criteria, the incidence of NMO was 0.029 per 100,000 person-years (95% confidence interval [CI] 0.014-0.051), and the prevalence (aged 16 years and older) was 0.566 per 100,000 (95% CI 0.370-0.830). Based on the 2015 IPND criteria, the incidence of NMOSD was 0.070 per 100,000 person-years (95% CI 0.046-0.102), and the prevalence (aged 16 years and older) was 1.09 per 100,000 (95% CI 0.808-1.440), without regional differences.

Conclusions: Our estimates of incidence and prevalence are similar to other Caucasian population-based studies using the 2015 IPND criteria. We found no geographical clustering in Denmark.
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http://dx.doi.org/10.1212/WNL.0000000000006645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329324PMC
December 2018

The role of gluten in multiple sclerosis: A systematic review.

Mult Scler Relat Disord 2019 Jan 23;27:156-163. Epub 2018 Oct 23.

Multiple Sclerosis Clinic, Department of Neurology, Rigshospitalet Glostrup and University of Copenhagen, Valdemar Hansens Vej 13, DK-2600 Denmark. Electronic address:

Background: There is an increasing interest in diet as a modifying factor in multiple sclerosis (MS), and gluten has been suggested to affect MS.

Objective: The aim of this systematic review is to qualitatively evaluate the evidence on the role of gluten in MS.

Methods: A review protocol was submitted to PROSPERO. A systematic literature search was conducted in PubMed, Web of Science, Scopus, Embase, Cab Abstracts, and Google Scholar. Studies on patients with MS, clinically isolated syndrome, or celiac disease presenting with MS-related markers were included, if they investigated effects of diets containing specified amounts of gluten or associations between gluten sensitivities and MS.

Results: Forty-nine publications presenting 50 studies/cases met the inclusion criteria. Study designs, methods, and outcomes varied broadly across studies. Two intervention studies found a positive effect of a gluten-free diet on disease-related markers in patients with MS. One prospective cohort study also found a positive effect of a gluten-free diet, while a survey found intake of cereal/bread to be protective against MS. Four observational studies did not find increased comorbidity of MS and celiac disease. Seventeen studies investigated the level of different gluten-sensitivity markers in patients with MS with inconsistent results. Finally, 12 cases and 13 posters/abstracts/master's theses contributed to shed light on the topic.

Conclusions: There is still not sufficient evidence to state whether gluten plays a role in MS, but limitations of current evidence have been identified and directions of future research have been suggested.
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http://dx.doi.org/10.1016/j.msard.2018.10.019DOI Listing
January 2019

Link between overweight/obese in children and youngsters and occurrence of multiple sclerosis.

J Neurol 2018 Dec 26;265(12):2755-2763. Epub 2018 Apr 26.

Department of Neurology, Rigshospitalet-Glostrup, Nordre Ringvej 57, 2600, Glostrup, Denmark.

Background/aims: The prevalence of overweight/obesity is a major problem in the world, and the number of MS cases is increasing. This literature study examines the relationship between overweight/obesity in children and adolescents and later occurrence of MS.

Method: This is a complete literature survey. The search database is primarily Pubmed using MeSH terms "multiple sclerosis", "obesity", and "overweight", and text words not to restrict searches.

Results: All included studies show a link between being overweight/obese and the presence of MS among people below 20 years of age. The relation is especially true for young girls. The same relation in boys is not significant.

Conclusion: The literature survey convincingly revealed a link between young overweight/obese and occurrence of MS, in particular for girls. There is a need for more and larger studies to investigate the molecular mechanisms that link obesity and MS.
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http://dx.doi.org/10.1007/s00415-018-8869-9DOI Listing
December 2018

Optical coherence tomography in multiple sclerosis.

Eye (Lond) 2018 05 2;32(5):884-888. Epub 2018 Feb 2.

Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

To summarize recent findings regarding the utility of optical coherence tomography in multiple sclerosis. We searched PubMed for relevant articles using the keywords 'optical coherence tomography multiple sclerosis'. Additional articles were found via references in these articles. We selected articles based on relevance. Optical coherence tomography has contributed to greater insights into the pathophysiology of multiple sclerosis. Loss of retinal nerve fibre layer and ganglion cell layer thickness correlate with clinical and paraclinical parameters such as visual function, disability and magnetic resonance imaging. Some studies indicate that OCT parameters may be able to predict disability progression and visual function in MS. OCT angiography has recently emerged as a novel technique to study MS. OCT has proven very useful with regards to research, monitoring and predicting disability in multiple sclerosis. It will be interesting to see how OCT angiography will contribute to this field.
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http://dx.doi.org/10.1038/s41433-017-0010-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944645PMC
May 2018

Retinal ganglion cell analysis in multiple sclerosis and optic neuritis: a systematic review and meta-analysis.

J Neurol 2017 Sep 31;264(9):1837-1853. Epub 2017 May 31.

Department of Neurology, Clinic of Optic Neuritis and Clinic of Multiple Sclerosis, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Nordre Ringvej 57, 2600, Glostrup, Denmark.

The aim of this study was to summarise existing findings regarding optical coherence tomography (OCT) measurements of ganglion cell layer (GCL) alterations in optic neuritis (ON) and multiple sclerosis (MS). Peer-reviewed studies published prior to April 2016 were searched using PubMed, EMBASE, Web of Science and Scopus. Studies were included if they measured GCL thickness using OCT in patients with either ON, MS or clinically isolated syndrome. For the meta-analysis, we compared GCL thickness in MS patients with and without prior ON, to healthy controls. 42/252 studies were reviewed. In acute ON, studies showed significant thinning of the GCL within the first 5 weeks (n = 5), earlier than retinal nerve fibre layer (RNFL) thinning. GCL thinning at 1-2 months after acute ON predicted visual function at 6 months (n = 3). The meta-analysis showed that the thickness of the GCL was significantly reduced in MS patients both with and without previous ON compared to healthy controls. GCL thinning was associated with visual function in most studies (n = 10) and expanded disability status scale (EDSS) scores (n = 6). In acute ON, thinning of the GCL is measurable prior to RNFL thinning, and GCL thickness after 1-2 months may predict visual function after 6 months. Furthermore, GCL thinning occurs in MS both with and without prior ON, and may be associated with visual function and EDSS score. This suggests that the GCL is a promising biomarker, which may be used to examine in vivo neurodegeneration in ON and MS.
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http://dx.doi.org/10.1007/s00415-017-8531-yDOI Listing
September 2017

Multifocal visual evoked potentials in optic neuritis and multiple sclerosis: A review.

Clin Neurophysiol 2017 07 11;128(7):1234-1245. Epub 2017 Apr 11.

Clinic of Optic Neuritis and Clinic of Multiple Sclerosis, Department of Neurology, Rigshospitalet - Glostrup, University of Copenhagen, Nordre Ringvej 57, 2600 Glostrup, Denmark. Electronic address:

Multifocal visual evoked potential (mf-VEP) represents a new approach to the classical full field (ff-)VEP with separate responses from up to 60 sectors of the visual field. A thorough literature survey of the use of mf-VEP in optic neuritis (ON) and multiple sclerosis (MS) is presented (38 published studies were retrieved). Mf-VEP provides direct topographical information of specific lesions and facilitates investigations on structural-functional correlations thus providing new methods for exploring the interplay between demyelination, atrophy and remyelination in MS. Good correlation was shown between mf-VEP and OCT, ff-VEP, MRI (MTR, DTI), 30-2 standard automated perimetry and low-contrast-visual acuity. All but one study showed superior sensitivity and specificity compared to ff-VEP, especially with regards to small, peripheral lesions or lesions of the upper visual field. Mf-VEP has shown superior sensitivity and specificity than established methods in diagnosing optic nerve lesions and tracking functional recovery following lesions. Abnormal mf-VEP responses in the fellow, non-ON afflicted eye may predict MS risk in ON patients. No standardization currently exists and no direct comparisons in ON and MS between at least 5 different commercially available mf-VEP systems have so far been published. Despite these limitations, mf-VEP is a promising new tool of diagnostic and prognostic value of mf-VEP in ON and MS.
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http://dx.doi.org/10.1016/j.clinph.2017.03.047DOI Listing
July 2017

Vaccines and multiple sclerosis: a systematic review.

J Neurol 2017 Jun 7;264(6):1035-1050. Epub 2016 Sep 7.

Department of Neurology, University of Copenhagen, Rigshospitalet Glostrup, Nordre Ringvej 57, 2600, Glostrup, Denmark.

Vaccinations are often the most effective tool against some disease known to mankind. This study offers a literature review on the role of vaccines regarding the risk of developing multiple sclerosis (MS) and MS relapse. The method used in this study is a systematic literature review on the database PubMed. The study found no change in risk of developing multiple sclerosis (MS) after vaccination against hepatitis B virus, human papillomavirus, seasonal influenza, measles-mumps-rubella, variola, tetanus, Bacillus Calmette-Guérin (BCG), polio, or diphtheria. No change in risk of relapse was found for influenza. Further research is needed for the potential therapeutic use of the BCG vaccine in patients in risk of developing MS and for the preventive potential of the tetanus and diphtheria vaccine.
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http://dx.doi.org/10.1007/s00415-016-8263-4DOI Listing
June 2017

Rhabdomyolysis following interferon-beta treatment in a patient with multiple sclerosis - A case report.

Mult Scler Relat Disord 2016 Jul 16;8:93-5. Epub 2016 May 16.

Department of Neurology, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, 2600 Glostrup, Denmark. Electronic address:

Background: Multiple sclerosis is an inflammatory disease of the central nervous system for which there is currently no cure. Interferon-beta-1-alpha is worldwide one of the most widely used treatments in multiple sclerosis. To our knowledge there is one previous reported case of rhabdomyolysis associated with Interferon-beta treatment.

Case Presentation: We describe a 30 year old man with relapsing remitting multiple sclerosis who developed rhabdomyolysis and increased creatine kinase following Interferon-beta-1-alpha therapy. After the medication was discontinued, the patient rapidly improved.

Conclusion: Clinicians should be aware of the possibility of rhabdomyolysis occurring during Interferon-beta-1-alpha therapy. In cases where patients complain of severe myalgia, and in particular if weakness is reported, creatine kinase activity should be measured to prevent irreversible rhabdomyolysis during Interferon-beta-1-alpha therapy in patients with multiple sclerosis.
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http://dx.doi.org/10.1016/j.msard.2016.05.005DOI Listing
July 2016

Zinc in Multiple Sclerosis: A Systematic Review and Meta-Analysis.

ASN Neuro 2016 06 9;8(3). Epub 2016 Jun 9.

Department of Neurology, Rigshospitalet - Glostrup, University of Copenhagen, Glostrup, Denmark.

In the last 35 years, zinc (Zn) has been examined for its potential role in the disease multiple sclerosis (MS). This review gives an overview of the possible role of Zn in the pathogenesis of MS as well as a meta-analysis of studies having measured Zn in serum or plasma in patients with MS. Searching the databases PubMed and EMBASE as well as going through reference lists in included articles 24 studies were found measuring Zn in patients with MS. Of these, 13 met inclusion criteria and were included in the meta-analysis. The result of the meta-analysis shows a reduction in serum or plasma Zn levels in patients with MS with a 95% CI of [-3.66, -0.93] and a p value of .001 for the difference in Zn concentration in μM. One of six studies measuring cerebrospinal fluid, Zn levels found a significant increase in patients with MS with controls. The studies measuring whole blood and erythrocyte Zn levels found up to several times higher levels of Zn in patients with MS compared with healthy controls with decreasing levels during attacks in relapsing-remitting MS patients. Future studies measuring serum or plasma Zn are encouraged to analyze their data through homogenous MS patient subgroups on especially age, sex, and disease subtype since the difference in serum or plasma Zn in these subgroups have been found to be significantly different. It is hypothesized that local alterations of Zn may be actively involved in the pathogenesis of MS.
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http://dx.doi.org/10.1177/1759091416651511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904428PMC
June 2016

25-Hydroxyvitamin D levels in acute monosymptomatic optic neuritis: relation to clinical severity, paraclinical findings and risk of multiple sclerosis.

J Neurol 2015 Jul 1;262(7):1646-54. Epub 2015 May 1.

Clinic of Optic Neuritis, Department of Neurology, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, 2600, Glostrup, Denmark,

Optic neuritis (ON) is a common first symptom of MS and only few studies have thus far investigated vitamin D at this early stage of MS. The objectives of the study were to examine total 25-hydroxyvitamin D levels (25HVITDL) in patients in acute (A) ON and to determine whether 25HVITD levels in AON (1) predict risk of RRMS and (2) are associated with visual tests of ON severity. A cross-sectional study was conducted of mean 25HVITDL differences between ON (n = 164) and MS (n = 948) patients and of prevalence of 25HVITDL deficiency (<50 nmol/L) in ON and MS (two-sample t test, χ (2) test). Associations between 25HVITDL and (1) clinical ON severity, (2) paraclinical findings suggestive of MS [logistic regression (LRA), Spearman correlation] and (3) hazard of MS development [Cox (C) RA] in ON patients were assessed. 25HVITDL were deseasonalized before analysis. The mean levels were 47.6 (ON) and 63.9 (MS) nmol/L (p < 0.0001), and a significantly higher prevalence of 25HVITD deficiency in ON (56 %; 35 %) (p < 0.0001), most pronounced in females, was shown. Associations were found between 25HVITDL and both CSF leukocyte count (ρ = -0.177, p = 0.028) and IgG index elevation (OR 0.980, p = 0.031). Forty-one ON patients developed MS during the study. Multivariate CRA showed no effect on hazard of MS (HR: 0.991, p 0.284). No association was found between 25HVITDL and visual tests (acuity, contrast vision) or OCT RNFL or GCL thickness. The study indicates a high prevalence of 25HVITD deficiency in AON. 25HVITDL was significantly associated with CSF leukocyte count, but not ON severity. The study indicates a possible role of vitamin D in the early stages of MS, but does not support the use of 25HVITDL as a predictor of MS development in acute ON.
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http://dx.doi.org/10.1007/s00415-015-7740-5DOI Listing
July 2015

Statin treatment in multiple sclerosis: a systematic review and meta-analysis.

CNS Drugs 2015 Apr;29(4):277-91

Clinic of Optic Neuritis and Clinic of Multiple Sclerosis, Neurological Department, Glostrup Hospital, University of Copenhagen, Nordre Ringvej 57, 2600, Glostrup, Denmark,

Background: Multiple sclerosis (MS) is a chronic inflammatory disease that leads to progressive disability. Statins [hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors] are widely prescribed drugs in hypercholesterolemia. They exert immunomodulatory and neurotrophic effects and are attractive candidates for MS treatment due to reliable safety profiles and favorable costs. Studies of statins in a murine MS model and in open-label trials in MS have shown decreased disease severity.

Objective: Our objective was to assess current evidence to support statin treatment in MS and clinically isolated syndrome (CIS).

Methods: We conducted a systematic literature review of EMBASE, PubMed, and CINAHL databases, clinical trials registries, and unpublished conference meeting abstracts as well as reference lists between 1 and 8 June 2014 and repeated it on 1 December 2014. Randomized controlled trials (RCTs) of statins, in any form or dosage, as monotherapy or add-on to established therapy in relapsing-remitting MS (RRMS), progressive MS, and CIS were included. Data were extracted using pre-defined fields to measure study quality. Meta-analysis was performed with regards to pre-defined outcome measures of relapse activity, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) progression, and adverse events using a fixed-effects model due to low heterogeneity between studies.

Results: Eight trials were included in the review [five of statin add-on to interferon (IFN)-β treatment in RRMS, one of statin monotherapy in CIS, one of statin monotherapy in optic neuritis (ON)/CIS, and one of statin monotherapy in secondary progressive MS (SPMS)]. Three trials with eligible characteristics had not been published in peer-reviewed journals and were therefore not included. Due to the low number of trials in CIS and SPMS, meta-analysis of primary outcomes was only performed for RRMS studies. Meta-analysis showed no significant effect of statin add-on to IFNβ therapy. Indeed, a trend towards an increase in disease activity was shown in the statin group with regards to new T2 lesions, proportion of patients with relapse, and whole brain atrophy but not for EDSS progression. In SPMS, statin monotherapy showed significant reduction in brain atrophy and disability progression but no effect on relapse rate. In CIS, a phase II trial showed no difference in relapse activity, MRI activity or risk of MS between statin monotherapy and placebo. In acute ON, statin monotherapy produced better visual outcome but no difference in relapse activity, MRI activity, or risk of MS.

Conclusions: The pleiotropic effects and effects in the murine model of MS could not be converted to a proven effect in relapsing MS and hence statin therapy either as a monotherapy or in combination with IFNβ treatment for RRMS, and statin monotherapy for CIS cannot at present be recommended. However, indications are that statins may be beneficial in SPMS. The benefit thereof and whether this is due to a direct immunomodulatory and neuroprotective effect warrant further studies.
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http://dx.doi.org/10.1007/s40263-015-0239-xDOI Listing
April 2015

Differential diagnoses to MS: experiences from an optic neuritis clinic.

J Neurol 2014 Jan 25;261(1):98-105. Epub 2013 Oct 25.

Clinic of Optic Neuritis, Glostrup Hospital, University of Copenhagen, 2600, Glostrup, Copenhagen, Denmark,

Optic neuritis (ON) is closely linked to multiple sclerosis (MS). It may, however, also be associated to a range of autoimmune or infectious diseases. The purpose of this study was to assess the differential diagnoses in patients with suspected ON. In this retrospective study, we reviewed the files of all patients referred to the Clinic of Optic Neuritis, Glostrup Hospital, University of Copenhagen, Denmark, between January 2000 and November 2011. All patients were referred by ophthalmologists with possible ON. Patients diagnosed with MS prior to referral were excluded from the study. A total of 643 patients were included in the study. Apart from ON, the most frequent diagnoses were tumors (n = 15), ischemic or hypertensive neuropathies (n = 13), and retinal or choroid disorders (n = 9). Six patients were diagnosed with neuromyelitis optica. Rarer causes of visual loss were infections (n = 5), giant cell arteritis (n = 4), sarcoidosis (n = 3), thyrotoxicosis (n = 2), and hereditary or toxic neuropathies (n = 2). Nine percent of patients referred to the Clinic of Optic Neuritis had symptoms caused by medical, neurosurgical or ophthalmic disorders, and 0.9 % of our patients had NMO. Though most of these conditions are rare, it is of importance to keep them in mind upon encountering patients with symptoms of ON.
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http://dx.doi.org/10.1007/s00415-013-7166-xDOI Listing
January 2014

Detection of antibodies to the 20s proteasome by ELISA.

J Immunoassay Immunochem 2013 ;34(4):384-92

Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.

The presence of antibodies against the 20S proteasome has been correlated with diseases like multiple sclerosis (MS) and systemic lupus erythematosus (SLE) but no definite association has been established. In order to investigate this further, we optimized an ELISA for proteasome antibodies and applied it to test a total of 324 serum and plasma samples from MS patients, SLE patients, and healthy controls. Our results yield a functional and reliable assay but no correlation between the amount of proteasome antibodies present and the development of MS or SLE could be established.
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http://dx.doi.org/10.1080/15321819.2012.755628DOI Listing
February 2014

Investigation of autoantibody profiles for cerebrospinal fluid biomarker discovery in patients with relapsing-remitting multiple sclerosis.

J Neuroimmunol 2012 Jan 15;242(1-2):26-32. Epub 2011 Dec 15.

Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark.

Using the UNIarray® marker technology platform, cerebrospinal fluid immunoglobulin G reactivities of 15 controls and 17 RRMS patients against human recombinant proteins were investigated. Patient cerebrospinal fluids were oligoclonal band positive and reactivities were compared to that of sex- and age-matched controls. We hereby aimed at the characterization of autoreactivity in patients with RRMS. Differences in autoreactivities between control and RRMS samples were identified comprising autoantigens identified in this study only and previously reported autoantigens as well. A combination of the 10-15 most significant proteins may be investigated further as autoantigens for diagnostic purposes. Additional investigations may include minimizing the number of proteins used in such diagnostic tests.
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http://dx.doi.org/10.1016/j.jneuroim.2011.08.013DOI Listing
January 2012

Simvastatin as add-on therapy to interferon β-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial.

Lancet Neurol 2011 Aug;10(8):691-701

Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective. We aimed to establish whether add-on of simvastatin, a statin with anti-inflammatory properties, improves this efficacy.

Methods: We enrolled treatment-naive patients with relapsing-remitting multiple sclerosis in a multicentre, placebo-controlled, double-blind, randomised, parallel-group trial of simvastatin (80 mg daily) as add-on treatment to intramuscular interferon beta-1a (30 μg weekly). After starting treatment with interferon beta, patients were randomly assigned (in computer-generated blocks of four patients) to simvastatin 80 mg per day or placebo for 1-3 years. Patients and treating and evaluating physicians were masked to treatment allocation. The primary outcome measure was annual rate of documented relapses; analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00492765.

Findings: We randomly assigned 307 patients to interferon beta plus simvastatin (n=151) or plus placebo (n=156). Annual rate of documented relapses was 0·19 (95% CI 0·13 to 0·28) in the simvastatin group and 0·14 (95% CI 0·09 to 0·23) in the placebo group (absolute difference 0·059, 95% CI -0·21 to 0·09; p=0·35). Time to first documented relapse (20th percentile) was 18·1 months in patients on simvastatin and 21·5 months in those on placebo (hazard ratio 1·21, 95% CI 0·74 to 1·99; p=0·51). Mean number of new or enlarging T2 lesions was 2·96 in the simvastatin group and 2·52 in the placebo group (ratio of new lesions, 1·17, 95% CI 8·89 to 1·55; p=0·25). Eight (6%) patients on simvastatin and 17 (13%) on placebo had no disease activity (odds ratio 0·42, 95% CI 0·17 to 1·00; p=0·05). No unexpected adverse events were seen. Generally, adverse events were mild and there were no group differences in infections or musculoskeletal disorders, including myalgia (five [3%] patients on simvastatin and nine [6%] on placebo). Rhabdomyolysis and myoglobinuria were not reported and there were no differences in serum creatine phosphokinase.

Interpretation: We found no beneficial effect of simvastatin as add-on therapy to interferon beta-1a. Although unlikely, we can not exclude that combination of other statins with other disease-modifying drugs still could be beneficial.

Funding: Biogen Idec.
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http://dx.doi.org/10.1016/S1474-4422(11)70144-2DOI Listing
August 2011

NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial.

Lancet Neurol 2009 Jun 4;8(6):519-29. Epub 2009 May 4.

Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective, and new more effective and safe strategies are needed. Our aim was to assess the efficacy of oral methylprednisolone as an add-on therapy to subcutaneous interferon beta-1a to reduce the yearly relapse rate in patients with relapsing-remitting multiple sclerosis.

Methods: NORMIMS (NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis) was a randomised, placebo-controlled trial done in 29 neurology departments in Denmark, Norway, Sweden, and Finland. We enrolled outpatients with relapsing-remitting multiple sclerosis who had had at least one relapse within the previous 12 months despite subcutaneous interferon beta-1a treatment (44 microg three times per week). We randomly allocated patients by computer to add-on therapy of either 200 mg methylprednisolone or matching placebo, both given orally on 5 consecutive days every 4 weeks for at least 96 weeks. The primary outcome measure was mean yearly relapse rate. Primary analyses were by intention to treat. This trial is registered, number ISRCTN16202527.

Findings: 66 patients were assigned to interferon beta and oral methylprednisolone and 64 were assigned to interferon beta and placebo. A high proportion of patients withdrew from the study before week 96 (26% [17 of 66] on methylprednisolone vs 17% [11 of 64] on placebo). The mean yearly relapse rate was 0.22 for methylprednisolone compared with 0.59 for placebo (62% reduction, 95% CI 39-77%; p<0.0001). Sleep disturbance and neurological and psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Bone mineral density had not changed after 96 weeks.

Interpretation: Oral methylprednisolone given in pulses every 4 weeks as an add-on therapy to subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis leads to a significant reduction in relapse rate. However, because of the small number of patients and the high dropout rate, these findings need to be corroborated in larger cohorts.
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http://dx.doi.org/10.1016/S1474-4422(09)70085-7DOI Listing
June 2009