Publications by authors named "Harald Hegen"

72 Publications

Retinal layer thinning predicts treatment failure in relapsing multiple sclerosis.

Eur J Neurol 2021 Mar 18. Epub 2021 Mar 18.

Department of Neurology, Medical University of Vienna, Vienna, Austria.

Background And Purpose: Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) thinning are markers of neuroaxonal degeneration in multiple sclerosis (MS), which is reduced by disease-modifying treatment (DMT). We aimed to investigate the potential of pRNFL and GCIPL thinning for prediction of DMT failure in relapsing MS (RMS).

Methods: In this 4-year prospective observational study on 113 RMS patients, pRNFL and GCIPL were measured at DMT initiation and after 12 months (M12) and 24 months (M24). Treatment failure was defined as 6-month confirmed Expanded Disability Status Scale (EDSS) progression and/or Symbol Digit Modalities Test (SDMT) worsening. Optimal cutoff values for predicting treatment failure were determined by receiver operating characteristic analyses and hazard ratios (HRs) by multivariable Cox regression adjusting for age, sex, disease duration, EDSS/SDMT, and DMT class.

Results: Thinning of GCIPL >0.5 μm/year at M24 showed superior value for treatment failure prediction (HR: 4.5, 95% confidence interval [CI]: 1.8-7.6, p < 0.001; specificity 91%, sensitivity 81%), followed by GCIPL >0.5 μm at M12 (odds ratio [OR]: 3.9, 95% CI: 1.4-6.9, p < 0.001; specificity 85%, sensitivity 78%), and pRNFL ≥2 μm/year at M24 (OR: 3.7, 95% CI: 1.1-6.5, p = 0.023; specificity 84%, sensitivity 69%), whereas pRNFL at M12 was not predictive.

Conclusions: GCIPL, and to a lesser degree pRNFL, thinning predicts disability progression after DMT initiation and may be a useful and accessible biomarker of treatment failure in RMS.
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http://dx.doi.org/10.1111/ene.14829DOI Listing
March 2021

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Front Neurol 2020 17;11:579438. Epub 2020 Dec 17.

Immunology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain.

We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression. Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case. In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.
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http://dx.doi.org/10.3389/fneur.2020.579438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780851PMC
December 2020

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score.

Eur J Neurol 2021 May 18;28(5):1609-1616. Epub 2021 Jan 18.

Department of Neurology, Medical University of Vienna, Vienna, Austria.

Background And Purpose: There is a lack of evidence guiding discontinuation of disease-modifying therapy (DMT) in relapsing multiple sclerosis (RMS). Thus, the objective of this study was to generate and validate a risk score for disease reactivation after DMT discontinuation in RMS.

Methods: We drew a generation and validation dataset from two separate prospectively collected observational databases including RMS patients who received interferon-β or glatiramer acetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n = 168), regression analysis was performed to identify clinical or magnetic resonance imaging (MRI) variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model and applied to the validation sample (n = 98).

Results: The variables included in the final model as independent predictors of disease reactivation were age at discontinuation, MRI activity at discontinuation, and duration of clinical stability (all p < 0.001). The resulting score was able to robustly identify patients at high (83%-85%), moderate (36%-38%), and low risk (7%) of disease reactivation within 5 years after DMT discontinuation in both cohorts.

Conclusions: The composite VIAADISC score is a valuable tool to inform and support patients and neurologists in the process of decision making to discontinue injectable DMTs.
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http://dx.doi.org/10.1111/ene.14705DOI Listing
May 2021

Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis.

Mult Scler J Exp Transl Clin 2020 Oct-Dec;6(4):2055217320966344. Epub 2020 Oct 29.

Department of Neurology, Medical University of Vienna, Vienna, Austria.

Background: PIRA (progression independent of relapse) has emerged as a term to quantify the proportion of disability worsening due to non-inflammatory neurodegenerative processes in multiple sclerosis (MS).

Objective: To determine the impact of PIRA on retinal thinning, a biomarker of neuroaxonal degeneration in MS, in comparison to traditional disability worsening and relapse.

Methods: In a 4-year, prospective observational study including 171 relapsing MS (RMS) patients, retinal thinning was determined by annual spectral-domain optical coherence tomography measuring macular ganglion-cell-and-inner-plexiform-layer (GCIPL) and peripapillary-retinal-nerve-fibre-layer (pRNFL). PIRA was defined as an expanded disability status scale (EDSS) or symbol digit modalities test (SDMT) worsening confirmed after 24 weeks with no relapse in the 30 days before or after the disability worsening.

Results: Each PIRA event was associated with a mean additional loss of GCIPL (1.8 µm) and pRNFL (1.9 µm), similar to the impact of EDSS and SDMT worsening. Overall relapse and relapse without subsequent EDSS worsening did not influence retinal thinning, while a relapse with EDSS worsening was associated with an additional loss of GCIPL (1.3 µm) and pRNFL (1.4 µm).

Conclusions: PIRA is associated with retinal thinning, likely reflecting neurodegenerative processes, not directly associated with focal inflammation. It might be a clinical measure to identify MS patients with ongoing MS-associated neurodegeneration.
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http://dx.doi.org/10.1177/2055217320966344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604994PMC
October 2020

Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta: a GWAS.

BMC Med 2020 11 4;18(1):298. Epub 2020 Nov 4.

Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str 22, 81675, Munich, Germany.

Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations.

Methods: We analyzed a large sample of 2757 genotyped and imputed patients from two cohorts (Sweden and Germany), split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis.

Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR) = 3.55 (95% confidence interval = 2.81-4.48), p = 2.1 × 10) and rs28366299 in IFNβ-1b s.c.-treated patients (OR = 3.56 (2.69-4.72), p = 6.6 × 10). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR = 2.88 (2.29-3.61), p = 7.4 × 10) while DR3-DQ2 was protective (OR = 0.37 (0.27-0.52), p = 3.7 × 10). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR = 7.35 (4.33-12.47), p = 1.5 × 10). These haplotypes exhibit large population-specific frequency differences. The best prediction models were achieved for ADA in IFNβ-1a s.c.-treated patients. Here, the prediction in the Swedish cohort showed AUC = 0.91 (0.85-0.95), sensitivity = 0.78, and specificity = 0.90; patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR = 73.9 (11.8-463.6, p = 4.4 × 10) of developing nADA. In the German cohort, the AUC of the same model was 0.83 (0.71-0.92), sensitivity = 0.80, specificity = 0.76, with an OR = 13.8 (3.0-63.3, p = 7.5 × 10).

Conclusions: We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.
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http://dx.doi.org/10.1186/s12916-020-01769-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641861PMC
November 2020

Cerebrospinal fluid protein in Guillain-Barré syndrome: Need for age-dependent interpretation.

Eur J Neurol 2021 Mar 30;28(3):965-973. Epub 2020 Nov 30.

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

Background And Purpose: Elevated cerebrospinal fluid (CSF) total protein in patients with acute ascending paresis is indicative of Guillain-Barré syndrome (GBS). Recent studies showed that the outdated, but still widely used upper reference limit (URL) for CSF total protein of 0.45 g/L leads to false-positive results, mainly as a result of lack of age-adjustment. The objective of this study was to assess the frequency of increased CSF total protein in adult GBS patients according to a new age-dependent URL.

Methods: Patients with GBS treated at the Medical University of Innsbruck between 2000 and 2018 were included in this study. Demographic, clinical, electrophysiological and CSF data were obtained from patients' medical charts. Frequency of increased CSF total protein depending on disease duration was compared using the conventional URL of 0.45 g/L and the age-dependent URL.

Results: Ninety-seven patients with GBS aged 57 ± 18 years, comprising 38% women, underwent CSF sampling within a median of 6 days after symptom onset. The median CSF total protein concentration was 0.65 g/L and correlated with disease duration. Overall, 74% of patients had elevated CSF total protein levels using the conventional URL, as opposed to 52% applying the age-dependent URL. At 0-3, 4-7, 8-14 and >14 days after disease onset, elevated CSF total protein was found in 46%, 84%, 78% and 100% of patients using the conventional URL, and in 32%, 53%, 65% and 64% of patients using the age-dependent URL. In multivariate analysis, significant predictors of elevated CSF total protein were disease duration and the demyelinating GBS variant. Similar results were obtained for CSF/serum albumin quotient (Q ).

Conclusion: Fewer true-positives for CSF total protein and Q must be considered in suspected GBS, especially in the early disease course.
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http://dx.doi.org/10.1111/ene.14600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898894PMC
March 2021

Recent developments in MOG-IgG associated neurological disorders.

Ther Adv Neurol Disord 2020 31;13:1756286420945135. Epub 2020 Jul 31.

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

In the past few years, acquired demyelinating syndromes of the central nervous system associated with antibodies against myelin oligodendrocyte glycoprotein (MOG) have evolved into a new inflammatory disease entity distinct from neuromyelitis optica spectrum disorders or multiple sclerosis. The meticulous clinical description of patients with MOG IgG antibodies (MOG-IgG) has been achieved by development and use of highly specific cell-based assays. MOG-IgG associated disorders comprise a wide spectrum of syndromes ranging from acute disseminated encephalomyelitis predominantly in children to optic neuritis or myelitis mostly in adults. In recent studies, phenotype of MOG-IgG associated disorders has further broadened with the description of cases of brainstem encephalitis, encephalitis with seizures and overlap syndromes with other types of autoimmune encephalitis. In this review, we provide an overview of current knowledge of MOG-IgG associated disorders, describe the clinical presentations identified, highlight differences from neuromyelitis optica spectrum disorders and multiple sclerosis, summarize clinical outcome and concepts of immune treatment, depict the underlying mechanisms of antibody pathogenicity and provide the methodological essentials of MOG-IgG assays.
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http://dx.doi.org/10.1177/1756286420945135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521831PMC
July 2020

Cerebrospinal fluid oligoclonal bands in Neuroborreliosis are specific for Borrelia burgdorferi.

PLoS One 2020 25;15(9):e0239453. Epub 2020 Sep 25.

Department of Neurology, Neuroimmunology Laboratory, Medical University of Innsbruck, Innsbruck, Austria.

Background: Cerebrospinal fluid (CSF) oligoclonal bands (OCB) occur in chronic or post-acute phase of inflammatory diseases of the central nervous system.

Objective: To determine whether CSF OCB in patients with neuroborreliosis (NB) are specific for borrelia burgdorferi senso lato.

Methods: We performed isoelectric focusing followed by immunoblotting in CSF of 10 NB patients and 11 controls (7 patients with multiple sclerosis, 2 patients with neuromyelitis optica spectrum disease, 1 patient with dementia and 1 patient with monoclonal gammopathy). Immunoblotting was performed using an uncoated as well as a borrelia antigen pre-coated nitrocellulose membrane (NCM). OCB were counted by visual inspection and photometric analysis. OCB were compared between uncoated und pre-coated NCM both in the NB and control group. For validation purposes inter-assay precision was determined by calculating the coefficient of variation (CV).

Results: Borrelia-specific OCB were found in the CSF of 9 NB patients and in none of the control subjects resulting in a sensitivity of 90% and a specificity of 100%. Number of NB specific OCB were 11±7 bands by photometric analyses compared to 9±5 bands by visual inspection. Validation experiments revealed an inconsistent inter-assay precision between visual and photometric analyses (NB uncoated: visual 28% versus photometric 14%, control subject uncoated: visual 16% versus photometric 24%).

Conclusions: In CSF samples with positive OCB, Borrelia-specific bands were detected in almost all NB patients and in none of the control subjects. Inconsistent inter-assay precision may be explained by a poor comparability of visual and photometric approach.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239453PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518929PMC
November 2020

Inner nuclear layer and olfactory threshold are interlinked and reflect inflammatory activity in multiple sclerosis.

Mult Scler J Exp Transl Clin 2020 Jul-Sep;6(3):2055217320945738. Epub 2020 Aug 24.

Department of Neurology, Medical University of Vienna, Vienna, Austria.

Background: Retinal inner nuclear layer (INL) and olfactory threshold (OT) are associated with inflammatory activity in multiple sclerosis (MS).

Objective: The study aims to investigate (a) whether there is an association of INL and OT in MS and (b) if changes in INL and OT follow a time pattern in relation to MS relapse.

Methods: We assessed INL by optical coherence tomography and OT by Sniffin' Sticks in three different cohorts: a cross-sectional MS cohort ( = 260), a longitudinal, 3-year cohort of MS ( = 141) and healthy controls ( = 30), and a longitudinal, 24-weeks cohort with acute MS relapse ( = 28) and stable MS controls ( = 27).

Results: Cross-sectionally, INL and OT were strongly correlated with number but not localization of relapse in the previous 12 months and INL correlated with OT. Longitudinally, INL was thicker and OT score was lower short term in times of relapse activity, but not long term and independent of relapse localization. In acute MS relapse, INL and OT were altered compared with stable MS, again, independent of relapse localization resolving over 12-24 weeks with faster approximation to stable MS after escalation of disease-modifying treatment.

Conclusions: INL and OT are interlinked markers of short-term inflammatory activity, following a nearly congruent time pattern and independent of relapse localization, possibly reflecting a proinflammatory state within the central nervous system.
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http://dx.doi.org/10.1177/2055217320945738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448136PMC
August 2020

Validation of inter-eye difference thresholds in optical coherence tomography for identification of optic neuritis in multiple sclerosis.

Mult Scler Relat Disord 2020 Oct 17;45:102403. Epub 2020 Jul 17.

Department of Neurology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Objective: To examine and validate thresholds for inter-eye differences in peripapillary retinal nerve fibre (pRNFL) and ganglion cell + inner plexiform layer (GCIPL) thicknesses for identifying unilateral optic neuritis in MS.

Methods: In this two-centre, cross-sectional study, optical coherence tomography was performed in 340 patients with clinically isolated syndrome (CIS) and MS. Cut-off values of inter-eye difference for identification of eyes with a history of unilateral ON were evaluated by receiver-operating characteristics analysis.

Results: For pRNFL ≥5 µm, sensitivity was 69% and specificity 68%, while for GCIPL ≥4 µm sensitivity was 67% and specificity 78%. The areas under the curve (AUC) were 0.72 (95% confidence interval: 0.64 - 0.79) for pRNFL and 0.78 (95%CI: 0.72 - 0.85) for GCIPL, indicating GCIPL as the superior model (p<0.001). When analysing only CIS patients, GCIPL inter-eye difference ≥4 µm also remained significant, while pRNFL inter-eye difference did not.

Interpretations: Inter-eye differences of ≥4 μm for GCIPL and to a lesser degree ≥5 μm for RNFL are robust thresholds for identifying unilateral optic nerve lesions. These thresholds could be used to demonstrate previous symptomatic and possibly asymptomatic ON and might be included into a new version of the diagnostic criteria.
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http://dx.doi.org/10.1016/j.msard.2020.102403DOI Listing
October 2020

Transverse myelitis as a rare presentation of antiphospholipid-antibody-associated disorders.

Mult Scler Relat Disord 2020 Oct 17;45:102405. Epub 2020 Jul 17.

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

We report the case of a 35-year-old male patient suffering from a clinical and radiological manifestation of a transverse myelitis associated with antiphospholipid antibodies. After a challenging diagnosis the patient improved substantially due to immunosuppressive treatment. The demyelinating spinal cord lesion and the impressive therapeutic outcome may support the possibility of a direct binding of antiphospholipid antibodies to CNS antigens and consequently leading to a neuroimmunological pathomechanism distinct from the well-known pro-thrombotic effect of antiphospholipid antibodies. In terms of clinical routine diagnostic this case report highlights a rare but notable differential diagnosis of Multiple Sclerosis-like syndromes.
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http://dx.doi.org/10.1016/j.msard.2020.102405DOI Listing
October 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.
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http://dx.doi.org/10.3389/fimmu.2020.01188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311656PMC
April 2021

Macular ganglion cell-inner plexiform layer thinning as a biomarker of disability progression in relapsing multiple sclerosis.

Mult Scler 2021 Apr 2;27(5):684-694. Epub 2020 Jul 2.

Department of Neurology, Medical University of Vienna, Vienna, Austria.

Background: Macular ganglion cell-inner plexiform layer (mGCIPL) is an emerging biomarker of neuroaxonal degeneration in multiple sclerosis (MS).

Objective: We aimed to determine cut-off values of mGCIPL thinning for discriminating between progressing and stable patients in relapsing multiple sclerosis (RMS).

Methods: This is a 3-year prospective longitudinal study on 183 RMS patients with annual optical coherence tomography. Best possible cut-off values of baseline mGCIPL and annual loss of macular ganglion cell-inner plexiform layer (aLmGCIPL) for discriminating clinically progressing (physical progression or cognitive decline) from stable patients were defined by receiver operating characteristics analysis and tested using multivariate regression models.

Results: Baseline mGCIPL thickness <77 µm was associated with an increased risk (hazard ratio: 2.7, 95% confidence interval (CI): 1.5-4.7,  < 0.001) of disability progression. An aLmGCIPL cut-off ⩾1 µm accurately identified clinically progressing patients (87% sensitivity at 90% specificity) and was a strong predictor of clinical progression (odds ratio: 18.3, 95% CI: 8.8-50.3).

Conclusion: We present evidence that cross-sectionally measured mGCIPL thickness and annualized thinning rates of mGCIPL are able to identify clinically progressing RMS with high accuracy.
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http://dx.doi.org/10.1177/1352458520935724DOI Listing
April 2021

Influence of physical activity on serum vitamin D levels in people with multiple sclerosis.

PLoS One 2020 11;15(6):e0234333. Epub 2020 Jun 11.

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

In most cases, multiple sclerosis (MS) patients reduce physical activity with disease progression and many patients are found to be vitamin D deficient. The aim of this study was to explore correlations between daily physical activity in everyday life and 25-hydroxyvitamin-D3 (25(OH)D3) serum levels in mildly disabled patients with an Expanded Disability Status Scale (EDSS) ≤ 4. We analyzed serum 25(OH)D3 levels and recorded daily physical activity (activity duration, number of steps, distance, energy expenditure) using an activity tracker for 14-days in 25 women and 15 men. Participants recorded their daily sunlight exposure time by diary during the study period. We found a positive correlation between physical activity and 25(OH)D3 levels in both, Pearson correlation (r = 0.221) and multivariate regression analysis (β = 0.236), which was stronger than correlation with sunlight exposure time (β = -0.081). EDSS and physical activity were weakly correlated (r = -0.228), but no correlation between EDSS and 25(OH)D3 levels was found (r = -0.077). There were no relevant differences in physical activity (p = 0.803) and 25(OH)D3 concentrations (p = 0.385) between the EDSS groups 0 - 1.5 and 2.0 - 4.0. In conclusion, physical activity has an effect on vitamin D levels independent of sunlight exposure time in people with MS (pwMS) with low-grade disability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289406PMC
August 2020

Late-onset neutropenia in a multiple sclerosis patient after first dose ocrelizumab switched from rituximab.

Mult Scler Relat Disord 2020 Aug 13;43:102155. Epub 2020 May 13.

Medical University of Innsbruck, Department of Neurology, Anichstraße 35, Innsbruck 6020, Austria. Electronic address:

Ocrelizumab is a humanized monoclonal anti-CD20 antibody approved for treatment of relapsing-remitting and primary progressive multiple sclerosis (MS). Before approval of this drug, the chimeric anti-CD20 antibody rituximab was used off-label for treatment of MS. On treatment with rituximab late-onset neutropenia (LON) was reported as a rare adverse event. Here we report the case of a patient with MS who first received rituximab without experiencing any hematologic abnormalities, but developed grade IV LON after switching to ocrelizumab. This first case of LON in a patient treated with different anti-CD20 antibodies highlights the necessity of regular hemogram examinations during ocrelizumab.
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http://dx.doi.org/10.1016/j.msard.2020.102155DOI Listing
August 2020

Commentary to "Letter to the editor: To treat or not to treat study - Comparative group inclusion considerations" for multiple sclerosis and related disorders.

Mult Scler Relat Disord 2020 May 31;40:101975. Epub 2020 Jan 31.

Department of Neurology, Medical University of Vienna, Austria.

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http://dx.doi.org/10.1016/j.msard.2020.101975DOI Listing
May 2020

International multicenter examination of MOG antibody assays.

Neurol Neuroimmunol Neuroinflamm 2020 03 5;7(2). Epub 2020 Feb 5.

From the Clinical Department of Neurology (M. Reindl, K.S., M. Ramberger, H.H.), Medical University of Innsbruck, Innsbruck, Austria; Oxford Autoimmune Neurology Group (M.W., M. Ramberger, M.I.L., J.P., S.R.I., P.W.), Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdom; Brain Autoimmunity Group (F.T., S.R., R.C.D., F.B.), Kids Neuroscience Centre at Kids Research at the Children's Hospital at Westmead, Brain and Mind Centre, University of Sydney, New South Wales, Australia; Department of Neurology (J.S., J.P.F., J.M., E.P.F., S.J.P.), Mayo Clinic, Rochester, MN; Euroimmun Medizinische Labordiagnostika AG (B.T., S.M., N.R., U.K., W.S., C.P.), Lübeck, Germany; Institute for Quality Assurance (ifQ) affiliated to Euroimmun (J.E., M.P.), Lübeck, Germany; Paediatric Neurology (K.R.), Witten/Herdecke University, Children's Hospital Datteln, Datteln, Germany; and Department of Neurology (T.B.), Medical University of Vienna, Austria.

Objective: To compare the reproducibility of 11 antibody assays for immunoglobulin (Ig) G and IgM myelin oligodendrocyte glycoprotein antibodies (MOG-IgG and MOG-IgM) from 5 international centers.

Methods: The following samples were analyzed: MOG-IgG clearly positive sera (n = 39), MOG-IgG low positive sera (n = 39), borderline negative sera (n = 13), clearly negative sera (n = 40), and healthy blood donors (n = 30). As technical controls, 18 replicates (9 MOG-IgG positive and 9 negative) were included. All samples and controls were recoded, aliquoted, and distributed to the 5 testing centers, which performed the following antibody assays: 5 live and 1 fixed immunofluorescence cell-based assays (CBA-IF, 5 MOG-IgG, and 1 MOG-IgM), 3 live flow cytometry cell-based assays (CBA-FACS, all MOG-IgG), and 2 ELISAs (both MOG-IgG).

Results: We found excellent agreement (96%) between the live CBAs for MOG-IgG for samples previously identified as clearly positive or negative from 4 different national testing centers. The agreement was lower with fixed CBA-IF (90%), and the ELISA showed no concordance with CBAs for detection of human MOG-IgG. All CBAs showed excellent interassay reproducibility. The agreement of MOG-IgG CBAs for borderline negative (77%) and particularly low positive (33%) samples was less good. Finally, most samples from healthy blood donors (97%) were negative for MOG-IgG in all CBAs.

Conclusions: Live MOG-IgG CBAs showed excellent agreement for high positive and negative samples at 3 international testing centers. Low positive samples were more frequently discordant than in a similar comparison of aquaporin-4 antibody assays. Further research is needed to improve international standardization for clinical care.
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http://dx.doi.org/10.1212/NXI.0000000000000674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051197PMC
March 2020

To treat or not to treat: Sequential individualized treatment evaluation in relapsing multiple sclerosis.

Mult Scler Relat Disord 2019 Dec 23;39:101908. Epub 2019 Dec 23.

Department of Neurology, Medical University of Vienna, Austria.

Background: The frequency and long-term prognosis of relapsing multiple sclerosis (RMS) never receiving disease-modifying treatment (DMT) is unclear.

Methods: We included 1186 RMS patients with a mean of 17.4 years follow-up and divided them into patients treated with any DMT (DMT) and patients untreated by shared (USD) or patient-autonomous decision (UAD).

Results: The USD group displayed features, which significantly differed from the two other groups: higher age at onset, mainly sensory onset symptoms, complete remission of onset symptoms, less T2 and contrast-enhancing T1 lesions on initial brain MRI. In a multivariate cox regression, USD was associated with lower risk for secondary progression (SPMS) conversion (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.55-0.97, p = 0.011) compared to DMT, while UAD was associated with an increased SPMS conversion risk only in the "McDonald era" (HR 1.19, CI 1.02-1.58, p = 0.028).

Conclusion: Apart from the doubtless substantial improvement of the overall prognosis of RMS by DMT, it seems likely that not every patient necessarily needs immediate or even "hard and early" treatment. A "watchful waiting" approach with continuous clinical evaluation might be instead a viable option in RMS patients with favorable prognostic features at onset.
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http://dx.doi.org/10.1016/j.msard.2019.101908DOI Listing
December 2019

Serum neurofilament light levels correlate with change of olfactory function in multiple sclerosis.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319885987. Epub 2019 Nov 5.

Department of Neurology, Medical University of Innsbruck, Austria.

Background: Serum neurofilament light chain levels (sNfL) and impairment of olfactory function emerge as biomarkers in multiple sclerosis (MS). However, the relation between sNfL and olfactory function in MS has not been investigated yet.

Objective: We aimed to determine whether sNfL levels correlate with olfactory function in relapsing-remitting (RR) MS.

Methods: We annually measured sNfL and olfactory function (Sniffin' Sticks test: Threshold (T) and combined discrimination-identification (DI) score) in 80 RRMS patients and compared sNfL to T and DI scores.

Results: T scores significantly correlated with sNfL levels at simultaneous measurement (-1.5 points, 95% CI: -2.6-0.5 per 10 pg/ml sNfL increase;  < 0.001 per 10 pg/ml sNfL increase), but not at temporally distant measurement. Patients with ≥2 sNfL measures above the 75th percentile displayed significantly larger DI decrease (median 3.0 points, IQR 2.0-4.5) compared to patients with no or only one sNfL measure above the 75th percentile (0.0, IQR -0.5-0.5,  < 0.001 and 1.0, IQR 0.0-3.30,  = 0.008, respectively). 13-18% of the variance in T and 22% in DI decrease could be predicted from sNfL levels.

Conclusions: sNfL correlates with different qualities of olfactory function in patients with RRMS further strengthening the value of olfactory function as a biomarker of inflammation and axonal damage in MS.
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http://dx.doi.org/10.1177/2055217319885987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831970PMC
November 2019

Serum hepcidin levels in multiple sclerosis.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319885984. Epub 2019 Nov 4.

Department of Neurology, Medical University of Vienna, Austria.

Background: Brain iron accumulation is associated with multiple sclerosis (MS). Hepcidin is the master regulator of iron homeostasis and distribution. Dysregulation of hepcidin is a feature of different chronic inflammatory diseases but has not been investigated in MS so far.

Objective: The aim of this study was to determine serum hepcidin levels of MS patients and healthy volunteers serving as controls and to investigate possible relations between hepcidin levels, disease activity and disease course.

Methods: In a cross-sectional design, we measured serum hepcidin levels in 71 MS patients and 16 healthy controls (HC). MS patients were sub-grouped in active relapsing-remitting MS (aRRMS), inactive (i)RRMS, active progressive MS (aPMS) and inactive (i)PMS. Blood parameters were measured by standard laboratory methods.

Results: Median hepcidin levels were 26.9 ng/ml (confidence interval (CI) 22.8; 30.9) in MS and 17.3 ng/ml (CI 12.8; 23.4) in HC with significant age and sex effects. Hepcidin correlates were in line with hepcidin as an indicator of iron stores. After correction for age and sex, hepcidin was neither associated with MS subgroups nor degree of disability and occurrence of relapses.

Conclusions: Serum hepcidin levels are not associated with disease activity and disease course in MS.
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http://dx.doi.org/10.1177/2055217319885984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831977PMC
November 2019

Serum neurofilament levels correlate with retinal nerve fiber layer thinning in multiple sclerosis.

Mult Scler 2020 11 31;26(13):1682-1690. Epub 2019 Oct 31.

Department of Neurology, Medical University of Vienna, Vienna, Austria.

Background: Serum neurofilament light chain (sNfL) levels and peripapillary retinal nerve fiber layer (pRNFL) are both emerging biomarkers of neuro-axonal damage in multiple sclerosis (MS). However, data on the relation between sNfL and pRNFL are scarce.

Objective: We aimed to determine the relation of sNfL levels with pRNFL thinning in a large cohort of relapsing-remitting (RR) MS patients.

Methods: We identified 80 patients from a prospective, 3-year observational study on retinal changes in RRMS with annual blood samples available. sNfL levels were measured using single-molecule array (Simoa) assay. Annualized loss of pRNFL (aLpRNFL) was determined by individual linear regression models. Correlations between single and repeated sNfL levels and aLpRNFL were analyzed using multivariate linear regression and mixed-effect models.

Results: After correction for sex, age, and baseline sNfL, an sNfL increase of 10 pg/mL was associated with an aLpRNFL of -0.7 µm (95% confidence interval (CI): (-1.3, -0.2),  < 0.001). Patients with ⩾2 sNfL measurements >75th percentile displayed higher aLpRNFL (2.2 µm, standard deviation (SD) 0.6) compared to patients with no sNfL measure >75th percentile (0.4 µm, SD 0.2,  < 0.001). Between 15% and 20% of the aLpRNFL variance could be predicted from sNfL levels.

Conclusion: sNfL levels contribute to the prediction of retinal thinning in patients with RRMS, strengthening its value as a biomarker of neuro-axonal damage.
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http://dx.doi.org/10.1177/1352458519882279DOI Listing
November 2020

Dataset for worldwide survey of cerebrospinal total protein upper reference values.

Data Brief 2019 Apr 7;23:103760. Epub 2019 Mar 7.

Division of Neurology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada.

This article reports data pertaining to a worldwide web-based survey referenced in the publication "Adult CSF Total Protein: Higher upper reference limits should be considered worldwide " (P.R. Bourque, et al., 2019). This survey was distributed to corresponding authors of the journal Neurology and the Journal of neurological sciences for the period of Jan-Dec 2017. The response rate was 36.9%. Additional results were collated through networking and national associations. There were 473 unique responses from clinical hospital laboratories in 69 countries: North America 178, South America 26, Europe 139, Africa 20, Asia 102 and Oceania 8. The upper reference limit for cerebrospinal fluid total protein ranged from 0.2 g/L to 0.8 g/L. 86.8% of the survey responses were 0.45 g/L or less. Data is presented separately for tertiary/academic and non-university/community centers.
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http://dx.doi.org/10.1016/j.dib.2019.103760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514267PMC
April 2019

Conversion and reversion of anti-John Cunningham virus antibody serostatus: A prospective study.

Brain Behav 2019 07 6;9(7):e01332. Epub 2019 Jun 6.

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

Introduction: Determination of antibodies against the John Cunningham virus (JCV) is an important tool for risk stratification in Natalizumab-treated multiple sclerosis (MS) patients. Six-monthly testing has been suggested for anti-JCV antibody negative patients and patients with low antibody index in order to detect changes of serostatus. We conducted a prospective study with predefined testing intervals in order to investigate the predictability of anti-JCV antibody status and the intervals for repetitive testing.

Methods: Our study included 109 patients at the MS Clinic of the Departments of Neurology, Medical Universities of Innsbruck and Salzburg. Blood withdrawals were performed at five time points: baseline, month 1, 3, 6, and 12. Patients' sera were sent to Unilabs, Copenhagen, Denmark, where anti-JCV antibodies were tested by a two-step enzyme-linked immunosorbent assay. Qualitative (negative/positive) and quantitative results (anti-JCV antibody index) were used for statistical analyses.

Results: In our cohort, 52.3% of the patients were positive for anti-JCV antibodies at baseline, with a significant correlation with age, but no association with sex or prior disease-modifying therapy. Seven patients converted and reverted from negative to positive status and vice versa around the cut-off index of 0.4, but no patient showed a permanent seroconversion from negative to highly positive anti-JCV antibody status.

Conclusion: Long-term anti-JCV antibody status, including seroconverters/-reverters around the cut-off index, is highly predictable by testing three times within short intervals, however, we cannot suggest clearly defined intervals for repetitive testing. The rate of real seroconverters, i.e., new infections with JCV, per year seems lower than previously described.
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http://dx.doi.org/10.1002/brb3.1332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625483PMC
July 2019

Free light chains in the cerebrospinal fluid. Comparison of different methods to determine intrathecal synthesis.

Clin Chem Lab Med 2019 Sep;57(10):1574-1586

Department of Neurology, Wilhelminenspital, Montleartstrasse 37, 1160 Vienna, Austria.

Background Free light chains (FLC) have been proposed as diagnostic biomarkers in the cerebrospinal fluid (CSF) of patients with inflammatory central nervous system (CNS) diseases. However, which method to use for determining an intrathecal FLC synthesis has not yet been clarified. The objective of this study was to compare the diagnostic performance of CSF FLC concentration, FLC quotient (QFLC), FLC index and FLC intrathecal fraction (FLCIF). Methods κ- and λ-FLC were measured by nephelometry under blinded conditions in CSF and serum sample pairs of patients with clinically isolated syndrome (CIS; n = 60), multiple sclerosis (MS; n = 60) and other neurological diseases (n = 60) from four different MS centers. QFLC was calculated as the ratio of CSF/serum FLC concentration, the FLC index as QFLC/albumin quotient and the percentage FLCIF by comparing QFLC to a previously empirically determined, albumin quotient-dependent reference limit. Results CSF FLC concentration, QFLC, FLC index and FLCIF of both the κ- and λ-isotype were significantly higher in patients with CIS and MS than in the control group, as well as in oligoclonal bands (OCB) positive than in OCB negative patients. Each parameter was able to identify MS/CIS patients and OCB positivity, however, diagnostic performance determined by receiver operating characteristic (ROC) analyses differed and revealed superiority of FLC index and FLCIF. Conclusions These findings support the diagnostic value of FLC measures that correct for serum FLC levels and albumin quotient, i.e. blood-CSF barrier function.
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http://dx.doi.org/10.1515/cclm-2018-1300DOI Listing
September 2019

The clinical significance of single or double bands in cerebrospinal fluid isoelectric focusing. A retrospective study and systematic review.

PLoS One 2019 15;14(4):e0215410. Epub 2019 Apr 15.

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

Background: The presence of ≥3 oligoclonal bands (OCB) in the cerebrospinal fluid (CSF) without corresponding bands in serum represents a definite pathological pattern, whereas the clinical significance of 1-2 CSF bands (borderline pattern) is poorly investigated.

Methods: We screened 1986 consecutive CSF and serum samples which were collected over a four-year time period and had results of isoelectric focusing (IEF) available. Of patients with borderline OCB we reviewed individual medical charts for assessment of clinical diagnoses. Where feasible, IEF was replicated and results of follow-up samples were obtained. IEF was performed using polyacrylamide gel followed by immunoblotting and IgG-specific antibody staining. Additionally, we performed a systematic literature review of the diagnostic specificity of OCB using different cut-offs for CSF-restricted bands.

Results: Out of 253 patients with borderline OCB, 21.7% had an inflammatory neurological disease (IND) of the central nervous system, comprising 4% multiple sclerosis patients, and 14.2% had a peripheral IND, whereas the remaining 64.1% of patients showed non-inflammatory diseases. Frequency of one or two CSF bands without corresponding serum bands did not differ between the disease groups. In a subgroup of 100 patients IEF was repeated. Of those, 73% were OCB negative, while no sample was positive. In 26 patients IEF results were available of a follow-up sample collected after a median of 27 months. Of those, 4 (15.4%) turned positive. Systematic literature review revealed a diagnostic specificity of OCB of 97% and 92% using a cut-off ≥3 and ≥2 CSF bands in patients with mainly non-inflammatory neurological diseases.

Conclusion: The clinical significance of one or two CSF-restricted bands is moderate and, hence, indicates a possible but not reliable proof of intrathecal B-cell activity. Sample re-testing, introduction of an additional diagnostic category, e.g. "possible intrathecal IgG synthesis", and follow-up lumbar puncture might be possible options to address this scenario.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215410PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464233PMC
January 2020

A Survey of Cerebrospinal Fluid Total Protein Upper Limits in Canada: Time for an Update?

Can J Neurol Sci 2019 05 27;46(3):283-286. Epub 2019 Mar 27.

Division of Neurology, Department of Medicine,The Ottawa Hospital and University of Ottawa,Ottawa, Ontario,Canada.

Background: The antiquated standard reference range of 0.15-0.45 g/L for cerebrospinal fluid total protein (CSF-TP) is well entrenched in medical literature and laboratory operating procedures across the world.

Methods: We conducted a web-based survey with a response rate of 34.9% through the listserv of the Canadian Neurological Sciences Federation. Additional laboratory reference data were collated by telephone interview of hospital laboratory technologists across Canada.

Results: A total of 142 site responses were obtained: 64.1% from academic/tertiary hospitals and 35.9% from community hospitals. A strong majority (80.4%) of both types of institutions reported using a CSF-TP upper reference limit of 0.45 g/L or less. As a rule, no age adjustments were implemented in CSF-TP-level interpretation.

Conclusions: Recent well-powered laboratory reference studies have documented CSF-TP upper reference limits that are above 0.6 g/L starting at age 50, with incremental limits partitioned by subsequent decades of age. The conventional 0.45 g/L limit could lead to false positive results. Our survey suggests there is a need to consider a wide adoption of data-driven, rather than historical, reference values.
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http://dx.doi.org/10.1017/cjn.2019.12DOI Listing
May 2019

Impairment of odor discrimination and identification is associated with disability progression and gray matter atrophy of the olfactory system in MS.

Mult Scler 2020 05 21;26(6):706-715. Epub 2019 Mar 21.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria/Neuroimaging Research Core Facility, Medical University of Innsbruck, Innsbruck, Austria.

Background: Impairment of odor discrimination (D), identification (I), and threshold (T) are characteristic features of multiple sclerosis (MS).

Objective: To identify patterns of gray matter concentration (GMC) associated with different qualities of olfactory function.

Methods: Olfactory function (T and combined DI score) was measured by Sniffin' Sticks-Test over 2 years longitudinally, and T1-weighted 3-T magnetic resonance imaging (MRI) was performed in 37 MS patients and 18 matched healthy controls (HCs). Statistical parametric mapping (SPM) was applied to objectively identify changes of voxel-wise-GMC throughout the entire brain volume and to correlate image parameters with odor function.

Results: SPM localized significant GMC decreases in the anterior cingulum as well as temporomesial and frontobasal brain areas of the MS group compared with HCs, and revealed significant correlations between lower DI scores and GMC decreases in the olfactory gyrus, anterior cingulum, temporal regions including the parahippocampus, and putamen. Contrarily, no correlations were found between T and GMC. Patients with disability progression had significantly lower mean temporomesial/putamen GMC (0.782 vs 0.804,  = 0.004) compared to patients without Expanded Disability Status Scale (EDSS) progression.

Conclusion: Impairment of DI, but not T is associated with GM atrophy in brain regions related to olfactory function. Further studies are warranted to investigate DI scores and temporomesial/putamen GMC as biomarkers for disability progression.
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http://dx.doi.org/10.1177/1352458519838205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232781PMC
May 2020

Adult CSF total protein upper reference limits should be age-partitioned and significantly higher than 0.45 g/L: a systematic review.

J Neurol 2019 Mar 8;266(3):616-624. Epub 2019 Jan 8.

Division of Neurology, Department of Medicine, The Ottawa Hospital and University of Ottawa, 1053 Carling Ave., Ottawa, ON, K1Y 4E9, Canada.

Background: Cerebrospinal fluid total protein (CSF-TP) is measured in the diagnosis of a range of immune or infectious disorders of the nervous system. Most laboratories and the medical literature use an antiquated, age-independent upper limit of 0.45 g/L. Therefore, we performed a systematic review of reference studies in the medical literature, with the primary objective of determining the CSF total protein upper reference limit (URL). Secondary objectives were to assess the effects of age, gender, laboratory methods, and methodological quality.

Methods: A pre-planned and peer-reviewed electronic search strategy was used to search Ovid Medline and EMBASE for 1960-2017. All records underwent title/abstract review, and potentially relevant records underwent independent full-text review by two researchers. The remaining studies underwent quality assessment using a modification of the QUADAS2 revised tool. CSF-TP upper reference limits extracted from these studies were used to compute weighted means.

Results: Twenty-two articles were retained for qualitative analysis and 20 for quantitative analysis. The weighted average of CSF-TP URL was 0.55 g/L, in studies with high methodological quality. Studies that examined the effect of age reported consistent correlations with advancing age, and CSF-TP URL values incrementally exceeded 0.60 g/L after age 50. There were no meaningful differences according to gender, laboratory method, or quality assessment score.

Conclusions: There is concordance in available literature to recommend increasing CSF total protein upper reference limits, and to consider implementing age-adjusted values above 0.60 g/L starting at age 50. This information merits worldwide dissemination, to reduce the risk of over-diagnosis.
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http://dx.doi.org/10.1007/s00415-018-09174-zDOI Listing
March 2019

Pregnancy and multiple sclerosis in the DMT era: A cohort study in Western Austria.

Mult Scler 2020 01 3;26(1):69-78. Epub 2018 Dec 3.

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

Background: Multiple sclerosis (MS) predominantly affects women of child-bearing potential. Pregnancy in MS is still a controversial issue lacking standardized treatment recommendations.

Objective: To examine the reciprocal effects of pregnancy, MS, and disease-modifying treatment (DMT).

Methods: We analyzed 387 pregnancies in 239 women with relapsing remitting multiple sclerosis (RRMS) and ⩾1 pregnancy, establishment of diagnosis >1 year before conception, and ⩾2 years of follow-up after delivery. Relapse rates and Expanded Disability Status Scale (EDSS) scores were compared in the year before conception, during pregnancy, and 2 years postpartum. Binary logistic regression was used to investigate predictors of risk for relapses and disability progression during pregnancy and postpartum.

Results: Risk of relapse and disability progression during pregnancy was predicted by pre-conception relapse activity, higher EDSS score at conception, use of highly effective disease-modifying treatment (H-DMT) pre-conception, and prolonged washout period. Postpartum relapse and disability progression was associated with relapse activity pre-conception and during pregnancy and use of H-DMT pre-conception. Early restart of DMT reduced the risk of postpartum relapse.

Conclusion: A personalized approach in planning pregnancy in women with MS while on H-DMT needs to be adopted. It seems reasonable maintaining natalizumab closer to conception and restarting the drug early postpartum to reduce the considerable risk of disease reactivation during early pregnancy and after delivery.
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http://dx.doi.org/10.1177/1352458518816614DOI Listing
January 2020

Smelling multiple sclerosis: Different qualities of olfactory function reflect either inflammatory activity or neurodegeneration.

Mult Scler 2020 01 22;26(1):57-68. Epub 2018 Nov 22.

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

Background: Peripapillary retinal nerve fiber layer (pRNFL) thickness and olfactory function are both emerging biomarkers in multiple sclerosis (MS). Impairment of odor identification and discrimination is an irreversible feature of more advanced MS suggested to be associated with neurodegeneration, while olfactory threshold is a transient feature of early, active MS possibly associated with short-term inflammatory disease activity.

Objective: The aim of this study was to validate the association of olfactory (dys)function and parameters of MS disease course in a large cohort of MS patients and to correlate olfactory function with pRNFL thickness as a surrogate biomarker of neurodegeneration.

Methods: In a cross-sectional design, olfactory function was assessed using the Sniffin' Sticks test, which quantifies three different qualities of olfactory function (threshold, discrimination, and identification). pRNFL thickness was measured by spectral-domain optical coherence tomography (OCT). Results were correlated with age, sex, disease duration, relapses, Expanded Disability Status Scale (EDSS), cognitive function, depression, smoking, and pRNFL thickness by multivariable linear regression models.

Results: We included 260 MS patients (mean age of 35.9 years, 68.7% female). Olfactory threshold correlated significantly with number of relapses in the year prior to assessment and shorter disease duration. Odor discrimination, identification, and their sum score were significantly correlated with longer disease duration, higher EDSS, and reduced cognitive function. pRNFL thickness was associated with identification and discrimination, but not with threshold.

Conclusion: Olfactory threshold is a marker of short-term inflammatory relapse activity unrelated to parameters of neurodegeneration, while odor identification and discrimination are markers of neurodegeneration mostly independent of relapse activity. Assessment of olfactory function provides an opportunity to stratify MS patients with regard to inflammation and neurodegeneration.
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http://dx.doi.org/10.1177/1352458518814113DOI Listing
January 2020