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      Longitudinal time-domain optic coherence study of retinal nerve fiber layer in IFNβ-treated and untreated multiple sclerosis patients

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          Abstract

          Quantification of the retinal nerve fiber layer (RNFL) by optical coherence tomography (OCT) has been proposed to provide an indirect measure for retinal axonal loss. The aim of the present study was to determine whether interferon beta (IFNβ) treatment impedes retinal axonal loss in multiple sclerosis (MS) patients. A total of 48 patients with MS (24 IFNβ-1b-treated and 24 untreated subjects) and 12 healthy controls were enrolled in a prospective longitudinal OCT study. OCT measurements were performed for both eyes of each subject at baseline, and at 3-, 6-, and 12-month follow-up examinations using a time-domain OCT. At each visit, we additionally recorded full-field visual evoked potential (VEP) responses and performed the paced auditory serial addition test (PASAT), in addition to expanded disability status scale (EDSS) scoring. Generalized estimation equation (GEE) was used to account for repeated measurements and paired-data. The model-based approach predicted a monthly reduction in the RNFL thickness by 0.19 µm in the eyes of the MS subjects. The reduction was estimated to be 0.17 µm in case of IFNβ-treatment and 0.16 µm in case of no treatment. Treatment duration and group allocation were not significantly associated with the RNFL thickness. Inclusion of further longitudinal data (EDSS, two and three second PASAT) in each of our models did not result in any significant association. In summary, over a period of one year no significant association between IFNβ-1b treatment and RNFL thinning was identified in patients with MS.

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          Longitudinal data analysis for discrete and continuous outcomes.

          Longitudinal data sets are comprised of repeated observations of an outcome and a set of covariates for each of many subjects. One objective of statistical analysis is to describe the marginal expectation of the outcome variable as a function of the covariates while accounting for the correlation among the repeated observations for a given subject. This paper proposes a unifying approach to such analysis for a variety of discrete and continuous outcomes. A class of generalized estimating equations (GEEs) for the regression parameters is proposed. The equations are extensions of those used in quasi-likelihood (Wedderburn, 1974, Biometrika 61, 439-447) methods. The GEEs have solutions which are consistent and asymptotically Gaussian even when the time dependence is misspecified as we often expect. A consistent variance estimate is presented. We illustrate the use of the GEE approach with longitudinal data from a study of the effect of mothers' stress on children's morbidity.
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            Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group.

            (1993)
            We report a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNB) in 372 ambulatory patients with relapsing-remitting multiple sclerosis (MS). Entry criteria included an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 and at least two exacerbations in the previous 2 years. One-third of the patients received placebo, one-third 1.6 million international units (MIU) of IFNB, and one-third 8 MIU of IFNB, self-administered by subcutaneous injections every other day. The primary end points were differences in exacerbation rates and proportion of patients remaining exacerbation-free. The annual exacerbation rate for patients receiving placebo was 1.27; for 1.6 MIU IFNB, 1.17; and for 8 MIU IFNB, 0.84 after 2 years. Exacerbation rates were significantly lower in both treatment groups compared with the placebo group (8 MIU versus placebo, p = 0.0001; 1.6 MIU versus placebo, p = 0.0101; and 8 MIU versus 1.6 MIU, p = 0.0086), suggesting a dosage effect. The reduction in exacerbation severity in the 8 MIU group was attributable to a twofold reduction in the frequency of moderate and severe attacks. More patients in the 8 MIU group (n = 36) were exacerbation-free at 2 years compared with the placebo group (n = 18; p = 0.007). EDSS scores changed little from baseline in both the placebo and treatment arms. Accordingly, a significant change in disability could not be discerned in this trial. Finally, in serial MRIs, MS activity was significantly less in the high-dose IFNB group.(ABSTRACT TRUNCATED AT 250 WORDS)
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              Quantifying axonal loss after optic neuritis with optical coherence tomography.

              To determine to what degree changes in retinal nerve fiber layer (RNFL) thickness after optic neuritis (ON) correlate with either visual recovery or impairment. ON can cause visible defects within the RNFL, which can be quantified using optical coherence tomography (OCT). It may be possible to predict visual recovery by measuring RNFL loss after ON. Fifty-four patients underwent repeated evaluations with optical coherence tomography and standardized ophthalmic testing after ON. Regression analyses were used to determine the relationship between RNFL thickness and visual function. Thinning of the RNFL was seen in the majority of patients (74%), and it tended to occur within 3 to 6 months of ON. The average RNFL value was thinner (p<0.0001) in the affected (78 microm) compared with the unaffected eye (100 microm). Patients with incomplete visual recovery demonstrated greater RNFL loss after ON. Regression analyses demonstrated a threshold of RNFL thickness (75 microm), below which RNFL measurements predicted persistent visual dysfunction. Determination of RNFL thickness may predict visual recovery after ON, and lower RNFL values correlate with impaired visual function. Optical coherence tomography may have a potential role as a surrogate marker for axonal integrity within the optic nerve among patients with ON. Ann Neurol 2006;59:963-969.
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                Author and article information

                Journal
                Exp Ther Med
                Exp Ther Med
                ETM
                Experimental and Therapeutic Medicine
                D.A. Spandidos
                1792-0981
                1792-1015
                July 2016
                27 April 2016
                27 April 2016
                : 12
                : 1
                : 190-200
                Affiliations
                [1 ]Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
                [2 ]Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, 45147 Essen, Germany
                [3 ]Department of Ophthalmology, Hannover Medical School, 30625 Hannover, Germany
                [4 ]Department of Psychiatry, Hannover Medical School, 30625 Hannover, Germany
                Author notes
                Correspondence to: Dr Refik Pul, Department of Neurology, Hannover Medical School, 1 Carl-Neuberg Street, 30625 Hannover, Germany, E-mail: pul.refik@ 123456mh-hannover.de
                Article
                ETM-0-0-3300
                10.3892/etm.2016.3300
                4906774
                27347038
                da09b249-5873-44c7-b11d-d95564233df1
                Copyright: © Pul et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 11 June 2015
                : 11 February 2016
                Categories
                Articles

                Medicine
                multiple sclerosis,interferon β-1b,optical coherence tomography,longitudinal study,retinal nerve fiber layer thickness

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