Hyperreflective dots in the avascular outer retina in relapsing-remitting multiple sclerosis.

BACKGROUND: Hyperreflective granular elements with a transient presence in the retina can be detected non-invasively by optical coherence tomography (OCT). Such foci or dots may represent aggregates of activated microglia. However, in multiple sclerosis an increased number of hyperreflective foci has so far not been demonstrated in the intrinsically hyporeflective and avascular outer nuclear layer of the retina where there are no fixed elements in healthy eyes. Therefore, the present study intended to investigate the presence of hyperreflective foci in the outer nuclear layer in patients with relapsing- remitting multiple sclerosis (RRMS) by using a high-resolution OCT scanning protocol. METHODS: This cross-sectional exploratory study examined 88 eyes in 44 RRMS patients and 106 eyes in 53 age- and sex-matched healthy subjects. None of the patients had any sign of retinal disease. All patients and healthy subjects each underwent one session of spectral domain OCT imaging. A total of 23,200 B-scans extracted from 8 × 8 mm blocks of linear B-scans at 60 µm intervals were analysed for hyperreflective foci in the outer nuclear layer of the retina. Analyses were made of the total block scan and a circular 6-mm diameter fovea-centered field in each eye. Multivariate logistic regression analysis was used to assess associations between parameters. RESULTS: Hyperreflective foci were observed in 31 out of 44 (70.5 %) multiple sclerosis patients compared to 1 out of 53 (1.8%) healthy subjects (p < 0.0001). From analyses of the total block scans, the median number of hyperreflective foci in the outer nuclear layer was 1 (range 0-13) in patients and 0 (range 0-2) in healthy subjects (p < 0.0001). In total, 66.2% of all hyperreflective foci were located within 6 mm of the center of the macula. There was no detectable association between the presence of hyperreflective foci and retinal nerve fiber layer or ganglion cell layer thickness. CONCLUSION: Hyperreflective granular foci in the avascular outer nuclear layer of the retina seen by OCT were almost completely absent in healthy subjects, whereas they were found, albeit at low density, in the majority of patients with RRMS. Hyperreflective foci can be repeatedly examined by non-invasive means and without pupil dilation, which opens a new field of investigation of infiltrating elements in an unmyelinated part of the central nervous system.

New, diagnostic flicker test for optic neuritis shows specific stages following disease onset.

BACKGROUND: Previously, results of the digital flicker test (DFT) have shown distinct patterns in acute optic neuritis (ON) and healthy eyes. We aimed to examine the diagnostic potential of the DFT in acute ON and to investigate the temporal development of the DFT response following ON while comparing with visual evoked potentials (VEP). METHODS: The DFT examines the subjective brightness of a flickering field, varied in 11 different frequencies from 0 to 60 Hz, compared to a steady field. Previous studies have indicated a pronounced darkness enhancement at medial frequencies in acute ON eyes. Darkness enhancement at medial frequencies was expressed as a quantitative covariate (DFTDE). Results were compared with healthy controls and follow-up measurements were compared with VEP. RESULTS: 112 patients were examined <31 days of onset (median 14.0 days (IQR:12.25)). 104 of 112 patients showed an abnormal flicker test (sensitivity 93%). DFT was abnormal in 2 of 55 healthy controls. The DFT showed normalization in 34% at 3 months, 36.4% at 6 months and 71.4% at >8 months from ON onset compared to 13.3%, 22.4% and 28.6% for VEP. Changes to the pattern of the DFT results were shown at specific stages during and following ON. CONCLUSIONS: The DFT is an easy-to-use and sensitive diagnostic test for acute ON. The flicker test shows a more pronounced temporal evolution following ON than VEP and may be of use monitoring the course of ON.

MIF in the cerebrospinal fluid is decreased during relapsing-remitting while increased in secondary progressive multiple sclerosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in the function of both the innate and adaptive immune systems and in neuroprotection and has recently been implicated in multiple sclerosis (MS). OBJECTIVES: Determination of MIF levels in the cerebrospinal fluid (CSF) of patients with distinct subtypes of MS and the cellular localization of MIF in human brain tissue. METHODS: The levels of MIF were investigated in CSF from patients with clinically isolated syndrome (CIS) (n = 26), relapsing-remitting MS (RRMS) (n = 22), secondary progressive MS (SPMS) (n = 19), and healthy controls (HCs) (n = 24), using ELISA. The effect of disease-modifying therapies in the RRMS and SPMS cohorts were examined. Cellular distribution of MIF in the human brain was studied using immunochemistry and the newly available OligoInternode database. RESULTS: MIF was significantly decreased in treatment-naïve CIS and RRMS patients compared to HCs but was elevated in SPMS. Interestingly, MIF levels were sex-dependent and significantly lower in women with CIS and RRMS. MIF expression in the human brain was localized to neurons, astrocytes, pericytes, and oligo5 oligodendrocytes but not in microglia. CONCLUSION: The finding that MIF was decreased in newly diagnosed CIS and RRMS patients but was high in patients with SPMS may suggest that MIF levels in CSF are regulated by local MIF receptor expression that affects the overall MIF signaling in the brain and may represent a protective mechanism that eventually fails.

Leveraging Visual Outcome Measures to Advance Therapy Development in Neuroimmunologic Disorders.

The visual system offers unparalleled precision in the assessment of neuroaxonal damage. With the majority of patients with multiple sclerosis (MS) experiencing afferent and efferent visual dysfunction, outcome measures capturing these deficits provide insight into neuroaxonal injury, even in those with minimal disability. Ideal for use in clinical trials, visual measures are generally inexpensive, accessible, and reproducible. Quantification of visual acuity, visual fields, visual quality of life, and electrophysiologic parameters allows assessment of function, whereas optical coherence tomography (OCT) provides reliable measures of the structural integrity of the anterior afferent visual pathway. The technology of oculomotor biometrics continues to advance, and discrete measures of fixation, smooth pursuit, and saccadic eye movement abnormalities are ready for inclusion in future trials of MS progression. Visual outcomes allow tracking of neuroaxonal injury and aid in distinguishing MS from diseases such as neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). OCT has also provided unique insights into pathophysiology, including the identification of foveal pitting in NMOSD, possibly from damage to Müller cells, which carry an abundance of aquaporin-4 channels. For some study designs, the cost-benefit ratio favors visual outcomes over more expensive MRI outcomes. With the next frontier of therapeutics focused on remyelination and neuroprotection, visual outcomes are likely to take center stage. As an international community of collaborative, committed, vision scientists, this review by the International MS Visual System Consortium (IMSVISUAL) outlines the quality standards, informatics, and framework needed to routinely incorporate vision outcomes into MS and NMOSD trials.

Multifocal visual evoked potential evaluation for diagnosis of acute optic neuritis and for prediction of visual outcome and ganglion cell layer thinning following optic neuritis.

BACKGROUND: While damage to the optic nerve following optic neuritis (ON) is readily quantifiable, the evaluation of prognosis for visual function and neuroaxonal loss in the acute ON is challenging. OBJECTIVE: The objective of this study is to investigate the value of multifocal visual evoked potential (mfVEP) in acute ON, diagnostically for acute ON and prognostically for visual outcome and subsequent ganglion cell/inner plexiform layer thickness (GCLIPLt). METHODS: A prospective cohort study of mfVEP and full-field visual evoked potential (ffVEP) in acute, unilateral ON (onset < 31 days) was conducted. Comparisons with healthy controls (n = 30) and association analysis with follow-up optical coherence tomography (OCT) measurements (of the GCLIPLt) and visual function (Sloan low-contrast visual acuity (LCVA)) were conducted. RESULTS: Seventy-nine ON patients were included (mean: 17 days from onset). Excluding measurements with conduction block, ffVEP (n = 54) and mfVEP (n = 44) showed sensitivities of 89% and 84% to a specificity of 97%. 65/79 patients were re-examined (mean: 200 days follow-up). mfVEP amplitude and latency inter-eye asymmetry in acute ON correlated with GCLIPLt (r = 0.587 and Spearman's ρ = 0.597, for both, p < 0.001). mfVEP amplitude correlated with LCVA inter-eye asymmetry at follow-up (r = 0.421, p < 0.001), mfVEP latency did not. CONCLUSION: mfVEP may support the prognostic evaluation of acute ON patients and prove valuable in future neuroprotective and remyelinating trials. In acute ON, the increase in diagnostic value of mfVEP to ffVEP may be limited due to widespread conduction block.

A woman in her forties with unilateral blurred vision and pain upon eye movement. / En kvinne i 40-årene med ensidig tåkesyn og smerter ved øyebevegelse.

BACKGROUND: Toxoplasmosis is a relatively common cause of infectious papillitis and neuroretinitis, which may affect both immunocompetent and immunodeficient patients. CASE PRESENTATION: A previously healthy woman in her mid-forties presented with subacute onset of unilateral blurred vision and retrobulbar pain exacerbated by eye movements. Ophthalmological assessment revealed decimal best-corrected visual acuity of 0.75, an ipsilateral swollen disc and a peripapillary infiltrate. Serology indicated acute infection with Toxoplasma gondii. Cerebral MRI showed a periventricular lesion, and oligoclonal bands were detected in the cerebrospinal fluid. INTERPRETATION: This case illustrates that even when symptoms, MRI and cerebrospinal fluid findings suggest demyelinating disease, differential diagnoses must be considered in order to mitigate the negative therapeutic and prognostic consequences of a misdiagnosis.

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

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.

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

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.

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

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.

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.

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, p = 0.0172-0.021). MfVEP mean latency (HR = 1.052, p = 0.006) only predicted MS conversion in univariate analysis. No significant predictive value was shown for the other parameters (p > 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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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)-ß 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 IFNß 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 IFNß 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.