Established Multiple Sclerosis Research Articles

Associations between cortical lesions, optic nerve damage, and disability at the onset of multiple sclerosis: insights into neurodegenerative processes.

BackgroundMultiple sclerosis cortical lesions are areas of demyelination and neuroaxonal loss. Retinal layer thickness, measured with optical coherence tomography (OCT), is an emerging biomarker of neuroaxonal loss. Studies have reported correlations between cortical lesions and retinal layer thinning in established multiple sclerosis, suggesting a shared pathophysiological process. Here, we assessed the correlation between cortical lesions and OCT metrics at the onset of multiple sclerosis, examining, for the first time, associations with physical or cognitive disability. ObjectiveTo examine the relationship between cortical lesions, optic nerve and retinal layer thicknesses, and physical and cognitive disability at the first demyelinating event. MethodsThirty-nine patients and 22 controls underwent 3T-MRI, optical coherence tomography, and clinical tests. We identified cortical lesions on phase-sensitive inversion recovery sequences, including occipital cortex lesions. We measured the estimated total intracranial volume and the white matter lesion volume. OCT metrics included peripapillary retinal nerve fibre layer (pRNFL), ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses. ResultsHigher total cortical and leukocortical lesion volumes correlated with thinner pRNFL (B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01; B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01, respectively). Leukocortical lesion number correlated with colour vision deficits (B = 0.58, 95 %CI 0.039 to 1,11, p = 0.036). Thinner GCIPL correlated with a higher Expanded Disability Status Scale (B = -0.06, 95 % CI -1.1 to -0.008, p = 0.026). MS diagnosis (n = 18) correlated with higher cortical and leukocortical lesion numbers (p = 0.004 and p = 0.003), thinner GCIPL (p = 0.029) and INL (p = 0.041). ConclusionThe association between cortical lesions and axonal damage in the optic nerve reinforces the role of neurodegenerative processes in MS pathogenesis at onset.

T1/T2-weighted ratio in multiple sclerosis: A longitudinal study with clinical associations

BackgroundT1w/T2-w ratio has been proposed as a clinically feasible MRI biomarker to assess tissue integrity in multiple sclerosis. However, no data is available in the earliest stages of the disease and longitudinal studies analysing clinical associations are scarce. ObjectiveTo describe longitudinal changes in T1-w/T2-w in patients with clinically isolated syndrome (CIS) and multiple sclerosis, and to investigate their clinical associations. MethodsT1-w/T2-w images were generated and the mean value obtained in the corresponding lesion, normal-appearing grey (NAGM) and white matter (NAWM) masks. By co-registering baseline to follow-up MRI, evolved lesions were assessed; and by placing the mask of new lesions to the baseline study, the pre-lesional tissue integrity was measured. ResultsWe included 171 CIS patients and 22 established multiple sclerosis patients. In CIS, evolved lesions showed significant T1-w/T2-w increases compared to baseline (+7.6%, P < 0.001). T1-w/T2-w values in new lesions were lower than in pre-lesional tissue (-28.2%, P < 0.001), and pre-lesional tissue was already lower than baseline NAWM (-7.8%, P < 0.001). In CIS at baseline, higher NAGM T1-w/T2-w was associated with multiple sclerosis diagnosis, and longitudinal decreases in NAGM and NAWM T1-w/T2-w were associated with disease activity. In established multiple sclerosis, T1-w/T2-w was inversely correlated with clinical disability and disease duration. ConclusionA decrease in T1-w/T2-w ratio precedes lesion formation. In CIS, higher T1-w/T2-w was associated with multiple sclerosis diagnosis. In established multiple sclerosis, lower T1-w/T2-w values were associated with clinical disability. The possible differential impact of chronic inflammation, iron deposition and demyelination should be considered to interpret these findings.

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis.

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single-molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing–remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation and neurite orientation dispersion and density imaging diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 versus 0.57, difference 0.036, 95% CI: 0.029–0.043, P < 0.001). Lesion volume (Spearman’s rho rs= 0.38, P < 0.001) and g-ratio (rs= 0.24, P < 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) [11/23 (48%) versus 2/15 (13%), P < 0.05]. These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity and help to identify individuals with a high degree of axonal damage at disease onset.

Perceived and objective cognitive impairment in newly diagnosed versus established multiple sclerosis: impact of disease duration.

Cognitive impairment (CI) is common in multiple sclerosis (MS), including newly diagnosed MS, where it is particularly underrecognised. Determining the presence of CI in the outpatient clinic often relies on patient-reported complaints, with limited time and resources in this setting. Prior studies have shown that self-reported cognition relates poorly to formal neuropsychological testing in the MS population and correlates more with factors such as anxiety, depression and fatigue. In this study, we assess the prevalence of perceived cognitive dysfunction in newly diagnosed MS patients and compare results with an established MS cohort. Thirty-nine patients with newly diagnosed MS (12 months following diagnosis) and 24 patients with an established diagnosis (3 years) were included. Similar levels of perceived and objective CI were seen in both groups. There was a strong correlation of perceived cognitive dysfunction with anxiety, mood and fatigue. Perceived cognition did not correlate with objective CI, assessed using the Brief International Cognitive Assessment in MS (BICAMS), in either group. Study findings add to the literature of perceived cognition in MS, in a newly diagnosed cohort. Findings are consistent with previous research using detailed neuropsychological assessments, confirming the sensitivity of BICAMS, applicable in a routine clinical setting.

The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells.

Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain. However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations. In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls. In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse. A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen's encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest. Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis. Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells. The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions. Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen's encephalitis. Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions. Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.

An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis.

In established multiple sclerosis, tissue abnormality-as assessed using magnetization transfer ratio-increases close to the lateral ventricles. We aimed to determine whether or not (i) these changes are present from the earliest clinical stages of multiple sclerosis; (ii) they occur independent of white matter lesions; and (iii) they are associated with subsequent conversion to clinically definite multiple sclerosis and disability. Seventy-one subjects had MRI scanning a median of 4.6 months after a clinically isolated optic neuritis (49 females, mean age 33.5 years) and were followed up clinically 2 and 5 years later. Thirty-seven healthy controls (25 females, mean age 34.4 years) were also scanned. In normal-appearing white matter, magnetization transfer ratio gradients were measured 1-5 mm and 6-10 mm from the lateral ventricles. In control subjects, magnetization transfer ratio was highest adjacent to the ventricles and decreased with distance from them; in optic neuritis, normal-appearing white matter magnetization transfer ratio was lowest adjacent to the ventricles, increased over the first 5 mm, and then paralleled control values. The magnetization transfer ratio gradient over 1-5 mm differed significantly between the optic neuritis and control groups [+0.059 percentage units/mm (pu/mm) versus -0.033 pu/mm, P = 0.010], and was significantly steeper in those developing clinically definite multiple sclerosis within 2 years compared to those who did not (0.132 pu/mm versus 0.016 pu/mm, P = 0.020). In multivariate binary logistic regression the magnetization transfer ratio gradient was independently associated with the development of clinically definite multiple sclerosis within 2 years (magnetization transfer ratio gradient odds ratio 61.708, P = 0.023; presence of T2 lesions odds ratio 8.500, P = 0.071). At 5 years, lesional measures overtook magnetization transfer ratio gradients as significant predictors of conversion to multiple sclerosis. The magnetization transfer ratio gradient was not significantly affected by the presence of brain lesions [T2 lesions (P = 0.918), periventricular T2 lesions (P = 0.580) or gadolinium-enhancing T1 lesions (P = 0.724)]. The magnetization transfer ratio gradient also correlated with Expanded Disability Status Scale score 5 years later (Spearman r = 0.313, P = 0.027). An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis, is clinically relevant, and may arise from one or more mechanisms that are at least partly independent of lesion formation.

Dissection of a Complex Disease Susceptibility Region Using a Bayesian Stochastic Search Approach to Fine Mapping.

Identification of candidate causal variants in regions associated with risk of common diseases is complicated by linkage disequilibrium (LD) and multiple association signals. Nonetheless, accurate maps of these variants are needed, both to fully exploit detailed cell specific chromatin annotation data to highlight disease causal mechanisms and cells, and for design of the functional studies that will ultimately be required to confirm causal mechanisms. We adapted a Bayesian evolutionary stochastic search algorithm to the fine mapping problem, and demonstrated its improved performance over conventional stepwise and regularised regression through simulation studies. We then applied it to fine map the established multiple sclerosis (MS) and type 1 diabetes (T1D) associations in the IL-2RA (CD25) gene region. For T1D, both stepwise and stochastic search approaches identified four T1D association signals, with the major effect tagged by the single nucleotide polymorphism, rs12722496. In contrast, for MS, the stochastic search found two distinct competing models: a single candidate causal variant, tagged by rs2104286 and reported previously using stepwise analysis; and a more complex model with two association signals, one of which was tagged by the major T1D associated rs12722496 and the other by rs56382813. There is low to moderate LD between rs2104286 and both rs12722496 and rs56382813 (r2 ≃ 0:3) and our two SNP model could not be recovered through a forward stepwise search after conditioning on rs2104286. Both signals in the two variant model for MS affect CD25 expression on distinct subpopulations of CD4+ T cells, which are key cells in the autoimmune process. The results support a shared causal variant for T1D and MS. Our study illustrates the benefit of using a purposely designed model search strategy for fine mapping and the advantage of combining disease and protein expression data.

Risk factors for multiple sclerosis, neuromyelitis optica and transverse myelitis

Background: Little is known about risk factors for neuromyelitis optica (NMO) or transverse myelitis (TM). Objective: The objective of this paper is to evaluate whether established multiple sclerosis (MS) risk factors, including smoking history, a history of infectious mononucleosis (IM), anti-EBNA1 Ab titers and HLA-DR15 are associated with NMO or TM. Methods: We conducted a case-control study among participants in the Accelerated Cure Project for Multiple Sclerosis (ACP) Repository, which includes patients with MS, NMO and TM. Controls include related and unrelated individuals without evidence of demyelinating disease. Analyses included 1237 cases of MS, 98 cases of NMO, 133 cases of TM and 488 healthy controls. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to assess the association between smoking, HLA-DR15, anti-EBNA1 Ab titers and a history of IM adjusting for gender, study site and ethnicity. Results: Overall, the association between smoking, IM, HLA-DR15 and anti-EBNA1 Ab titers and odds of MS were as expected and no significant interactions were observed. However, there was little evidence of association between these MS risk factors and odds of NMO or TM. Conclusions: Established MS risk factors do not appear to be associated with susceptibility to TM or NMO and, among MS patients, these risk factors appear to act independently.

Genetic risk variants in African Americans with multiple sclerosis.

To assess the association of established multiple sclerosis (MS) risk variants in 3,254 African Americans (1,162 cases and 2,092 controls). Human leukocyte antigen (HLA)-DRB1, HLA-DQB1, and HLA-A alleles were typed by molecular techniques. Single nucleotide polymorphism (SNP) genotyping was conducted for 76 MS-associated SNPs and 52 ancestry informative marker SNPs selected throughout the genome. Self-declared ancestry was refined by principal component analysis of the ancestry informative marker SNPs. An ancestry-adjusted multivariate model was applied to assess genetic associations. The following major histocompatibility complex risk alleles were replicated: HLA-DRB1*15:01 (odds ratio [OR] = 2.02 [95% confidence interval: 1.54-2.63], p = 2.50e-07), HLA-DRB1*03:01 (OR = 1.58 [1.29-1.94], p = 1.11e-05), as well as HLA-DRB1*04:05 (OR = 2.35 [1.26-4.37], p = 0.007) and the African-specific risk allele of HLA-DRB1*15:03 (OR = 1.26 [1.05-1.51], p = 0.012). The protective association of HLA-A*02:01 was confirmed (OR = 0.72 [0.55-0.93], p = 0.013). None of the HLA-DQB1 alleles were associated with MS. Using a significance threshold of p < 0.01, outside the major histocompatibility complex region, 8 MS SNPs were also found to be associated with MS in African Americans. MS genetic risk in African Americans only partially overlaps with that of Europeans and could explain the difference of MS prevalence between populations.

Multiple sclerosis presenting as a relapsing amnestic syndrome

Although neuropsychiatric symptoms are increasingly recognised in early established multiple sclerosis,1–3 it is unusual for patients to present with solitary cognitive or neuropsychiatric symptoms,4–12 including depressive symptoms4–7 ,10 ,11 and...

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

BackgroundNo treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach".Methods/designMSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway.ResultsTen participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm.ConclusionsIn addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability.Trial registrationClinicalTrials.gov (NCT00395200).

Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis

Sir, Although recent studies have demonstrated a clear association of Epstein-Barr virus (EBV) infection with multiple sclerosis (Zaadstra et al. , 2008; Lunemann and Munz, 2009; Salvetti et al. , 2009), there has been much debate if and where the virus acts in the pathogenic cascade of multiple sclerosis and whether the virus needs to gain entry to the central nervous system (CNS). A recent study reported in Brain by Willis et al. (2009) showed that there is little evidence for the presence of EBV in the central nervous system of people with multiple sclerosis. These findings contrast greatly with the studies by Serafini et al. (2007) that have described abundant EBV positive cells in multiple sclerosis, and the presence of ectopic B cell follicles enriched with EBV infected cells in some patients. Willis and co-workers used a variety of validated methods to determine the presence of EBV in the CNS of patients with B cell infiltrates within the meninges and parenchyma. The paper described two crucial observations. Unlike Serafini et al. (2007), Willis et al. did not find the presence of EBV to be a characteristic feature of multiple sclerosis (aptly the title of the paper). Second, ectopic follicles, suggested by Serafini et al. to harbour EBV infected B cells, were not observed, despite scrutiny of meningeal tissues where these follicles should have been present. Clearly, the issue of whether EBV is indeed present in the CNS is crucial not only to determine the impact of the virus on the disease in the CNS, but also for diagnostic pathology in general. The studies reveal the vagaries of pathological detection methods for infectious agents such as EBV. Care in the practice and interpretation of such methodologies are of course key for correct diagnosis and proving pathogenic …

Up-Regulation of Soluble Axl and Mer Receptor Tyrosine Kinases Negatively Correlates with Gas6 in Established Multiple Sclerosis Lesions

Multiple sclerosis is a disease that is characterized by inflammation, demyelination, and axonal damage; it ultimately forms gliotic scars and lesions that severely compromise the function of the central nervous system. Evidence has shown previously that altered growth factor receptor signaling contributes to lesion formation, impedes recovery, and plays a role in disease progression. Growth arrest-specific protein 6 (Gas6), the ligand for the TAM receptor tyrosine kinase family, consisting of Tyro3, Axl, and Mer, is important for cell growth, survival, and clearance of debris. In this study, we show that levels of membrane-bound Mer (205 kd), soluble Mer ( approximately 150 kd), and soluble Axl (80 kd) were all significantly elevated in homogenates from established multiple sclerosis lesions comprised of both chronic active and chronic silent lesions. Whereas in normal tissue Gas6 positively correlated with soluble Axl and Mer, there was a negative correlation between Gas6 and soluble Axl and Mer in established multiple sclerosis lesions. In addition, increased levels of soluble Axl and Mer were associated with increased levels of mature ADAM17, mature ADAM10, and Furin, proteins that are associated with Axl and Mer solubilization. Soluble Axl and Mer are both known to act as decoy receptors and block Gas6 binding to membrane-bound receptors. These data suggest that in multiple sclerosis lesions, dysregulation of protective Gas6 receptor signaling may prolong lesion activity.

Homogeneity of active demyelinating lesions in established multiple sclerosis

Four different patterns of demyelination have been described in active demyelinating lesions of multiple sclerosis (MS) patients that were biopsied shortly after disease onset. These patterns were suggested to represent heterogeneity of the underlying pathogenesis. The aim of this study was to determine whether lesion heterogeneity also exists in an unselected collection of autopsy material from patients with established MS. All MS brain tissue available in the VU Medical Center was assessed for the presence of active demyelinating lesions using magnetic resonance imaging-guided sampling and immunohistochemistry. Tissue blocks containing active demyelinating lesions were evaluated for the presence of complement and antibody deposition, oligodendrocyte apoptosis, differential loss of myelin proteins, and hypoxia-like damage using histology, immunohistochemistry, and confocal microscopy. Blocks with active demyelinating lesions were compared with blocks with active (nondemyelinating) and inactive lesions. Complement and antibodies were consistently associated with macrophages in areas of active demyelination. Preferential loss of myelin proteins, extensive hypoxia-like damage, and oligodendrocyte apoptosis were absent or rare. This pattern was observed in all tissue blocks containing active demyelinating lesions; lesion heterogeneity between patients was not found. The immunopathological appearance of active demyelinating lesions in established MS is uniform. Initial heterogeneity of demyelinating lesions in the earliest phase of MS lesion formation may disappear over time as different pathways converge in one general mechanism of demyelination. Consistent presence of complement, antibodies, and Fcgamma receptors in phagocytic macrophages suggests that antibody- and complement-mediated myelin phagocytosis is the dominant mechanism of demyelination in established MS.

Magnetization transfer histograms in clinically isolated syndromes suggestive of multiple sclerosis

In established multiple sclerosis, magnetization transfer ratio (MTR) histograms reveal abnormalities of normal-appearing white matter (NAWM) and grey matter (NAGM). The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with clinically isolated syndromes suggestive of multiple sclerosis. Magnetization transfer imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a clinically isolated syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, white matter and grey matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed multiple sclerosis if this occurred sooner (n = 20). Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects. The MTR histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram. Mean NAWM and NAGM MTR were also reduced in the patients who developed clinically definite multiple sclerosis and multiple sclerosis according to the McDonald criteria but not in the 24 patients with normal T2-weighted brain magnetic resonance imaging (MRI). MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of multiple sclerosis.

Demyelination and Neurological Sequelae in Etanercept and Infliximab Therapies: A Review of the Literature

Etanercept (Enbrel) and infliximab (Remicade) are two relatively new drugs, referred to as biologics, which target the cytokine tumor necrosis factor-α (TNF-α). Both are used in the treatment of psoriasis and psoriatic arthritis. Recently, there have been rare reports of demyelinating and neurological sequelae in patients while on these therapies. The authors sought to systematically review the reported cases of new-onset neurological symptoms and exacerbation of established multiple sclerosis (MS) found in the literature to determine the causality, if any, of demyelinating events by these therapies. Although these two medications may uncover latent multiple sclerosis in patients who are prone to the disease, no cause-and-effect relationship can currently be established.

A randomized trial of intravenous immunoglobulin in inflammatory demyelinating optic neuritis

Several immunomodulatory agents have been shown to favorably influence the short-term natural history of multiple sclerosis. Corticosteroids may shorten the duration of clinical and magnetic resonance imaging evidence of recent clinical worsening in multiple sclerosis and optic neuritis, but their effect is incomplete and transient. No treatment has been identified to reverse long-standing neurologic dysfunction in demyelinating disease. Remyelination is seen in established multiple sclerosis plaques, raising the possibility that therapeutic intervention could enhance clinical recovery. Studies in animal models of demyelinating disease have shown that administration of immunoglobulin (Ig) induces central nervous system remyelination. The purpose of this study was to determine whether intravenous immunoglobulin (IVIg) reverses chronic visual impairment in multiple sclerosis patients with optic neuritis. In this double blind, placebo-controlled Phase II trial, 55 patients with persistent acuity loss after optic neuritis were randomized to receive either IVIg 0.4 g/kg daily for five days followed by three single infusions monthly for three months, or placebo. The trial was terminated by the National Eye Institute because of negative results when 55 of the planned 60 patients had been enrolled. Fifty-two patients completed the scheduled infusions, and 53 patients completed 12 months of follow-up. Analysis of this data indicated that a difference between treatment groups was not observed for the primary outcome measure, improvement in logMAR visual scores at 6 months (p = 0.766). Exploratory secondary analyses suggested that IVIg treatment was associated with improvement in visual function (including logMAR visual scores at 6 months and visual fields at 6 and 12 months) in patients with clinically stable multiple sclerosis during the trial. The authors conclude that IVIg administration does not reverse persistent visual loss from optic neuritis to a degree that merits general use.—Nancy J. Newman

Lack of restriction of T cell receptor β variable gene usage in cerebrospinal fluid lymphocytes in acute optic neuritis

OBJECTIVESThere have been many studies reporting restricted patterns of T cell receptor usage in established multiple sclerosis and these have led to clinical trials of immunomodulation directed at deleting clonal...

The role of magnetic resonance techniques in understanding and managing multiple sclerosis.

Magnetic resonance (MR) techniques have had a major impact in the last 10-15 years in understanding and managing multiple sclerosis. This review summarizes the current uses of MR in multiple sclerosis, based on the proceedings of a recent international workshop, under four headings: (i) technical issues; (ii) role in diagnosis; (iii) natural history studies in understanding the disease; (iv) application in clinical trials. The theory and methodology of relevant technical issues is outlined, in order to provide a framework with which to understand the potential and limitations of MR in addressing biological and clinical questions in multiple sclerosis. The principles underlying signal-to-noise and contrast-to-noise ratio are discussed, along with the techniques and clinical results for conventional and fast spin echo T2-weighted imaging, fluid-attenuated inversion recovery, detection of blood-brain barrier break down and hypointense lesions on T1-weighted images, magnetization transfer, T2 decay-curve analysis, MR spectroscopy, spinal cord imaging, diffusion imaging, and quantification of lesion load and atrophy. MRI has an extremely valuable role in confirming the clinical diagnosis of multiple sclerosis. T2-weighted brain imaging remains the standard diagnostic tool, but in some instances it is usefully complemented with gadolinium enhancement and spinal imaging. The caveat that the diagnosis of multiple sclerosis remains primarily a clinical one cannot be over-emphasized. Serial MRI studies have added much to our understanding of the natural history and pathophysiology of the disease. Blood-brain barrier breakdown is a consistent early feature of new lesion development in relapsing-remitting and secondary progressive multiple, sclerosis, and this usually correlates with active inflammation and myelin breakdown. A number of the acute MR changes are reversible, but chronic persistent abnormalities in a number of MR parameters, such as reduced N-acetyl aspartate, low magnetization transfer ratios, atrophy and T1-hypointensity, suggest the presence of demyelination and/or axonal degeneration in many chronic lesions. The presence and extent of T2-weighted MRI abnormalities at first presentation with a clinically isolated syndrome suggestive of demyelination strongly predicts the risk of developing clinically definite multiple sclerosis in the next few years. In established multiple sclerosis, however, the correlations between T2 abnormalities and disability are modest. This poor relationship partly relates to the discrepancy between lesion site and function in attempting to correlate locomotor disability with brain MRI findings. However, the correlations between brain lesion load and cognitive dysfunction in multiple sclerosis, whilst more evident, are still modest. A more important limitation is the low pathological specificity of abnormalities seen on T2-weighted images. Stronger correlations have been found between disability and new putative MR markers for demyelination and/or axonal degeneration. Serial studies using multiple MR techniques are now needed to further clarify pathophysiological mechanisms in multiple sclerosis. Serial MR has become an important tool in monitoring treatment efficacy. It provides data which can be readily analysed in a blinded fashion and which directly inspects the pathological evolution; it also enables a rapid and sensitive measure of treatment outcome in early relapsing-remitting and secondary progressive disease. Because of the modest clinical correlations it is, however, still appropriate that the definitive determinant of treatment efficacy remains a clinical one. Further work is needed to address issues of quality control in serial studies, statistical calculation of appropriate sample sizes, and optimization of the nature and frequency of MR outcomes measured.

Pregnancy Is Associated With a Lower Risk of Onset and a Better Prognosis in Multiple Sclerosis

The effects of pregnancy were studied in a multiple sclerosis incidence cohort. In order to eliminate interaction bias between the disease and pregnancy, analysis of the risk of relapse during pregnancy and the puerperium was limited to the onset bout, using fecundity figures for Sweden. The risk of onset bout was significantly reduced during pregnancy while the risk of onset bout in the post-partum period did not differ significantly from the risk during non-pregnancy periods. We also found a decreased risk of multiple sclerosis onset in parous compared with nulliparous women. The association between nulliparity and multiple sclerosis tended to increase with age. Furthermore, the effect of pregnancy on the long-term prognosis in established multiple sclerosis was analysed by comparing the risk of change from a relapsing-remitting to a chronic progressive course and the risk of reaching level 6 of the Disability Status Scale in women with pregnancy after multiple sclerosis onset with that in non-pregnant control patients, matched for neurological deficit, disease duration and age. There was a significantly decreased risk of a progressive course in women who were pregnant after multiple sclerosis onset.