Cancer risk, disease-modifying therapy, and age in multiple sclerosis: A retrospective population-based cohort study.

BACKGROUND: Long-term population-based safety studies are needed to investigate cancer outcomes in people with multiple sclerosis (MS) treated with modern disease-modifying therapy (DMT). OBJECTIVES: To investigate if exposure to DMT increases the risk of invasive cancer in MS. METHODS: We used population-based administrative health data from Alberta, Canada between 2008 and 2018. DMT exposure was defined in two ways: first as exposure to any DMT, and second by DMT type (modulating, sequestering, depleting). Study outcome was time to first diagnosis of invasive cancer. Cancer risk was compared to the general population using standardized incidence ratios (SIRs) and to the unexposed MS cases using hazard ratios (HRs). RESULTS: The analysis included 14,313 MS cases: 5,801 (40.5 %) were exposed to DMT. Median (interquartile range) follow-up was 8.4 (4.3, 10.4) years. Compared to the general population, there was no difference in cancer risk for the overall MS population (SIR: 0.94, 95 % confidence interval [CI]: 0.87, 1.02) or the DMT-exposed MS cases (SIR: 0.89; 95 % CI: 0.75, 1.05). Compared to unexposed MS cases, we found an interaction with age for exposure to any DMT (p = 0.001) and modulating DMT (p = 0.001), indicating that a difference in the risk of cancer associated with DMT depends on age. Cancer risk was not associated with exposure to sequestering DMT (HR: 1.28, 95 % CI: 0.78, 2.08) or depleting DMT (HR: 2.29, 95 % CI: 0.86, 6.14). CONCLUSIONS: Cancer risk for MS patients was similar to the general population. In the MS population, the age-dependent effect of DMT for cancer risk suggests a higher risk of cancer with age 62 or older and a protective effect at younger age. Further investigation is required to clarify whether the interaction between DMT exposure and age is a causal effect.

Longitudinal advanced MRI case report of white matter radiation necrosis.

Radiation necrosis mostly occurs in and near the radiation field. We used magnetic resonance imaging to study radiation-induced necrosis of atypical onset, severity, and extent following stereotactic radiosurgery for a symptomatic arteriovenous malformation. Susceptibility-sensitive imaging, T1-relaxation, myelin water imaging, and magnetic resonance spectroscopy were acquired three times up to 52 months postradiosurgery. Increasing water content outside the radiation field, contralateral neuronal loss, and gliosis were detected over time. Our findings suggest that radiation-induced vasculopathic changes spread more diffusely than previously described. An autoimmune response to brain antigens could underlie white matter changes outside the initial radiation field.

Resilience, trust, and civic engagement in the post-CCSVI era.

BACKGROUND: Scientific and financial investments in chronic cerebrospinal venous insufficiency (CCSVI) research have been made to address both the hope for and scepticism over this interventional strategy for MS. Despite limited evidence in support of the CCSVI hypothesis, the funding of clinical research was responsive to a demand by the public rarely seen in the history of medicine. We characterize patient perspectives about the CCSVI research trajectory, with particular attention to its impact on other non-pharmaceutical areas of MS research with a focus on stem cell interventions. METHODS: Semi-structured interviews with 20 MS patients across Canada who did not have CCSVI interventions. Interviews were analysed for recurring themes and individual variations using the constant comparative approach. RESULTS: Participants had a critical view of the divestment of funds from longstanding research to support CCSVI trials. They retain a sense of optimism, however, about emerging evidence for stem cell interventions for MS, and highlight the need for greater caution and conscientious communication of advances in medicine and science. CONCLUSIONS: The unrealized hopes for CCSVI challenged but did not undermine the resilience of patient communities. The narrative that unfolded highlights the importance of drawing a socially-minded space for public participation in science.

Paraneoplastic Neuromyelitis Optica Spectrum Disorder: A single center cohort description with two cases of histological validation.

BACKGROUND: Paraneoplastic syndromes are remote effects of cancer caused by an autoimmune response triggered by tumor cells. Paraneoplastic Neuromyelitis Optica Spectrum Disorders (NMOSD) has been previously described, but the underlying mechanism for these rare cases is not well characterized. This paper presents a newly described case series of paraneoplastic NMOSD, including 2 new histological types of cancer and histological validation. METHODS: The UBC NMO clinic database was surveyed and identified 6 patients with paraneoplastic NMOSD. In 2 cases, aquaporin-4 (AQP4) immunoreactivity was assessed on patients' tumor specimens. RESULTS: The mean age at NMOSD diagnosis was 56 years old and 5/6 patients were older than 50 years old. 4/6 patients with paraneoplastic NMOSD have positive AQP4 antibodies. The median time between NMOSD and cancer was 12 months. Two new cancer types- serous ovarian carcinoma and adrenocortical carcinoma - were found in paraneoplastic NMOSD cases. A serous ovarian carcinoma and a thymoma, found in patients with AQP4 serological evidence, showed a positive reactivity to AQP4 immunostaining. CONCLUSIONS: Our findings will increase the recognition of NMOSD as a paraneoplastic syndrome. Cancer cells can express AQP4, increasing the likelihood of a direct mechanism between cancer cells and the development of NMOSD in paraneoplastic cases.

Analysis of NOD-like receptor NLRP1 in multiple sclerosis families.

The implementation of exome sequencing technologies has started to unravel the genetic etiology of familial multiple sclerosis (MS). A homozygote p.G587S mutation in NLRP1 has been suggested as potentially causative for the onset of MS in an affected sibling pair, who later developed malignant melanoma. To validate the proposed role of recessive NLRP1 mutations in the pathological mechanisms of MS, we examined exome sequencing data from 326 MS patients from Canada for the identification of NLRP1 missense and nonsense variants. This analysis did not identify the previously described p.G587S mutation; however, three patients with potential NLRP1 compound heterozygote mutations were observed. Haplotype and segregation analyses indicate that the variants observed in these patients were inherited in cis, and do not segregate with disease within families. Thus, the analysis of MS patients from Canada failed to identify potentially pathogenic mutations in NLRP1, including the previously described p.G587S mutation. Further studies are necessary to confirm a role of NLRP1 in the pathophysiology of MS.

Characterization of brain tumours with spin-spin relaxation: pilot case study reveals unique T 2 distribution profiles of glioblastoma, oligodendroglioma and meningioma.

Prolonged spin-spin relaxation times in tumour tissue have been observed since some of the earliest nuclear magnetic resonance investigations of the brain. Over the last three decades, numerous studies have sought to characterize tumour morphology and malignancy using quantitative assessment of T 2 relaxation times, although attempts to categorize and differentiate tumours have had limited success. However, previous work must be interpreted with caution as relaxation data were typically acquired using a variety of multiple echo sequences with a range of echoes and T 2 decay curves and were frequently fit with monoexponential analysis. We defined the distribution of T 2 components in three different human brain tumours (glioblastoma, oligodendroglioma, meningioma) using a multi-echo sequence with a greater number of echoes and a longer acquisition window than previously used (48 echoes, data collection out to 1120 ms) with no a priori assumptions about the number of exponential components contributing to the T 2 decay. T 2 relaxation times were increased in tumour tissue and each tumour showed a distinct T 2 distribution profile. Tumours have complex and unique compartmentalization characteristics. Quantitative assessment of T 2 relaxation in brain cancer may be useful in evaluating different grades of brain tumours on the basis of their T 2 distribution profile, and has the potential to be a non-invasive diagnostic tool which may also be useful in monitoring therapy. Further study with a larger sample size and varying grades of tumours is warranted.

Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case-control study protocol for dimethyl fumarate-induced lymphopenia.

INTRODUCTION: Adverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF) is a licensed disease-modifying therapy for the treatment of multiple sclerosis (MS). The use of DMF in MS has been associated with a severe reduction in lymphocyte counts and reports of progressive multifocal leukoencephalopathy. Here, we outline the protocol for a case-control study designed to discover genomic variants associated with DMF-induced lymphopenia. The ultimate goal is to replicate these findings and create an efficient and adaptable approach towards the identification of genomic markers that could assist in mitigating adverse drug reactions in MS. METHODS AND ANALYSIS: The population sample will comprise DMF-exposed patients with MS, with cases representing those who developed lymphopenia and controls who did not. DNA genotyping will take place using a high-throughput genome-wide array. Fine mapping and imputation will be performed to focus in on the potentially causal variants associated with lymphopenia. Multivariable logistic regression will be used to compare genotype and allele frequencies between the cases and the controls, with consideration of potential confounders. The association threshold will be set at p<1.0×10-5 for the discovery of genomic association analyses to select variants for replication. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the respective research ethics board, which includes written informed consent. Findings will be disseminated widely, including at scientific conferences, via podcasts (targeted at both healthcare professionals as well as patients and the wider community), through patient engagement and other outreach community events, written lay summaries for all participants and formal publication in peer-reviewed scientific journals.

Susceptibility-sensitive MRI of multiple sclerosis lesions and the impact of normal-appearing white matter changes.

Susceptibility-sensitive magnetic resonance imaging (MRI) has gained importance in multiple sclerosis (MS) research because of its versatility, high resolution and excellent sensitivity to changes in tissue structure and composition. In particular, mapping of the resonance frequency of the MR signal and quantitative susceptibility mapping (QSM) have been explored for the description of MS lesions. Many current studies utilizing these techniques attribute increases in the MR frequency or QSM to elevated tissue iron content, in addition to myelin loss. However, this common interpretation is inconsistent with recent histopathological studies. Here, we investigate the nature of MR frequency shifts related to MS lesions by comparing post-mortem MRI data with histology, and contrast them with numerical simulations of the MR signal. We demonstrate that iron accumulation is not the driving source of the MR frequency or QSM image contrast in our sample; rather, most chronic MS lesions are characterized by advanced loss of both myelin and iron. Moreover, our results suggest that the appearance of MS lesions on MR frequency maps and QSM depends on changes in the non-lesional white matter surrounding the lesions. Understanding and accounting for these changes is essential for the quantitative interpretation of MR frequency or QSM data in white matter.

Common genetic etiology between "multiple sclerosis-like" single-gene disorders and familial multiple sclerosis.

Several single-gene disorders with clinical and radiological characteristics similar to those observed in multiple sclerosis (MS) patients have been described. To evaluate whether this phenotypic overlap can be ascribed to a common genetic etiology, 28 genes known to present pathogenic mutations for 24 of these disorders were sequenced in 270 MS patients. All identified variants were genotyped in 2131 MS cases and 830 healthy controls, and those exclusively observed in patients were assessed for segregation within families. This analysis identified 9 rare variants in 6 genes segregating with disease in 13 families. Four different mutations were identified in CYP27A1, including a reported pathogenic mutation for cerebrotendinous xanthomatosis (p.R405W), which was observed in six patients from a multi-incident family, three diagnosed with MS, two with an undefined neurological disease and one seemingly healthy. A LYST p.V1678A and a PDHA1 p.K387Q mutation were both observed in five MS patients from three separate multi-incident families. In addition, CLCN2 p.V174G, GALC p.D162E and POLG p.R361G were each identified in two MS patients from one family. This study suggests a shared genetic etiology between MS and the characterized single-gene disorders, and highlights cholesterol metabolism and the synthesis of oxysterols as important biological mechanisms for familial MS.

Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis.

Genetic variants in the purinergic receptors P2RX4 and P2RX7 have been shown to affect susceptibility to multiple sclerosis (MS). In this study, we set out to evaluate whether rare coding variants of major effect could also be identified in these purinergic receptors. Sequencing analysis of P2RX4 and P2RX7 in 193 MS patients and 100 controls led to the identification of a rare three variant haplotype (P2RX7 rs140915863:C>T [p.T205M], P2RX7 rs201921967:A>G [p.N361S], and P2RX4 rs765866317:G>A [p.G135S]) segregating with disease in a multi-incident family with six family members diagnosed with MS (logarithm of odds = 3.07). Functional analysis of this haplotype in HEK293 cells revealed impaired P2X7 surface expression (P < 0.01), resulting in over 95% inhibition of adenosine triphosphate (ATP)-induced pore function (P < 0.001) and a marked reduction in phagocytic ability (P < 0.05). In addition, transfected cells showed 40% increased peak ATP-induced inward current (P < 0.01), and a greater Ca2+ response to the P2X4 135S variant compared with wild type (P < 0.0001). Our study nominates rare genetic variants in P2RX4 and P2RX7 as major genetic contributors to disease, further supporting a role for these purinergic receptors in MS and the disruption of transmembrane cation channels leading to impairment of phagocytosis as the pathological mechanisms of disease.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 µg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis.

BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections. CONCLUSIONS: Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann-La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570 .).

Birth outcomes in newborns fathered by men with multiple sclerosis exposed to disease-modifying drugs.

OBJECTIVE: The aim of this study was to determine the incidence of births fathered by men with multiple sclerosis (MS) exposed to a disease-modifying drug (DMD) around the time of conception, and investigate the association between DMD exposure and birth outcomes in newborns of exposed and unexposed MS fathers. METHODS: Population-based databases in British Columbia (BC), Canada, (the BCMS database, Vital Statistics Birth Registry, Population Data BC Consolidation File/Census GeoData, BC PharmaNet and the BC Perinatal Database Registry) were linked in this retrospective cohort study (1996 to 2010). Multivariate models were used to examine the association between interferon-beta (IFNß) or glatiramer acetate (GA) exposure (within 64 days prior to or at conception; i.e., the duration of spermatogenesis) with birth weight and gestational age of newborns. RESULTS: Of 195 births fathered by men with relapsing-onset MS, 80 births (41%) were to fathers treated with a DMD before their child was born, with 53/195 (27%) exposed within 64 days prior to or at the time of conception. Of the 53 exposed births, 37 were to IFNß and 16 to GA. Mean birth weight of IFNß-exposed and GA-exposed newborns was similar to that of unexposed newborns (adjusted difference: -107 g for both, p>0.3). IFNß-exposed and GA-exposed newborns also had comparable mean gestational ages relative to unexposed newborns (adjusted difference: -0.5 and -0.3 weeks, respectively, p>0.2). CONCLUSIONS: About one in three would-be fathers with MS were exposed to IFNß or GA around the time of conception; there was no compelling evidence to suggest that exposure was associated with either lower birth weight or gestational age.

Association of smoking with risk of multiple sclerosis: a population-based study.

Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have shown an association between smoking and MS risk. Here, in a population-based Canadian cohort, we investigate the relationship between personal and maternal smoking exposure and the risk of MS. Using the longitudinal Canadian database, 3,157 MS cases and 756 spouse controls were administered questionnaires on active and passive smoking history. Mothers of cases and controls were also asked about their smoking exposure during pregnancy. The MS cases were more likely to have smoked than spouse controls (odds ratio 1.32, 95 % confidence interval 1.10-1.60, p = 0.003). This association was driven by an excess of ever-smokers in male MS cases. No association was seen with maternal active or passive smoking exposure during pregnancy. Ever-smoking is associated with increased MS risk in males. Further work is needed to understand the mechanism underlying this association.

Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years.

BACKGROUND: Teriflunomide, an oral disease-modifying therapy in development for patients with relapsing forms of multiple sclerosis (RMS), was well tolerated and effective in reducing magnetic resonance imaging (MRI) lesions in 179 RMS patients in a phase 2 36-week, placebo-controlled study. METHODS: A total of 147 patients who completed the core study entered an open-label extension. Teriflunomide patients continued their assigned dose, and placebo patients were re-allocated to teriflunomide, 7 mg/day or 14 mg/day. An interim analysis was performed at a cut-off on January 8 2010. RESULTS: The mean and median duration of study treatment, including both the core and extension phase, from baseline to the interim cut-off, was 5.6 years (standard deviation: 2.7 years) and 7.1 years (range: 0.05-8.5 years), respectively. Of 147 patients, 62 (42.2%) discontinued (19% due to treatment-emergent adverse events (TEAEs)). The most common TEAEs were mild infections, fatigue, sensory disturbances and diarrhoea. No serious opportunistic infections occurred, with no discontinuations due to infection. Asymptomatic alanine aminotransferase increases (≤3× upper limit of normal (ULN)) were common (7 mg, 64.2%; 14 mg, 62.1%); increases >3×ULN were similar across groups (7 mg, 12.3%; 14 mg, 12.1%). Mild decreases in neutrophil counts occurred; none led to discontinuation. The incidence of malignancies was comparable to that of the general population, and cases were not reminiscent of those observed in immunocompromised patients. Annualised relapse rates remained low, minimal disability progression was observed, with a dose-dependent benefit with teriflunomide 14 mg for several MRI parameters. CONCLUSION: Teriflunomide had a favourable safety profile for up to 8.5 years.

Texture analysis differentiates persistent and transient T1 black holes at acute onset in multiple sclerosis: a preliminary study.

BACKGROUND AND OBJECTIVE: The persistence of new enhancing T1 hypointense lesions (acute black holes, ABHs) in multiple sclerosis (MS) cannot be predicted visually at lesion onset. Texture analysis using the polar Stockwell transform (PST) applied to conventional MR images however shows promise in quantifying tissue injury early. The objective of this study was to explore whether ABHs that persist (pABHs) differ from those that are transient (tABHs) using PST texture analysis. METHODS: Fifteen ABHs (8 pABHs; 7 tABHs) from 9 patients were analyzed on 3T images obtained during a clinical trial. Persistence was defined as remaining T1 hypointense 5-8 months later. NAWM regions were examined to control for changes unrelated to ABHs. RESULTS: At first appearance, there was higher coarse texture indicating greater tissue damage in the pABHs than in the tABHs (p<0.01). Both had greater coarse texture than the contralateral and general NAWM (p≤0.01). No difference was identified in normalized signal intensity between pABHs and tABHs and neither demonstrated location preference. While tABHs tended to be smaller than pABHs there was no correlation between lesion size and texture (r=0.44, p>0.05). Furthermore, coarse texture content appeared to predict persistence of individual lesions. CONCLUSIONS: This preliminary study suggests that PST texture could predict persistence of tissue injury based on the severity of structural disorganization within acute lesions. While confirmation of this data is required texture analysis may prove to be a valuable tool to quantify tissue damage and predict recovery in proof-of-concept neuroprotection and repair trials.

Escalating immunotherapy of multiple sclerosis.

Basic disease-modifying treatment for relapsing forms of active multiple sclerosis (MS) is now available in many countries with high prevalence rates, for this chronic inflammatory disease of the central nervous system. Several lines of evidence support early immunomodulatory treatment with either recombinant interferon-beta or glatiramer acetate, and positive results from phase III trials encourage start of treatment even in patients with clinically isolated syndromes (CIS). However, currently available drugs for basic therapy are only partially effective and patients may still encounter relapses or disease progression. As treatment-refractory, clinically active MS can quickly lead to irreversible neurological disability there is an urgent need for effective escalating strategies. Patients with suboptimal treatment response to basic therapy have been treated with combination therapies, cytotoxic drugs (such as mitoxantrone and cyclophosphamide) or autologous hematopoietic stem cell transplantation. Recently, the monoclonal antibody, natalizumab, was added to this armamentarium. None of these strategies have been vigorously evaluated in large randomized, controlled phase III trials with patients who failed basic therapy. Therefore, the decision to escalate immunotherapy is still based on limited evidence. This article will review potential candidates for intensified immunosuppression and call for innovative study designs to better evaluate escalating immunotherapy in MS.

The role of MRI in the diagnosis of multiple sclerosis.

There is no single test that is diagnostic of MS, including MRI. The lesions detected with MRI are pathologically nonspecific. The principles of MS diagnosis are based on showing dissemination of white matter lesions in space and time. MRI is the most sensitive method for revealing asymptomatic dissemination of lesions in space and time. The pattern and evolution of MRI lesions, in the appropriate clinical setting, has made MRI abnormalities invaluable criteria for the early diagnosis of MS. The first important role for MRI in the diagnosis of MS allows for an early diagnosis of MS for CIS patients using the IP diagnostic criteria, including MRI for dissemination in space (DIS) and time (DIT). The sensitivity of diagnosing MS within the first year after a single attack is 94%, with a specificity of 83%. The MRI evidence required to support the diagnosis varies, depending on the strength of the clinical findings. Allowing a new MRI lesion to substitute for a clinical attack doubles the number of CIS patients who can be diagnosed as having MS within 1 year of symptom onset. Increasing the sensitivity of the test with more lenient criteria, as recommended by the AAN subcommittee, can result in decreased specificity. The second important role for MRI in the diagnostic work-up of suspected MS patients is to rule out alternative diagnoses obvious on MRI, such as spinal stenosis and most brain tumors. Characteristic lesions that favor MS include Dawson Fingers, ovoid lesions, corpus callosum lesions, and asymptomatic spinal cord lesions. However, other white matter diseases can have similar appearances on MRI. Persistent gadolinium enhancement greater than three months, lesions with mass effect, and meningeal enhancement suggest other disorders. A standardized MRI protocol for brain and spinal cord is crucial for comparing across studies or between centers. T2W MRI cannot distinguish between acute and chronic lesions. Gadolinium provides useful information about new lesion activity and is helpful in ruling out alternative diagnoses such as neoplasm, vascular malformations, and leptomeningeal disease. A single gadolinium-enhanced MRI can potentially provide evidence for dissemination in space and time. Spinal cord imaging is equally valuable to rule out spinal stenosis or tumor, and for detecting asymptomatic lesions when brain imaging is nondiagnostic in patients suspected of having MS. Precise criteria may be too suggestive that MS can be diagnosed by MRI and a negative MRI at the time of CIS does not rule out MS. MRI evidence plays a supportive role in what is ultimately a clinical diagnosis of MS, in the appropriate clinical situation, and always at the exclusion of alternative diagnoses.