Natural History Of Multiple Sclerosis Research Articles

The Study of Remyelinating Therapies in Multiple Sclerosis: Visual Outcomes as a Window Into Repair.

Amelioration of disability in multiple sclerosis requires the development of complementary therapies that target neurodegeneration and promote repair. Remyelination is a promising neuroprotective strategy that may protect axons from damage and subsequent neurodegeneration. A review of key literature plus additional targeted search of PubMed and Google Scholar was conducted. There has been a rapid expansion of clinical trials studying putative remyelinating candidates, but further growth of the field is limited by the lack of consensus on key aspects of trial design. We have not yet defined the ideal study population, duration of therapy, or the appropriate outcome measures to detect remyelination in humans. The varied natural history of multiple sclerosis, coupled with the short time frame of phase II clinical trials, requires that we develop and validate biomarkers of remyelination that can serve as surrogate endpoints in clinical trials. We propose that the visual system may be the most well-suited and validated model for the study potential remyelinating agents. In this review, we discuss the pathophysiology of demyelination and summarize the current clinical trial landscape of remyelinating agents. We present some of the challenges in the study of remyelinating agents and discuss current potential biomarkers of remyelination and repair, emphasizing both established and emerging visual outcome measures.

Immunoglobulin levels are higher at multiple sclerosis onset - a part of natural history?

Changes in immunoglobulin (Ig) levels may occur in association with various drugs targeting immunity, including disease-modifying drugs (DMD) and corticosteroids (CS) used to treat multiple sclerosis (MS). However, kinetics of Ig levels during the natural history of MS is poorly described. To describe the natural history of the Ig levels in MS. Monocentric retrospective study examining changes in Ig levels in relation with CS intake in a series of 304 consecutive MS patients (and 1204 samples) followed or hospitalized for 7 years in a single centre. Ig levels are routinely collected in MS patients followed in our centre. IgG levels were higher in samples taken at diagnosis than in those taken after the onset of MS symptoms. This effect was also observed in patients remaining free of DMD or CS since onset. On the other hand, overall Ig levels remained stable across fixed time points ranging from 1 to 20 years after onset CONCLUSION: An unanticipated finding of this study was the transient higher IgG levels in samples taken at onset, which suggests that strong inflammatory processes may occur early.

Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers.

Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course.

Mortality of multiple sclerosis in Iceland population-based mortality of MS in incidence and prevalence cohorts.

Mortality is an important feature of the natural history of multiple sclerosis (MS). We report the mortality of all individuals with MS in Iceland, identified in a nationwide population-based study. The results are based on a prevalence cohort and an incidence cohort. The prevalence cohort consisted of all patients with MS (n = 526) living in Iceland on the 31 December 2007. The incidence cohort consisted of all residents of Iceland (n = 222) diagnosed with MS during 2002 to 2007. Mortality was determined by following both the incidence cohort (from diagnosis) and the prevalence cohort (from the prevalence day) until death or 31 December 2020. The mortality, associated with MS, was compared with that expected in the Icelandic population (standardized mortality ratio (SMR)). (a) Prevalence cohort (n = 526). The mean follow up was 12.0 years (range 0.3-13.0). The SMR was 1.6 (95% confidence interval (CI) 1.3-2.0). (b) Incidence cohort (n = 222). The mean follow up was 15.4 years (range 3.7-18.5). The SMR was 1.2 (95% CI 0.6-2.2). During the follow-up period, there was a substantial increase in mortality among the patients with MS, compared with the general population. There was no increase in mortality among the incidence cohort, when followed for up to 18.5 years following diagnosis.

Interrogating large multiple sclerosis registries and databases: what information can be gained?

Although substantial progress has been made in understanding the natural history of multiple sclerosis (MS) and the development of new therapies, many questions concerning disease behavior and therapeutics remain to be answered. Data generated from real-world observational studies, based on large MS registries and databases and analyzed with advanced statistical methods, are offering the scientific community answers to some of these questions that are otherwise difficult or impossible to address. This review focuses on observational studies published in the last 2 years designed to compare the effectiveness of escalation vs. induction treatment strategies, to assess the effectiveness of treatment in pediatric-onset and late-onset MS, and to identify the clinical phenotype of secondary progressive (SP)MS. The main findings originating from real-world studies suggest that MS patients who will qualify for high-efficacy disease-modifying therapies (DMTs) should be offered these as early as possible to prevent irreversible accumulation of neurological disability. Especially pediatric patients derive substantial benefits from early treatment. In patients with late-onset MS, sustained exposure to DMTs may result in more favorable outcomes. Data-driven definitions are more accurate in defining transition to SPMS than diagnosis based solely on neurologists' judgment. Patients, physicians, industry, and policy-makers have all benefited from real-world evidence based on registry data, in answering questions of diagnostics, choice of treatment, and timing of treatment decisions.

How to choose initial treatment in multiple sclerosis patients: a case-based approach.

Immunotherapy dramatically changed the natural history of multiple sclerosis (MS), which was classically associated with severe disability. Treatment strategies advocate that early control of disease activity is crucial to avoid progressive disability, and the use of high efficacy drugs may be beneficial, but safety is a concern. Choosing the disease-modifying therapy is challenging in clinical practice and should be further discussed. To discuss the state of art of selecting the initial therapy for relapsing MS patients. We used a case-based approach followed by clinical discussion, exploring therapeutic options in different MS settings. We presented clinical cases profile compatible with the use of MS therapies, classified into moderate and high efficacy. In the moderate efficacy group, we discussed interferons, glatiramer acetate, teriflunomide and dimethyl fumarate, while in the high efficacy group we discussed fingolimod, cladribine, natalizumab, ocrelizumab, alemtuzumab and ofatumumab. Advances in MS treatment are remarkable. Strong evidence supports the use of early high efficacy therapy. However, biomarkers, clinical and radiologic prognostic factors, as well as patients' individual issues, should be valued and considered for a personalized treatment decision.

Multiple Sclerosis in a Multi-Ethnic Population in Houston, Texas: A Retrospective Analysis.

Multiple Sclerosis (MS) is a progressive neurodegenerative disease that affects more than 2 million people worldwide. Increasing knowledge about MS in different populations has advanced our understanding of disease epidemiology and variation in the natural history of MS among White and minority populations. In addition to differences in incidence, African American (AA) and Hispanic patients have greater disease burden and disability in earlier stages of disease compared to White patients. To further characterize MS in AA and Hispanic populations, we conducted a retrospective chart analysis of 112 patients treated at an MS center in Houston, Texas. Here, we describe similarities and differences in clinical presentation, MRI findings, treatment regimens, disability progression, and relapse rate. While we found several similarities between the groups regarding mean age, disability severity, and degree of brain atrophy at diagnosis, we also describe a few divergences. Interestingly, we found that patients who were evaluated by a neurologist at symptom onset had significantly decreased odds of greater disability [defined as Expanded Disability Status Scale (EDSS) > 4.5] at last presentation compared to patients who were not evaluated by a neurologist (OR: 0.04, 95% CI: 0.16–0.9). We also found that active smokers had significantly increased odds of greater disability both at diagnosis and at last clinical encounter compared to nonsmokers (OR: 2.44, 95% CI: 1.10–7.10, OR= 2.44, 95% CI: 1.35–6.12, p = 0.01, respectively). Additionally, we observed significant differences in treatment adherence between groups. Assessment of the degree of brain atrophy and progression over time, along with an enumeration of T1, T2, and gadolinium-enhancing brain lesions, did not reveal differences across groups.

Sustained disease remission after discontinuation of disease modifying treatments in relapsing-remitting multiple sclerosis

BackgroundThe natural history of multiple sclerosis (MS) following discontinuation of a first-line disease-modifying treatment (DMT) in relapsing-remitting (RR-) MS patients is controversial, as few data are available on the risk of disease reactivation. This study aims to investigate the disease course after DMT discontinuation in selected RR-MS patients, exploring potential predictive factors of disease reactivation. MethodsRR-MS patients, aged 18-65, who had discontinued a first-line DMT were selected from 1107 clinical records. Relapses, disability worsening and new brain lesions, before and after DMT interruption, were retrospectively evaluated. Potentially predictive baseline characteristics of disease reactivation were also analysed. ResultsN= 60 patients were included, median age and treatment duration were 47.8 (22.1-64.3) and 7.2 (0.5-17.8) years respectively. Median clinical follow-up after discontinuation was 4.6 (0.5-16.6) years. No disease rebound occurred. Mean annualized disease activity and relapse rate after discontinuation were both lower than during treatment(0.10±0.05 vs 0.15 ±0.05; p=0.017). A NEDA-3 period on treatment ≥5.5 years was associated with a low rate (7.7%) and a low risk of new disease activity (aHR 0.16, CI 0.03-0.78, p=0.024; Cox regression model multivariate analysis). The patients with NEDA-3 period threshold above 5.5 years showed a higher probability of surviving to disease reactivation than others (p=0.014). ConclusionIn most of the MS patients who showed a long NEDA-3 period while on treatment remission of disease activity persists following first-line DMT discontinuation, suggesting that prolonged suppression of disease activity on treatment can determine long term sustained remission of the disease also in absence of treatment.

The apparently milder course of multiple sclerosis: changes in the diagnostic criteria, therapy and natural history.

In the past decade, changes have occurred in the spectrum of multiple sclerosis courses. The natural history of multiple sclerosis appears milder from the first sign of demyelinating disease to the progressive course, probably as a result of an interplay between several factors including changes in the diagnostic criteria, changes in the epidemiology of multiple sclerosis, impact of early and appropriate disease-modifying treatment and improvement of the general state of health in the population. It has been suggested to regard incidental findings of demyelinating lesions in MRI in individuals without any history of clinical symptoms consistent with neurological dysfunction, so-called radiological isolated syndrome, as the initial course of multiple sclerosis. New diagnostic criteria have enabled the multiple sclerosis diagnosis in many patients at the first clinical demyelinating event, clinically isolated syndrome. The remaining patients with clinically isolated syndrome have a more benign prognosis, and for relapsing-remitting multiple sclerosis, the prognosis has become more favourable. Reduced disease activity in patients with relapsing-remitting multiple sclerosis can partly be ascribed to more efficacious new disease-modifying therapies but decrease in disease activity has also be seen in placebo-treated patients in clinical trials. This may be explained by several factors: change in the diagnostic criteria, more explicit inclusion criteria, exclusion of high-risk patients e.g. patients with co-morbidities, and more rigorous definitions of relapses and disease worsening. However, these factors also make the disease course in patients treated with disease-modifying therapies seem more favourable. In addition, change in the therapeutic target to stable disease (no evidence of disease activity = no relapses, no disease worsening and no MRI activity) could by itself change the course in relapsing-remitting multiple sclerosis. The effectiveness of disease-modifying drugs has reduced the transition from relapsing-remitting to secondary progressive multiple sclerosis. The concept of progressive multiple sclerosis has also evolved from two very distinct categories (primary progressive and secondary progressive multiple sclerosis) to a unified category of progressive multiple sclerosis, which can then be split into the categories of active or inactive. Also, an increasing tendency to treat progressive multiple sclerosis with disease-modifying therapies may have contributed to change the course in progressive multiple sclerosis. In conclusion, during the past decade the entire course of multiple sclerosis from the first sign of a demyelinating disorder through the progressive course appears to be milder due to a complex interplay of several factors.

Prevalence and impact of comorbidities in patients with multiple sclerosis

Multiple sclerosis is a chronic, inflammatory and degenerative disease of the central nervous system. In most cases it is characterised by the recurring focal neurological deficit, which may become progressive over time. Given the chronic nature of the disease, patients may present with additional diseases (comorbidities), which affect the natural history of the disease and its treatment in different ways. To summarise the available evidence regarding the influence of comorbidities on the natural history of multiple sclerosis. Patients with multiple sclerosis are at greater risk than the general population of developing both acute and chronic comorbidities. It has been shown that comorbidities can delay the diagnosis of multiple sclerosis after clinical onset, increase the rates of relapses and of accumulation of disability. Comorbidities also influence aspects of the choice of treatment and therapy adherence. Finally, comorbidities also increase the mortality rate and reduce the quality of life of patients with multiple sclerosis. Screening, diagnosis and treatment of comorbidities are a key aspect of caring for patients with multiple sclerosis to improve their long-term prognosis in terms of disability, quality of life and mortality.

Outcomes in a Modern Cohort of Treated Patients with Multiple Sclerosis from Diagnosis Up to 15 Years.

Before disease-modifying therapies (DMTs) were available, the natural history of multiple sclerosis (MS) regarding attainment of accepted disability milestones was reported with fairly wide variance comparing outcomes across studies. The influence of DMTs on these outcomes is unknown. This study aimed to calculate attainment of disability milestones during the first 15 years after onset of DMT-treated relapsing forms of MS (RMS). As a retrospective study, all available disability data (collected routinely) on all newly diagnosed patients with RMS seen and initially diagnosed in a single clinic between 1989 and 2006 were reviewed. Times from first symptoms and diagnosis until first treatment with DMTs were also reviewed. Time-to-event statistics were applied using disability milestones. Mean follow-up of 184 adult patients from symptom onset was 13.7 years. Of patients followed up for 15 years after onset, 16 of 86 (19%) reached an Expanded Disability Status Scale (EDSS) score of 6.0. Estimated median time to reach an EDSS score of 3.0 was 10.7 years and to reach an EDSS score of 4.0 was 18.1 years. There were striking differences between the present results and older data sets and similar results to the few available modern data sets. This analysis of a modern treated RMS cohort provides outcomes data that may be compared favorably with the natural history of RMS.

Head-to-head drug comparisons in multiple sclerosis

Disease-modifying drugs are changing the natural history of multiple sclerosis (MS). However, currently available clinical trial data are insufficient to develop accurate personalized treatment algorithms to assign the best possible treatment to each person with MS according to disease features, treatment history, and comorbidities. Such accurate algorithms would require the presence of numerous head-to-head trials of long duration, which is virtually impossible, given the economic costs, required time, and difficulties with attrition. Thus, efforts are being made to compare relative treatment efficacy through observational designs, using large multicenter prospective cohorts or "big MS data," and network meta-analyses. Although such studies can yield useful information, they are liable to biases and their results should be confirmed in other study populations, including smaller, single-center cohorts, where some of these biases can be minimized. In this View article, we analyze the potential benefits and biases of all these strategies alternative to head-to-head trials in MS. Finally, we propose the combination of all these types of studies to obtain reliable head-to-head drug comparisons in the absence of randomized designs.

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Outcomes and treatment management of a French cohort suffering from multiple sclerosis: A retrospective epidemiological study

BackgroundDespite a recent interest in Real World Data, such studies are scarce in multiple sclerosis (MS) disease. The objective was to describe the patients, disease progression and use of DMDs in France and compare clinical effectiveness of first-line injectable DMDs. MethodsWe conducted a retrospective multicenter study in France, using data collected by 11 expert centers with the EDMUS software. ResultsOverall, 15,039 French MS patients were followed for a mean of 11.5 years. Mean age at start of disease was 32 years and 74% were women. After the disease onset, median time to reach EDSS 3 was 11 years and 51.8% of patients were relapse-free 2 years after the disease's onset. The mean delay between onset of disease and initiation of treatment was 5.7 ± 6.9 years. Over time, it decreased from 8.8 ± 7.8 to 0.7 ± 0.7 years for initiation of treatment before 2000 vs. after 2010, respectively. Two years after the initiation of treatment, the persistence rate of injectable disease modifying drugs (DMDs) was 60.7%. The effectiveness of these drugs were quite similar. ConclusionThis study brings new insight on the natural history of MS and the use and effectiveness of injectable DMDs in this condition.

Does pregnancy affect women with multiple sclerosis? A prospective study in Western China

Objectives: Pregnancy is considered to be protective for multiple sclerosis (MS) but little is known about Asian MS women. Our study aimed to investigate whether pregnancy affects the course of MS and whether MS affects pregnancy in a Chinese cohort.Methods: We established a database (2009–2016) of 94 females with MS in the Department of Neurology at West China Hospital. From this database, we enrolled females who had been pregnant before or after the clinical onset of MS and consecutively followed up the patients and their offspring for at least one year after delivery. We registered their demographic, clinical and pregnancy-related information, as well as the annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score.Results: We enrolled 55 females with MS and 126 pregnancies. Among them, 14 females had 15 deliveries after MS onset. In these 15 full-term pregnancies after MS onset, the average ARR decreased from 0.46 ± 0.52 in the year before pregnancy to 0.07 ± 0.26 (P = .034) during pregnancy and no drug exposure were observed during pregnancy. The average EDSS score at one year after delivery (1.50 ± 1.72) was higher than that at conception (0.77 ± 1.35; P = .045).Conclusions: The natural history of MS during pregnancy suggests that full-term pregnancy protects MS females from relapse. However, the disability of MS females may develop after delivery.

Impacting The Natural History of Multiple Sclerosis: A Report on the First Generation of Treated Patients (P5.030)

Impacting The Natural History of Multiple Sclerosis: A Report on the First Generation of Treated Patients (P5.030)

A randomised, controlled clinical trial of narrowband UVB phototherapy for clinically isolated syndrome: The PhoCIS study.

BackgroundThe natural history of multiple sclerosis (MS) typically presents with the clinically isolated syndrome (CIS), an episode of neurological symptoms caused by central nervous system inflammation or demyelination that does not fulfil the diagnostic criteria for MS.ObjectiveAs preclinical studies have suggested that exposure to ultraviolet radiation (UVR) could regulate the development of MS, the Phototherapy for CIS (PhoCIS trial) was established to examine the effects of narrowband UVB phototherapy on patients with CIS, and their conversion to MS.MethodsOf the 20 participants, half received 24 sessions of narrowband UVB exposure over eight weeks; participants in both arms were followed for 12 months. All participants were supplemented to 25-hydroxyvitamin D3 levels of >80 nmol/l.ResultsBy 12 months, 100% of those in the no phototherapy arm and 70% in the phototherapy arm had converted to MS, although this difference was not statistically significant.ConclusionThis study provides a basis for further studies to determine if there are any benefits of the therapeutic effects of narrowband UVB radiation on MS progression.

Pediatric multiple sclerosis: epidemiology, clinical aspects, diagnosis and treatment.

Neurodegenerative Disease ManagementVol. 7, No. 6s SupplementPediatric multiple sclerosis: epidemiology, clinical aspects, diagnosis and treatmentAngelo GhezziAngelo Ghezzi*Author for correspondence: E-mail Address: angelo.ghezzi@asst-valleolona.it Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Via Pastori 4, 21013, Gallarate, ItalySearch for more papers by this authorPublished Online:16 Nov 2017https://doi.org/10.2217/nmt-2017-0037AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: diagnosisMRIpediatric multiple sclerosisReferences1 Ghezzi A, Baroncini D, Zaffaroni M, Comi G. Pediatric versus adult MS: similar or different? Mult. Scler. Demyelinating Disord. 2, 5 (2017).Crossref, Google Scholar2 Ghezzi A. Clinical characteristics of multiple sclerosis with early onset. Neurol. Sci. 25(Suppl. 4), S336–S339 (2004).Crossref, Medline, Google Scholar3 Renoux C, Vukusic S, Mikaeloff Y et al. Natural history of multiple sclerosis with childhood onset. N. Engl. J. Med. 356(25), 2603–2613 (2007).Crossref, Medline, CAS, Google Scholar4 Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69(2), 292–302 (2011).Crossref, Medline, Google Scholar5 Krupp LB, Tardieu M, Amato MP et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult. Scler. 19(10), 1261–1267 (2013).Crossref, Medline, Google Scholar6 Verhey LH, Branson HM, Shroff MM et al. MRI parameters for prediction of multiple sclerosis diagnosis in children with acute CNS demyelination: a prospective national cohort study. Lancet Neurol. 10(12), 1065–1073 (2011).Crossref, Medline, Google Scholar7 Neuteboom RF, Boon M, Catsman Berrevoets CE et al. Prognostic factors after a first attack of inflammatory CNS demyelination in children. Neurology 71(13), 967–973 (2008).Crossref, Medline, CAS, Google Scholar8 Heussinger N, Kontopantelis E, Gburek-Augustat J et al. Oligoclonal bands predict multiple sclerosis in children with optic neuritis. Ann. Neurol. 77(6), 1076–1082 (2015).Crossref, Medline, Google Scholar9 Hacohen Y, Absoud M, Deiva K et al. Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. Neurol. Neuroimmunol. Neuroinflamm. 2(2), e81 (2015).Crossref, Medline, Google Scholar10 Sadaka Y, Verhey LH, Shroff MM et al. 2010 McDonald criteria for diagnosing pediatric multiple sclerosis. Ann. Neurol. 72(2), 211–223 (2012).Crossref, Medline, Google Scholar11 Ghezzi A. Randomized clinical trials (RCTs) in pediatric multiple sclerosis: are they really necessary? Mult. Scler. 23(7), 1042–1043 (2017).Crossref, Medline, Google Scholar12 Ghezzi A, Banwell B, Boyko A et al. The management of multiple sclerosis in children: a European view. Mult. Scler. 16(10), 1258–1267 (2010).Crossref, Medline, Google Scholar13 Chitnis T, Tenembaum S, Banwell B et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis. Mult. Scler. 18(1), 116–127 (2012).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByObesity in Pediatric-Onset Multiple Sclerosis20 July 2021 | Neurology - Neuroimmunology Neuroinflammation, Vol. 8, No. 5Needs and Experiences of Children and Adolescents with Pediatric Multiple Sclerosis and Their Caregivers: A Systematic Review25 May 2021 | Children, Vol. 8, No. 6 Vol. 7, No. 6s Follow us on social media for the latest updates Metrics Downloaded 201 times History Received 8 September 2017 Accepted 19 September 2017 Published online 16 November 2017 Published in print November 2017 Information© 2017 Future Medicine LtdKeywordsdiagnosisMRIpediatric multiple sclerosisFinancial & competing interests disclosureA Ghezzi has received honoraria from Almirall, Biogen, Genzyme, Merck-Serono, Novartis and Teva; and speakers’ bureau from Biogen, Genzyme, Merck-Serono, Novartis and Teva. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Writing assistance was provided by Content Ed Net (Madrid, Spain), with funding from Almirall SA (Barcelona, Spain).PDF download

Alemtuzumab therapy 2017

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system comprising of inflammation, demyelinisation and neurodegeneration. The natural history of MS is heterogenous. Owing to the vast range and severity of the symptoms MS can cause the effect of the disease on one's cognitive and physical status is unpredictable. According to the new, phenotype based classification two subgroups can be distinguished; relapsing-remitting (RR) and progressive MS. Relapsing-remitting MS can be further divided into active and inactive disease. The activity of the disease can be proven either clinically and/or by radiological means. A patient's disease is considered inactive, if it fulfills the criteriae set in the "no evidence of disease activity-3" (NEDA-3) concept, meaning that no progression can be seen on the MRI scans, the patient is relapse free and there is no worsening on any disability scale. Nowadays a paradigm shift can be seen in the treatment of MS. The aim of this shift is to provide each and every patient with the most potent medication best suiting his/her illness as soon as possible. Alemtuzumab offers a great option as either a first line treatment or as escalation therapy for patients with a highly active disease. The efficacy of alemtuzumab was proven in two phase III trials (CARE-MS I, II), where it was compared to subcutaneous interferon b-1a, administered three times weekly. In both studies alemtuzumab was superior to subcutaneous interferon b-1a in terms of relapse rate reduction, in all scouted MRI parameters. In the CARE-MS II trial it was found superior in terms of progression slowing. In the studies' first 2 years 32% and 39% of the alemtuzumab treated patients managed to achieve the NEDA-3 state (data from CARE-MS II and I respectively). At the end of the 4 year extension of both studies these numbers have increased to 60% and 55% respectively. The aim of our synopsis is to suggest neurologists an evidence based guideline, a therapeutic algorithm to be used when they give their MS patients the very best, personalised treatment, and also to appoint the recently introduced alemtuzumab to its proper place in the algorithm.

The outcome spectrum of multiple sclerosis: disability, mortality, and a cluster of predictors from onset.

Interest in the long-term natural history of multiple sclerosis (MS) is being revived, as disability endpoints become increasingly important with the advent of highly efficacious long range but potentially harmful drugs. MS had an increasingly benign course, probably due to better assessment and changing diagnostic criteria. Incidence cohorts reduce inclusion bias, capturing both extreme benign and severe cases. We conducted a 50-year follow-up of an incidence cohort of Gothenburg residents with MS onset in 1950-1964 (n = 254; 212 with an initial relapsing-remitting course and 42 with a monophasic course, diagnostic criteria according to Poser). Patients were followed longitudinally until censoring, death, or study termination in 2012 and evaluated using Kaplan-Meier estimates and Cox regression analysis. Median time to secondary progression was 15 years. Median time to EDSS6 and EDSS7 was 26 and 48 years (n = 254), respectively. The cumulative risk of reaching EDSS6 was 50% at 55 years of age and 80% at 80 years of age (n = 212). A score based on a cluster of clinical features at onset predicted secondary progression, EDSS6, EDSS7, and EDSS10 (hazard ratio 1.6-2.3 per score unit for women, 0.99-1.49 for men). This score predicted the disease course during five decades indirectly, by predicting time to secondary progression. Age at onset predicted the course in men, with 3-6% yearly increase in the risk of reaching disability milestones. The present incidence cohort provided hard outcome data in untreated patients over several decades.