Brain health: time matters in multiple sclerosis

Open AccessPublished:July 07, 2016DOI:https://doi.org/10.1016/j.msard.2016.07.003

      Highlights

      • Consensus recommendations on MS diagnosis, management and treatment are presented.
      • Neurological reserve, a component of brain health, can compensate for CNS damage.
      • We propose a therapeutic strategy that aims to maximize lifelong brain health.
      • Proactive monitoring, shared decision-making and improved treatment access are key.
      • Early referral, diagnosis and treatment initiation are also of crucial importance.

      Abstract

      Introduction

      We present international consensus recommendations for improving diagnosis, management and treatment access in multiple sclerosis (MS). Our vision is that these will be used widely among those committed to creating a better future for people with MS and their families.

      Methods

      Structured discussions and literature searches conducted in 2015 examined the personal and economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and barriers to accessing disease-modifying therapies (DMTs).

      Results

      Delays often occur before a person with symptoms suggestive of MS sees a neurologist. Campaigns to raise awareness of MS are needed, as are initiatives to improve access to MS healthcare professionals and services.
      We recommend a clear treatment goal: to maximize neurological reserve, cognitive function and physical function by reducing disease activity. Treatment should start early, with DMT and lifestyle measures. All parameters that predict relapses and disability progression should be included in the definition of disease activity and monitored regularly when practical. On suboptimal control of disease activity, switching to a DMT with a different mechanism of action should be considered. A shared decision-making process that embodies dialogue and considers all appropriate DMTs should be implemented. Monitoring data should be recorded formally in registries to generate real-world evidence.
      In many jurisdictions, access to DMTs is limited. To improve treatment access the relevant bodies should consider all costs to all parties when conducting economic evaluations and encourage the continuing investigation, development and use of cost-effective therapeutic strategies and alternative financing models.

      Conclusions

      The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.

      Graphical Abstract

      Abbreviations1:

      AAN (American Academy of Neurology), ABN (Association of British Neurologists), AUD (Australian dollars), CIS (clinically isolated syndrome), CNS (central nervous system), DMT (disease-modifying therapy), EDSS (Kurtzke Expanded Disability Status Scale), EMA (European Medicines Agency (the European regulatory authority)), EUReMS (European Register for Multiple Sclerosis), FDA (Food and Drug Administration (the US regulatory authority)), GP (general practitioner (family or primary care physician)), HTA (health technology assessment), MoA (mechanism of action), MRI (magnetic resonance imaging), MS (multiple sclerosis), NEDA (no evidence of disease activity), NRSPMS (non-relapsing secondary progressive multiple sclerosis), PPMS (primary progressive multiple sclerosis), QALY (quality-adjusted life year), RCT (randomized controlled trial), RIS (radiologically isolated syndrome), RRMS (relapsing–remitting multiple sclerosis), RSPMS (relapsing secondary progressive multiple sclerosis), RWE (real-world evidence), SPMS (secondary progressive multiple sclerosis), US$ (US dollars), (euros)

      Keywords

      1. Preface

      This report presents an expert, evidence-based position for policy recommendations aimed at improving outcomes for people with multiple sclerosis (MS). It summarizes the evidence and consensus findings from the structured discussions of a global author group, comprising clinicians, researchers, specialist nurses, health economists and representatives from patient groups, all with expertise and experience in the area of MS.
      In summarizing the available data, this report:
      • demonstrates the personal and economic impact of MS (Section 4)
      • examines the reasons behind delays in diagnosis (Section 5)
      • presents the evidence base for a therapeutic strategy that aims to maximize lifelong brain health, centred around a more urgent approach to management, which involves:
        • early intervention with therapies most likely to provide optimal benefit and safety for each person with MS on an individualized basis (Section 6)
        • regular monitoring of disease activity and safety parameters (Section 7)
        • switching therapy based on evidence of disease activity (Section 8)
      • provides guidance on how to improve access to treatment in order to create the optimal environment for this therapeutic strategy (Section 9).
      Our vision is that the report and its recommendations will be used widely among those committed to creating a better future for people with MS and their families. Healthcare professionals, patient groups, healthcare authorities, health technology assessors, insurance companies, payers, regulatory authorities, government bodies, pharmaceutical companies and other relevant stakeholders who influence care quality can affect these outcomes; all have a responsibility to strive towards the highest possible standards of care.

      2. Executive summary

      MS is an incurable chronic disease in which the body’s own immune system destroys tissue in the brain and spinal cord. It is the leading cause of non-traumatic disability among young and middle-aged adults in many developed countries, and it affects 2.3 million people worldwide (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ). Although there is no cure for MS, therapies exist that can alter the disease course by reducing disease activity and slowing down the accumulation of disability. This report recommends specific actions that aim to achieve the best possible outcome for every person with MS (Appendix A).
      A therapeutic strategy that offers the best chance of preserving brain and spinal cord tissue early in the disease course needs to be widely accepted – and urgently adopted (Fig. A.1). Even in the early stages of MS, cognition, emotional well-being, quality of life, day-to-day activities and ability to work can be markedly affected by the damage occurring in the brain and spinal cord. As the disease progresses, increasing disability – such as difficulties in walking – imposes a heavy burden on people with MS and on their families. It also leads to substantial economic losses for society, owing to diminished working capacity.
      Significant delays often occur before a person with symptoms suggestive of MS sees a neurologist for diagnosis and treatment. This is despite diagnosis being 10 times more rapid now than in the 1980s (
      • Marrie R.A.
      • Cutter G.
      • Tyry T.
      • Hadjimichael O.
      • Campagnolo D.
      • Vollmer T.
      Changes in the ascertainment of multiple sclerosis.
      ) and substantial evidence that early treatment is more effective than later treatment. Campaigns to raise awareness of MS among the general public and among clinicians who make referrals are urgently needed, as they have the potential to improve outcomes by enabling earlier diagnosis. Initiatives to improve access to specialist MS healthcare professionals and specialized diagnostic procedures are also needed.
      Early intervention is vital. Appropriate lifestyle interventions, treatment with a therapy that can reduce disease activity and consideration of rapid switching to another therapy if monitoring reveals a suboptimal response are crucial elements of the strategy. Involving people with MS proactively in decision-making and in managing their disease is also key to the successful management of MS. Healthcare professionals should encourage those in their care to play a fully informed, shared role in treatment decisions and to live a ‘brain-healthy’ lifestyle.
      Regular monitoring of disease activity and recording this information formally are the cornerstone of the strategy recommended by the authors. The results of clinical examinations and brain scans will enable personalized treatment for every person with MS and will generate long-term real-world evidence that can be used by regulatory bodies, health technology assessors, payers and clinicians for evaluating therapeutic strategies.
      Offering the full range of therapies that can reduce disease activity improves the chance of finding the best option for each person with MS. The number of effective therapies continues to grow, providing increasing scope to tailor treatment to individual needs. In many jurisdictions, however, access to therapies is limited by licensing stipulations, prescribing guidelines or reimbursement decisions; these typically lag behind the most recent clinical trial data and real-world evidence. We therefore call on regulatory bodies, healthcare authorities, insurance companies, health technology assessors and payers to improve access to therapies, so that personalized treatment can be optimized. We also recommend that the relevant bodies consider all costs to all parties when conducting economic evaluations and that they encourage the continuing investigation, development and use of cost-effective therapeutic strategies and alternative financing models.
      Major public policy changes are needed in order to translate recent advances in the diagnosis and treatment of MS into improved outcomes. Enabling and promoting widespread adoption of the therapeutic strategy for MS recommended in this report has the potential to minimize disease activity and maximize lifelong brain health for those with the disease. It is time to make a real difference to the lives of people with MS and their families – and to avoid many of the long-term economic and personal costs that result from unnecessary irreversible disability.

      3. Endorsements

      The organizations listed below endorse the recommendations made in this report.
      • Accelerated Cure Project for Multiple Sclerosis.
      • ACTRIMS (Americas Committee for Treatment and Research in Multiple Sclerosis).
      • BCTRIMS (Brazilian Committee for Treatment and Research in Multiple Sclerosis).
      • Consortium of Multiple Sclerosis Centers.
      • ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis).
      • European Brain Council.
      • European Multiple Sclerosis Platform.
      • International Organization of Multiple Sclerosis Nurses.
      • International Society of Neuroimmunology.
      • LACTRIMS (Latin-American Committee for Treatment and Research in Multiple Sclerosis).
      • MENACTRIMS (Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis).
      • MexCTRIMS (Mexican Committee for Treatment and Research in Multiple Sclerosis).
      • Multiple Sclerosis Association of America.
      • Multiple Sclerosis Australia.
      • Multiple Sclerosis International Federation.
      • Multiple Sclerosis Ireland.
      • Multiple Sclerosis Research Australia.
      • Multiple Sclerosis Society (UK).
      • Multiple Sclerosis Society of Canada.
      • Multiple Sclerosis Trust.
      • Multippel Sklerose Forbundet (Norwegian Multiple Sclerosis Society).
      • National Multiple Sclerosis Society (USA).
      • Neuroförbundet (Swedish Neurological Association).
      • PACTRIMS (Pan-Asian Committee for Treatment and Research in Multiple Sclerosis).
      • RUCTRIMS (Russian Committee for Treatment and Research in Multiple Sclerosis).
      • Shift.ms.
      • Société Francophone de la Sclérose en Plaques (Francophone Multiple Sclerosis Society).
      • Unie ROSKA (Czech MS Society).
      • The Work Foundation.

      4. Raise awareness of the global burden of multiple sclerosis

      Key points:
      • In MS, tissue in the brain, spinal cord and optic nerve is destroyed by the body’s own immune system, often leading to physical disability and cognitive impairment.
      • MS typically affects young adults in the prime of life. For many, bouts of symptoms (relapses), disability progression, fatigue and cognitive impairment markedly reduce their quality of life and ability to work or study.
      • As disability worsens, personal and economic costs soar. Most of this additional burden falls on people with MS and on family members, many of whom become lifelong caregivers.
      • Early and appropriate treatment can markedly reduce disease activity and accumulation of disability, but there is currently no cure for MS.

      4.1 Multiple sclerosis affects young adults worldwide

      MS is a progressive neurodegenerative disease that typically affects young adults in the prime of life, causing irreversible physical and mental disability. It is the leading cause of non-traumatic disability among young and middle-aged people in many developed countries (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ). MS is the most common cause of wheelchair use among those aged 18–64 years (

      Kaye, H.S., Kang, T., LaPlante, M.P., 2000. Mobility Device Use in the United States. National Institute on Disability and Rehabilitation Research, US Department of Education. 〈http://www.disabled-world.com/pdf/mobility-report.pdf〉 (accessed 03.07.15.).

      ), and the third most common cause of paralysis (after stroke and spinal cord injury) across all age groups (

      Cahill, A., Fredine, H., Zilberman, L., 2009. Prevalence of Paralysis Including Spinal Cord Injuries in the United States. 2008 Christopher and Dana Reeve Foundation Paralysis Resource Center (PRC), Division of Disability and Health Policy, Center for Development and Disability (CDD) of the University of New Mexico School of Medicine. 〈http://cdd.unm.edu/%5C/dhpd/pdfs/InitialBriefing32609.pdf〉 (accessed 21.01.15.).

      ) in the USA. The disease thus negatively affects the lives of people with MS and their families, and leads to large, long-term health and economic burdens.
      Globally, the estimated number of people with MS has increased from 2.1 million in 2008 (

      World Health Organization, 2008. Atlas Multiple Sclerosis Resources in the World 2008. World Health Organization. 〈http://www.who.int/mental_health/neurology/Atlas_MS_WEB.pdf〉 (accessed 19.01.15.).

      ) to 2.3 million in 2013 (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ). Better reporting and diagnosis (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ) and improved survival (
      • Marrie R.A.
      • Yu N.
      • Blanchard J.
      • Leung S.
      • Elliott L.
      The rising prevalence and changing age distribution of multiple sclerosis in Manitoba.
      ) may have contributed to this change, although the disease has been shown to be on the increase in a UK population (
      • Hirst C.
      • Ingram G.
      • Pickersgill T.
      • Swingler R.
      • Compston D.A.
      • Robertson N.P.
      Increasing prevalence and incidence of multiple sclerosis in South East Wales.
      ). MS is found worldwide but it becomes more common with increasing distance from the equator, particularly in the northern hemisphere (
      • Simpson Jr., S.
      • Blizzard L.
      • Otahal P.
      • Van der Mei I.
      • Taylor B.
      Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis.
      ). It is most prevalent in North America, Europe, Australia, New Zealand (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ), other countries with Caucasian populations (

      Multiple Sclerosis International Federation, 2013i. Atlas of MS database data export: prevalence of MS, 2013. Multiple Sclerosis International Federation. 〈http://www.atlasofms.org〉 (accessed 06.02.15.).

      ) and Iran (
      • Etemadifar M.
      • Sajjadi S.
      • Nasr Z.
      • Firoozeei T.S.
      • Abtahi S.H.
      • Akbari M.
      • et al.
      Epidemiology of multiple sclerosis in Iran: a systematic review.
      ). The causes of MS are unclear, but risk is partially determined by a complex interaction between genetic (
      • Robertson N.P.
      • Clayton D.
      • Fraser M.
      • Deans J.
      • Compston D.A.
      Clinical concordance in sibling pairs with multiple sclerosis.
      ,
      • Carton H.
      • Vlietinck R.
      • Debruyne J.
      • De Keyser J.
      • D'Hooghe M.B.
      • Loos R.
      • et al.
      Risks of multiple sclerosis in relatives of patients in Flanders, Belgium.
      ,
      • Willer C.J.
      • Dyment D.A.
      • Risch N.J.
      • Sadovnick A.D.
      • Ebers G.C.
      Twin concordance and sibling recurrence rates in multiple sclerosis.
      ,
      • De Jager P.L.
      • Jia X.
      • Wang J.
      • de Bakker P.I.
      • Ottoboni L.
      • Aggarwal N.T.
      • et al.
      Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci.
      ) and environmental (
      • Martyn C.N.
      • Cruddas M.
      • Compston D.A.
      Symptomatic Epstein-Barr virus infection and multiple sclerosis.
      ,
      • Levin L.I.
      • Munger K.L.
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      • Lennette E.T.
      • Spiegelman D.
      • et al.
      Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis.
      ,
      • Handunnetthi L.
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      • Ebers G.C.
      Multiple sclerosis, vitamin D, and HLA-DRB1*15.
      ,
      • Levin L.I.
      • Munger K.L.
      • O'Reilly E.J.
      • Falk K.I.
      • Ascherio A.
      Primary infection with the Epstein-Barr virus and risk of multiple sclerosis.
      ,
      • Solomon A.J.
      • Whitham R.H.
      Multiple sclerosis and vitamin D: a review and recommendations.
      ,
      • Handel A.E.
      • Williamson A.J.
      • Disanto G.
      • Dobson R.
      • Giovannoni G.
      • Ramagopalan S.V.
      Smoking and multiple sclerosis: an updated meta-analysis.
      ,
      • Simpson Jr., S.
      • Blizzard L.
      • Otahal P.
      • Van der Mei I.
      • Taylor B.
      Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis.
      ,
      • Torkildsen O.
      • Grytten N.
      • Aarseth J.
      • Myhr K.M.
      • Kampman M.T.
      Month of birth as a risk factor for multiple sclerosis: an update.
      ,
      • Disanto G.
      • Pakpoor J.
      • Morahan J.M.
      • Hall C.
      • Meier U.C.
      • Giovannoni G.
      • et al.
      Epstein-Barr virus, latitude and multiple sclerosis.
      ,
      • Berg-Hansen P.
      • Moen S.M.
      • Harbo H.F.
      • Celius E.G.
      High prevalence and no latitude gradient of multiple sclerosis in Norway.
      ,
      • Breuer J.
      • Schwab N.
      • Schneider-Hohendorf T.
      • Marziniak M.
      • Mohan H.
      • Bhatia U.
      • et al.
      Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity.
      ,
      • Fiddes B.
      • Wason J.
      • Sawcer S.
      Confounding in association studies: month of birth and multiple sclerosis.
      ,
      • Spelman T.
      • Gray O.
      • Trojano M.
      • Petersen T.
      • Izquierdo G.
      • Lugaresi A.
      • et al.
      Seasonal variation of relapse rate in multiple sclerosis is latitude dependent.
      ,
      • Torkildsen O.
      • Aarseth J.
      • Benjaminsen E.
      • Celius E.
      • Holmoy T.
      • Kampman M.T.
      • et al.
      Month of birth and risk of multiple sclerosis: confounding and adjustments.
      ;
      • Marsh-Wakefield F.
      • Byrne S.N.
      Photoimmunology and multiple sclerosis.
      ) factors.
      Typically, MS is diagnosed in young, active people in their 20s or 30s (
      • Compston A.
      • Coles A.
      Multiple sclerosis.
      ), and about two-thirds of those affected are women (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ). MS therefore affects people with the potential for many decades of employment ahead of them, who also may be making decisions about starting and raising families.

      4.2 Multiple sclerosis is progressive and irreversible

      4.2.1 Brain tissue is damaged and brain volume is lost

      In MS, the immune system mistakenly attacks and damages tissue in the brain, spinal cord and optic nerve, collectively known as the central nervous system (CNS). This results in lesions (areas of acute injury) that can be seen in a brain scan or post-mortem examination, as well as diffuse damage that is more difficult to observe (
      • Filippi M.
      • Rocca M.A.
      MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system.
      ). Although repair mechanisms operate in the CNS, repair is often incomplete, some nerve tissue is irreversibly destroyed and the brain begins to atrophy (decrease in volume) more rapidly than in people unaffected by MS (
      • Trapp B.D.
      • Ransohoff R.
      • Rudick R.
      Axonal pathology in multiple sclerosis: relationship to neurologic disability.
      ,
      • De Stefano N.
      • Narayanan S.
      • Francis G.S.
      • Arnaoutelis R.
      • Tartaglia M.C.
      • Antel J.P.
      • et al.
      Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability.
      ,
      • Kuhlmann T.
      • Lingfeld G.
      • Bitsch A.
      • Schuchardt J.
      • Bruck W.
      Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time.
      ,
      • Schirmer L.
      • Albert M.
      • Buss A.
      • Schulz-Schaeffer W.J.
      • Antel J.P.
      • Bruck W.
      • et al.
      Substantial early, but nonprogressive neuronal loss in multiple sclerosis (MS) spinal cord.
      ,
      • De Stefano N.
      • Giorgio A.
      • Battaglini M.
      • Rovaris M.
      • Sormani M.P.
      • Barkhof F.
      • et al.
      Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes.
      ,
      • Sbardella E.
      • Tona F.
      • Petsas N.
      • Pantano P.
      DTI measurements in multiple sclerosis: evaluation of brain damage and clinical implications.
      ).
      In healthy adults, a small amount of brain atrophy occurs with ageing – in the region of 0.1–0.5% per year (
      • De Stefano N.
      • Stromillo M.L.
      • Giorgio A.
      • Bartolozzi M.L.
      • Battaglini M.
      • Baldini M.
      • et al.
      Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis.
      ). However, in many people with untreated MS the brain typically atrophies at a much higher rate, at about 0.5–1.35% per year (Fig. 1) (
      • De Stefano N.
      • Airas L.
      • Grigoriadis N.
      • Mattle H.P.
      • O'Riordan J.
      • Oreja-Guevara C.
      • et al.
      Clinical relevance of brain volume measures in multiple sclerosis.
      ,
      • De Stefano N.
      • Stromillo M.L.
      • Giorgio A.
      • Bartolozzi M.L.
      • Battaglini M.
      • Baldini M.
      • et al.
      Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis.
      ). Accelerated brain atrophy starts early, often before a diagnosis of MS (Fig. 2a), and proceeds throughout the course of the disease if left untreated (
      • De Stefano N.
      • Giorgio A.
      • Battaglini M.
      • Rovaris M.
      • Sormani M.P.
      • Barkhof F.
      • et al.
      Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes.
      ). The goal of treating MS should be to prevent damage to the brain and spinal cord that leads to accelerated atrophy.
      Fig. 1
      Fig. 1Brain atrophy in many people with MS is faster than usual and proceeds throughout the disease course. This example uses atrophy rates from studies in people with untreated MS (
      • De Stefano N.
      • Giorgio A.
      • Battaglini M.
      • Rovaris M.
      • Sormani M.P.
      • Barkhof F.
      • et al.
      Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes.
      ,
      • De Stefano N.
      • Airas L.
      • Grigoriadis N.
      • Mattle H.P.
      • O'Riordan J.
      • Oreja-Guevara C.
      • et al.
      Clinical relevance of brain volume measures in multiple sclerosis.
      ) and healthy individuals (
      • De Stefano N.
      • Stromillo M.L.
      • Giorgio A.
      • Bartolozzi M.L.
      • Battaglini M.
      • Baldini M.
      • et al.
      Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis.
      ) to illustrate how brain atrophy may be accelerated in a person with MS disease onset at 25 years of age.
      Reproduced with permission from Oxford PharmaGenesis Ltd. © 2016 Oxford PharmaGenesis Ltd.
      Fig. 2
      Fig. 2The damage caused by MS typically leads to relapses followed by progressive disease. a. The brains of people with MS shrink (atrophy) more rapidly than usual as a result of damage caused by the disease. b. The brain can use its neurological reserve to compensate for damage by remodelling itself. However, when neurological reserve is used up, the clinical symptoms of the disease may progress. c. MS causes lesions – acute areas of damage to the brain and spinal cord that accumulate over time. If a lesion noticeably disrupts nerve function, it leads to a relapse (an attack of clinical symptoms). d. A typical MS disease course involves relapses, followed by progressive disease. e. A person with MS may have a variety of diagnoses over time (see text for details), but disease-modifying therapies are effective only in the early stages when relapses are still present. CIS, clinically isolated syndrome; NRSPMS, non-relapsing secondary progressive multiple sclerosis; RIS, radiologically isolated syndrome; RRMS, relapsing–remitting multiple sclerosis; RSPMS, relapsing secondary progressive multiple sclerosis.
      Reproduced with permission from Oxford PharmaGenesis Ltd. © 2015 Oxford PharmaGenesis Ltd.

      4.2.2 Symptom burden worsens as damage to the brain accumulates

      The brain appears to have an inbuilt neurological reserve – a finite capacity to retain function by remodelling itself to compensate for loss of nerve cells, loss of nerve fibres and atrophy. It does this partly by rerouting signals via undamaged areas or adapting undamaged areas to take on new functions (
      • Rocca M.A.
      • Mezzapesa D.M.
      • Falini A.
      • Ghezzi A.
      • Martinelli V.
      • Scotti G.
      • et al.
      Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis.
      ,
      • Rocca M.A.
      • Filippi M.
      Functional MRI in multiple sclerosis.
      ). This ability is present in addition to the mechanisms that exist to repair physical damage to the CNS. Neurological reserve and repair mechanisms explain why MS-related brain damage may go undetected during the early phase of the disease – and therefore why MS may be undiagnosed and untreated for a long time. There is evidence that cognitive impairment is present in a significant proportion of people before the clinical symptoms of MS appear – sometimes years before (
      • Sinay V.
      • Perez Akly M.
      • Zanga G.
      • Ciardi C.
      • Racosta J.M.
      School performance as a marker of cognitive decline prior to diagnosis of multiple sclerosis.
      ). It is therefore important to diagnose MS as early as possible (Section 5), before neurological reserve is exhausted and the progressive stage of the disease begins (Fig. 2b).
      Usually, damage to the CNS is first detected when clinical symptoms appear. Symptoms may take the form of an attack (known as a relapse, or bout), when a lesion develops in a location that noticeably disrupts nerve function, although most lesions (~90%) do not directly lead to relapses (Fig. 2c and d) (
      • Barkhof F.
      • Scheltens P.
      • Frequin S.T.
      • Nauta J.J.
      • Tas M.W.
      • Valk J.
      • et al.
      Relapsing-remitting multiple sclerosis: sequential enhanced MR imaging vs clinical findings in determining disease activity.
      ,
      • Kappos L.
      • Moeri D.
      • Radue E.W.
      • Schoetzau A.
      • Schweikert K.
      • Barkhof F.
      • et al.
      Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group.
      ). Clinically evident progression of symptoms can also occur from the onset if neurological reserve is exhausted before a relapse occurs; however, progressive disease most often manifests after a period of relapses and remissions. Occasionally, lesions are detected before any clinical symptoms appear, on a brain scan (
      • Okuda D.T.
      • Mowry E.M.
      • Beheshtian A.
      • Waubant E.
      • Baranzini S.E.
      • Goodin D.S.
      • et al.
      Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome.
      ) that is conducted for another purpose (for example, headaches).
      The range of symptoms experienced by a person with MS (Fig. 3) (
      • Compston A.
      • Coles A.
      Multiple sclerosis.
      ,
      • Giovannoni G.
      • Foley J.
      • Brandes D.
      Hidden disabilities in multiple sclerosis – the impact of multiple sclerosis on patients and their caregivers.
      ) can depend on the locations of lesions in the CNS. The most common clinical symptoms reported when first visiting a healthcare professional are sensory (40% of people with MS; numbness, tingling, burning pain), motor (39% of people with MS; weakness, stiffness, clumsiness, difficulty with walking), visual (30%) and fatigue (30%; a feeling of lacking physical or mental energy that interferes with usual or desired activities) (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ).
      First-person account (

      Mayo Clinic, 2010. Sharing Mayo Clinic. ESCP (Edie's Spinal Cord Problem). Mayo Clinic. 〈http://sharing.mayoclinic.org/discussion/escp-edies-spinal-cord-problem/〉 (accessed 11.02.15.).

      )
      The fine motor coordination in my left hand was affected, at times my speech was slurred, and the stiffness in my legs made walking extremely tiring and difficult… I had gone from a very healthy and physically active person to a very handicapped one. My whole life had changed.
      With permission from Mayo Clinic.
      First-person account (
      • Borreani C.
      • Bianchi E.
      • Pietrolongo E.
      • Rossi I.
      • Cilia S.
      • Giuntoli M.
      • et al.
      Unmet needs of people with severe multiple sclerosis and their carers: qualitative findings for a home-based intervention.
      )
      I always need help… That really kills me. I’ve stopped going out because I’m afraid of doing it in my pants… I’m always scared of sudden incontinence and creating a stink.
      Fig. 3
      Fig. 3The symptoms of MS (
      • Compston A.
      • Coles A.
      Multiple sclerosis.
      ,
      • Giovannoni G.
      • Foley J.
      • Brandes D.
      Hidden disabilities in multiple sclerosis – the impact of multiple sclerosis on patients and their caregivers.
      ) are distressing and exhausting.
      Reproduced with permission from Oxford PharmaGenesis Ltd. © 2015 Oxford PharmaGenesis Ltd.

      4.2.3 Multiple sclerosis typically involves relapses and progression

      People with brain lesions who have not yet had any clinical symptoms are said to have radiologically isolated syndrome (RIS) (Fig. 2d and e). About one-third of people with RIS will go on to experience at least one attack of clinical symptoms within 5 years (
      • Okuda D.T.
      • Siva A.
      • Kantarci O.
      • Inglese M.
      • Katz I.
      • Tutuncu M.
      • et al.
      Radiologically isolated syndrome: 5-year risk for an initial clinical event.
      ). An initial attack of symptoms is known as a clinically isolated syndrome (CIS) (Fig. 2d and e) (
      • Miller D.
      • Barkhof F.
      • Montalban X.
      • Thompson A.
      • Filippi M.
      Clinically isolated syndromes suggestive of multiple sclerosis, Part I: natural history, pathogenesis, diagnosis, and prognosis.
      ). Many people (approximately 30–70%) with CIS will develop MS, even though they may not initially meet the full diagnostic criteria for the disease (
      • Miller D.
      • Barkhof F.
      • Montalban X.
      • Thompson A.
      • Filippi M.
      Clinically isolated syndromes suggestive of multiple sclerosis, Part I: natural history, pathogenesis, diagnosis, and prognosis.
      ).
      About 80–90% of people with MS will initially have the relapsing–remitting form of the disease (RRMS) (Fig. 2d and e) (
      • Compston A.
      • Coles A.
      Multiple sclerosis.
      ,
      • Koch M.
      • Kingwell E.
      • Rieckmann P.
      • Tremlett H.
      The natural history of secondary progressive multiple sclerosis.
      ). People with RRMS experience acute (sudden) attacks of symptoms (relapses). Usually, a relapse develops over a few days, before the symptoms plateau and ease off (remit) over the following few weeks or months (
      • Leary S.M.
      • Porter B.
      • Thompson A.J.
      Multiple sclerosis: diagnosis and the management of acute relapses.
      ); during this time CNS repair mechanisms operate and neurological reserve is ‘used up’ to remodel and compensate for the damage (
      • Rocca M.A.
      • Mezzapesa D.M.
      • Falini A.
      • Ghezzi A.
      • Martinelli V.
      • Scotti G.
      • et al.
      Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis.
      ,
      • Rocca M.A.
      • Filippi M.
      Functional MRI in multiple sclerosis.
      ). Although complete physical recovery from a relapse often occurs (most likely early on) (
      • Berkovich R.
      Treatment of acute relapses in multiple sclerosis.
      ), relapses can also be associated with a sustained increase in disability (
      • Lublin F.D.
      • Baier M.
      • Cutter G.
      Effect of relapses on development of residual deficit in multiple sclerosis.
      ,
      • Cutter G.
      • Chin P.
      • Francis G.
      • Meng X.
      • Hashmonay R.
      • Lublin F.
      Relapse is associated with residual deficits in relapsing-remitting multiple sclerosis: analysis of FREEDOMS Data (P07.118).
      ). Incomplete recovery from relapses contributes to stepwise disability progression (
      • Leary S.M.
      • Porter B.
      • Thompson A.J.
      Multiple sclerosis: diagnosis and the management of acute relapses.
      ,
      • Berkovich R.
      Treatment of acute relapses in multiple sclerosis.
      ).
      If and when neurological reserve and repair mechanisms are exhausted, and can no longer compensate for damage, a stage of progressive disability begins, called secondary progressive MS (SPMS) (
      • Schwartz C.E.
      • Quaranto B.R.
      • Healy B.C.
      • Benedict R.H.
      • Vollmer T.L.
      Cognitive reserve and symptom experience in multiple sclerosis: a buffer to disability progression over time?.
      ). In SPMS, disability progressively worsens (with or without relapses) (
      • Compston A.
      • Coles A.
      Multiple sclerosis.
      ,
      • Weiner H.L.
      The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease?.
      ;
      • Lublin F.D.
      • Reingold S.C.
      • Cohen J.A.
      • Cutter G.R.
      • Sorensen P.S.
      • et al.
      Defining the clinical course of multiple sclerosis: the 2013 revisions.
      ), especially the ability to walk (
      • Confavreux C.
      • Vukusic S.
      • Moreau T.
      • Adeleine P.
      Relapses and progression of disability in multiple sclerosis.
      ). Typically, there is an ‘overlap’ phase during which relapses still occur (relapsing SPMS, RSPMS), followed by progression with no relapses (non-relapsing SPMS, NRSPMS) (Fig. 2d and e). If RRMS is left untreated, 50–60% of people develop SPMS within 15–20 years and it takes only 14 years on average for people to become unable to walk for 100 m unaided (
      • Scalfari A.
      • Neuhaus A.
      • Daumer M.
      • Muraro P.A.
      • Ebers G.C.
      Onset of secondary progressive phase and long-term evolution of multiple sclerosis.
      ). In addition, about 10–15% of people with MS have a progressive disease course from the outset, with a gradual progression of clinical symptoms in the absence of relapses (known as primary progressive MS; PPMS) (
      • Miller D.H.
      • Leary S.M.
      Primary-progressive multiple sclerosis.
      ).

      4.2.4 Appropriate drug treatment can reduce disease activity

      The key therapeutic strategy in MS should be to minimize relapses, lesions and brain atrophy at all stages of the disease. This is especially important in early disease, when it is possible to reduce the number of new lesions and amount of brain inflammation, both of which lead to atrophy. This approach aims to maximize brain health, productivity and quality of life.
      A number of disease-modifying therapies (DMTs) have been approved in various jurisdictions for treating CIS and relapsing forms of MS. These drugs can directly affect the disease course by reducing relapses, slowing disability progression, reducing the number of new lesions and slowing the rate of brain atrophy (6, 7, 8). To date, no DMTs have been approved for PPMS, and the only DMT to have been approved in a small number of jurisdictions for NRSPMS has since been removed from the market in the USA. Relapsing forms of MS are therefore the main focus of the DMT-related sections of this report.

      4.3 Multiple sclerosis affects all areas of life

      4.3.1 Quality of life decreases as the disease advances

      Disability in MS is typically measured using the Kurtzke Expanded Disability Status Scale (EDSS), which allocates increasing numerical values to greater levels of physical disability (0.0, normal neurological functioning; 10.0, death) (
      • Kurtzke J.F.
      Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
      ). However many factors that affect quality of life, such as mental health, vitality (
      • Naci H.
      • Fleurence R.
      • Birt J.
      • Duhig A.
      Economic burden of multiple sclerosis: a systematic review of the literature.
      ), cognitive impairment (
      • Zwibel H.L.
      • Smrtka J.
      Improving quality of life in multiple sclerosis: an unmet need.
      ) and fatigue (
      • Khan F.
      • Amatya B.
      • Galea M.
      Management of fatigue in persons with multiple sclerosis.
      ), are either not included or are poorly measured by the EDSS. Even in the early stages of MS, cognitive impairment may result in a lower quality of life (
      • Glanz B.I.
      • Healy B.C.
      • Rintell D.J.
      • Jaffin S.K.
      • Bakshi R.
      • Weiner H.L.
      The association between cognitive impairment and quality of life in patients with early multiple sclerosis.
      ), have a negative impact upon day-to-day activities (
      • Rao S.M.
      • Leo G.J.
      • Ellington L.
      • Nauertz T.
      • Bernardin L.
      • Unverzagt F.
      Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning.
      ,
      • Kalmar J.H.
      • Gaudino E.A.
      • Moore N.B.
      • Halper J.
      • Deluca J.
      The relationship between cognitive deficits and everyday functional activities in multiple sclerosis.
      ) and lead to a reduced ability to work (
      • Rao S.M.
      • Leo G.J.
      • Ellington L.
      • Nauertz T.
      • Bernardin L.
      • Unverzagt F.
      Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning.
      ,
      • Benedict R.H.
      • Wahlig E.
      • Bakshi R.
      • Fishman I.
      • Munschauer F.
      • Zivadinov R.
      • et al.
      Predicting quality of life in multiple sclerosis: accounting for physical disability, fatigue, cognition, mood disorder, personality, and behavior change.
      ). Persistent or sporadic fatigue also leads to a lower quality of life (
      • Khan F.
      • Amatya B.
      • Galea M.
      Management of fatigue in persons with multiple sclerosis.
      ) (see first-person account below) and affects about 75% of all people with MS (
      • Lerdal A.
      • Celius E.G.
      • Krupp L.
      • Dahl A.A.
      A prospective study of patterns of fatigue in multiple sclerosis.
      ).
      First-person account (

      Multiple Sclerosis Society UK, 2015. Every Day is Different. Multiple Sclerosis Society UK. 〈http://www.mssociety.org.uk/ms-support/community-blog/2015/01/every-day-different〉 (accessed 29.01.15.).

      )
      What a silly word ‘fatigue’ is. It sounds like ‘I need to have a quick sit-down on this sofa’. In reality it’s more like ‘I can hardly move and my brain has shut down on me, I feel like I’ve just had a heavy bout of flu’.
      It’s hard to predict when fatigue will strike. Sometimes I have to cancel meeting up with friends, or cut short a very happy outing when my energy slumps. I have to build in rest days to avoid a crash-and-burn episode of fatigue. These make my diary seem fuller than it really is. ‘No I can’t meet on Wednesday, it’s got to be a rest day’. I am lucky to have friends who are understanding of fatigue.
      With permission from the Multiple Sclerosis Society.
      When making decisions about how healthcare resources should be allocated, it is necessary to compare how different diseases affect health-related quality of life. In the cost-effectiveness analyses that drive such decisions, a person’s perspective on their state of health is measured using utility, a value between 1 (full health) and 0 (death). A number of studies have shown that people with MS report a lower utility than the general population, even early in the disease when physical disability is minimal, and that they experience a rapid decrease in utility with increasing disability (Fig. 4) (
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Fredrikson S.
      • Jonsson B.
      Costs and quality of life of patients with multiple sclerosis in Europe.
      ,
      • Orme M.
      • Kerrigan J.
      • Tyas D.
      • Russell N.
      • Nixon R.
      The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK.
      ,
      • Kobelt G.
      • Texier-Richard B.
      • Lindgren P.
      The long-term cost of multiple sclerosis in France and potential changes with disease-modifying interventions.
      ,
      • Naci H.
      • Fleurence R.
      • Birt J.
      • Duhig A.
      Economic burden of multiple sclerosis: a systematic review of the literature.
      ,
      • Zwibel H.L.
      • Smrtka J.
      Improving quality of life in multiple sclerosis: an unmet need.
      ).
      Fig. 4
      Fig. 4People with MS report a rapid decline in health status (utility) even early in the disease course; this continues to worsen with increasing disability (
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Fredrikson S.
      • Jonsson B.
      Costs and quality of life of patients with multiple sclerosis in Europe.
      ,
      • Kobelt G.
      • Texier-Richard B.
      • Lindgren P.
      The long-term cost of multiple sclerosis in France and potential changes with disease-modifying interventions.
      ). EDSS, Kurtzke Expanded Disability Status Scale.
      Reproduced and adapted from J. Neurol. Neurosurg. Psychiatry, Kobelt G., Berg J., Lindgren P. et al. 77, 918–26, © 2006 with permission from BMJ Publishing Group Ltd.
      Although advancing age can be expected to lead to a decrease in utility, people with MS in the 18–29-year age group already rate their own health status lower than those aged 80 years or older in the general population do. Also, when individuals in the same age group are compared, the average utility is about 0.2–0.3 points lower for people with MS compared with the general population (Fig. 5) (

      Kobelt, G., Kasteng, F., 2009. Access to Innovative Treatments in Multiple Sclerosis in Europe. The European Federation of Pharmaceutical Industry Associations (EFPIA). 〈http://www.comparatorreports.se/Access%20to%20MS%20treatments%20-%20October%202009.pdf〉 (accessed 20.01.15.).

      ).
      First-person account (
      • Ploughman M.
      • Austin M.W.
      • Murdoch M.
      • Kearney A.
      • Godwin M.
      • Stefanelli M.
      The path to self-management: a qualitative study involving older people with multiple sclerosis.
      )
      My mother is 20 years older than I am and I can’t keep up with her. I do feel that I’ve been cheated. I have been made an old woman before my time.
      Fig. 5
      Fig. 5People with MS report a lower average health status (mean utility) than those of a similar age in the general population (

      Kobelt, G., Kasteng, F., 2009. Access to Innovative Treatments in Multiple Sclerosis in Europe. The European Federation of Pharmaceutical Industry Associations (EFPIA). 〈http://www.comparatorreports.se/Access%20to%20MS%20treatments%20-%20October%202009.pdf〉 (accessed 20.01.15.).

      ). EDSS, Kurtzke Expanded Disability Status Scale.
      Reproduced and adapted with permission from Gisela Kobelt from Kobelt G., Kasteng F. Access to innovative treatments in multiple sclerosis in Europe. The European Federation of Pharmaceutical Industry Associations (EFPIA) 2009 (

      Kobelt, G., Kasteng, F., 2009. Access to Innovative Treatments in Multiple Sclerosis in Europe. The European Federation of Pharmaceutical Industry Associations (EFPIA). 〈http://www.comparatorreports.se/Access%20to%20MS%20treatments%20-%20October%202009.pdf〉 (accessed 20.01.15.).

      ). © Gisela Kobelt 2009.
      Many studies have shown that the worsening of symptoms that results from disability progression markedly affects day-to-day living and quality of life (
      • Lobentanz I.S.
      • Asenbaum S.
      • Vass K.
      • Sauter C.
      • Klosch G.
      • Kollegger H.
      • et al.
      Factors influencing quality of life in multiple sclerosis patients: disability, depressive mood, fatigue and sleep quality.
      ,
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ,
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Kerrigan J.
      • Russell N.
      • Nixon R.
      Costs and quality of life of multiple sclerosis in the United Kingdom.
      ,
      • Miller A.
      • Dishon S.
      Health-related quality of life in multiple sclerosis: the impact of disability, gender and employment status.
      ,
      • Naci H.
      • Fleurence R.
      • Birt J.
      • Duhig A.
      Economic burden of multiple sclerosis: a systematic review of the literature.
      ). The symptoms that emerge during relapses last for weeks to months and also lead to restricted mobility (
      • Parkin D.
      • Jacoby A.
      • McNamee P.
      • Miller P.
      • Thomas S.
      • Bates D.
      Treatment of multiple sclerosis with interferon beta: an appraisal of cost-effectiveness and quality of life.
      ), a temporary worsening of pain (
      • Parkin D.
      • Jacoby A.
      • McNamee P.
      • Miller P.
      • Thomas S.
      • Bates D.
      Treatment of multiple sclerosis with interferon beta: an appraisal of cost-effectiveness and quality of life.
      ), an increased risk of symptoms of depression (
      • Moore P.
      • Hirst C.
      • Harding K.E.
      • Clarkson H.
      • Pickersgill T.P.
      • Robertson N.P.
      Multiple sclerosis relapses and depression.
      ), a lower quality of life and reduced function (
      • Naci H.
      • Fleurence R.
      • Birt J.
      • Duhig A.
      Economic burden of multiple sclerosis: a systematic review of the literature.
      ,
      • Oleen-Burkey M.
      • Castelli-Haley J.
      • Lage M.J.
      • Johnson K.P.
      Burden of a multiple sclerosis relapse: the patient's perspective.
      ); these are on top of the significant symptom burden that may already have accumulated.

      4.3.2 Multiple sclerosis often results in unemployment

      Unemployment levels among people with MS are higher than those in the general population, even at low levels of physical disability (Fig. 6) (
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Fredrikson S.
      • Jonsson B.
      Costs and quality of life of patients with multiple sclerosis in Europe.
      ,
      • Kobelt G.
      • Texier-Richard B.
      • Lindgren P.
      The long-term cost of multiple sclerosis in France and potential changes with disease-modifying interventions.
      ,

      Eurostat, 2015. Employment (Main Characteristics and Rates) – Annual Averages [lfsi_emp_a]. Employment Rate (25 to 54 years) and Employment Rate (55 to 64 years) in 2005. Eurostat. 〈http://tinyurl.com/Eurostat-employment-rate〉 (accessed 17.06.15.).

      ). This suggests that the ability to work is affected early on; the most likely reasons for this are problems such as cognitive decline, fatigue, depression and anxiety, which are not fully captured by the EDSS. This observation is supported by real-world evidence (evidence obtained from outside the clinical trial setting), which indicates that cognitive impairment (
      • Julian L.J.
      • Vella L.
      • Vollmer T.
      • Hadjimichael O.
      • Mohr D.C.
      Employment in multiple sclerosis. Exiting and re-entering the work force.
      ,
      • Ruet A.
      • Deloire M.
      • Hamel D.
      • Ouallet J.C.
      • Petry K.
      • Brochet B.
      Cognitive impairment, health-related quality of life and vocational status at early stages of multiple sclerosis: a 7-year longitudinal study.
      ) and fatigue, as well as problems with hand function and mobility (
      • Julian L.J.
      • Vella L.
      • Vollmer T.
      • Hadjimichael O.
      • Mohr D.C.
      Employment in multiple sclerosis. Exiting and re-entering the work force.
      ), are associated with an increased likelihood of becoming unemployed. As physical disability progresses, the proportion of people with MS who are unemployed rises markedly (Fig. 6) (
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Fredrikson S.
      • Jonsson B.
      Costs and quality of life of patients with multiple sclerosis in Europe.
      ,
      • Kobelt G.
      • Texier-Richard B.
      • Lindgren P.
      The long-term cost of multiple sclerosis in France and potential changes with disease-modifying interventions.
      ,

      Eurostat, 2015. Employment (Main Characteristics and Rates) – Annual Averages [lfsi_emp_a]. Employment Rate (25 to 54 years) and Employment Rate (55 to 64 years) in 2005. Eurostat. 〈http://tinyurl.com/Eurostat-employment-rate〉 (accessed 17.06.15.).

      ). Case studies have shown, however, that the chances of people with MS remaining in the workforce can be improved by using approaches that focus on ability (rather than on disability), such as adapting working environments, working hours and job roles (

      Swiss Multiple Sclerosis Society, 2011. From Disability to Ability at Work: Successful Case Management Approaches in Multiple Sclerosis. Swiss Multiple Sclerosis Society. 〈https://www.multiplesklerose.ch/sites/default/files/shop/documents/casemanagement_en.pdf〉 (accessed 24.04.15.).

      ). Indeed, a Europe-wide campaign focusing on supporting sustainable employment was launched in March 2015 by the European Multiple Sclerosis Platform (

      European Multiple Sclerosis Platform, 2015a. European Employment Pact for People with Multiple Sclerosis. European Multiple Sclerosis Platform. Brussels, Belgium. 〈http://www.emsp.org/attachments/article/299/EMSP_PACT.pdf〉 (accessed 24.04.15.).

      ).
      First-person account (
      • Ploughman M.
      • Austin M.W.
      • Murdoch M.
      • Kearney A.
      • Godwin M.
      • Stefanelli M.
      The path to self-management: a qualitative study involving older people with multiple sclerosis.
      )
      One of the things that I found difficult was losing friendship because you are no longer in the workforce. It becomes a pretty lonely thing.
      Fig. 6
      Fig. 6The proportion of people with MS who are in employment is greatly reduced even at low levels of physical disability, and decreases markedly as disability increases (
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Fredrikson S.
      • Jonsson B.
      Costs and quality of life of patients with multiple sclerosis in Europe.
      ,
      • Kobelt G.
      • Texier-Richard B.
      • Lindgren P.
      The long-term cost of multiple sclerosis in France and potential changes with disease-modifying interventions.
      ,

      Eurostat, 2015. Employment (Main Characteristics and Rates) – Annual Averages [lfsi_emp_a]. Employment Rate (25 to 54 years) and Employment Rate (55 to 64 years) in 2005. Eurostat. 〈http://tinyurl.com/Eurostat-employment-rate〉 (accessed 17.06.15.).

      ). EDSS, Kurtzke Expanded Disability Status Scale. The range (shaded areas) and median (dotted lines) of the proportion of the general population in employment are shown for the age groups stated for the countries listed. It should be noted that, in many of these countries, people retire at less than 65 years of age.
      Reproduced and adapted from J. Neurol. Neurosurg. Psychiatry, Kobelt G., Berg J., Lindgren P. et al. 77, 918–26, © 2006 with permission from BMJ Publishing Group Ltd.

      4.3.3 Being a caregiver can be a lifetime commitment

      Despite the devastating impact of the disease, the life expectancy of people with MS is reduced by only 5–10 years (
      • Bronnum-Hansen H.
      • Stenager E.
      • Hansen T.
      • Koch-Henriksen H.
      Survival and mortality rates among Danes with MS.
      ,
      • Grytten Torkildsen N.
      • Lie S.A.
      • Aarseth J.H.
      • Nyland H.
      • Myhr K.M.
      Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway.
      ,
      • Kaufman D.W.
      • Reshef S.
      • Golub H.L.
      • Peucker M.
      • Corwin M.J.
      • Goodin D.S.
      • et al.
      Survival in commercially insured multiple sclerosis patients and comparator subjects in the U.S..
      ,
      • Marrie R.A.
      • Elliott L.
      • Marriott J.
      • Cossoy M.
      • Blanchard J.
      • Leung S.
      • et al.
      Effect of comorbidity on mortality in multiple sclerosis.
      ); this indicates that many individuals live a long time with substantial disability. As a result, nearly one-third of people with MS need care, about 80% of which is provided ‘informally’ by unpaid caregivers such as relatives (
      • Hillman L.
      Caregiving in multiple sclerosis.
      ). As the disease progresses, the need for care gradually increases. A typical informal caregiver spends more than 4 h per day on caring activities over many years, which is both physically and emotionally draining (
      • Hillman L.
      Caregiving in multiple sclerosis.
      ). Thus, the personal costs of disability progression fall not just on people with MS but also on their families.
      Caregiver account (
      • Borreani C.
      • Bianchi E.
      • Pietrolongo E.
      • Rossi I.
      • Cilia S.
      • Giuntoli M.
      • et al.
      Unmet needs of people with severe multiple sclerosis and their carers: qualitative findings for a home-based intervention.
      )
      My old life has vanished. It’s just me, my husband, and his disease. That’s all. The disease stands between me and my husband. I used to work, now my life is dedicated to him. This is all very depressing and I don’t know how long I can go on.

      4.4 Costs of multiple sclerosis soar as the disease progresses

      The total costs of MS to society include direct medical and non-medical costs, and indirect costs (Fig. 7). In Europe, the overall annual cost of MS to society has been estimated at €15.5 billion. This represents an average annual cost of €37,000 per person with MS (

      Kobelt, G., Kasteng, F., 2009. Access to Innovative Treatments in Multiple Sclerosis in Europe. The European Federation of Pharmaceutical Industry Associations (EFPIA). 〈http://www.comparatorreports.se/Access%20to%20MS%20treatments%20-%20October%202009.pdf〉 (accessed 20.01.15.).

      ), comparable with averages of $52,000 (€39,000) in the USA (
      • Kobelt G.
      • Berg J.
      • Atherly D.
      • Hadjimichael O.
      Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States.
      ) and AUD 49,000 (€33,000) in Australia (
      • Palmer A.J.
      • Colman S.
      • O'Leary B.
      • Taylor B.V.
      • Simmons R.D.
      The economic impact of multiple sclerosis in Australia in 2010.
      ). (For ease of comparison, all monetary values in this section have been adjusted to 2010 values using the Consumer Price Index.)
      Fig. 7
      Fig. 7The total societal costs of MS are borne mainly by health and social care services, people with MS and their families. DMT, disease-modifying therapy; GP, general practitioner (family or primary care physician).
      Reproduced with permission from Oxford PharmaGenesis Ltd. © 2015 Oxford PharmaGenesis Ltd.
      This annual cost per person is greater than that for other long-term conditions such as asthma (
      • Braman S.S.
      The global burden of asthma.
      ), chronic obstructive pulmonary disease (a collection of chronic lung problems) (
      • Chapman K.R.
      • Mannino D.M.
      • Soriano J.B.
      • Vermeire P.A.
      • Buist A.S.
      • Thun M.J.
      • et al.
      Epidemiology and costs of chronic obstructive pulmonary disease.
      ,
      • Miravitlles M.
      • Sicras A.
      • Crespo C.
      • Cuesta M.
      • Brosa M.
      • Galera J.
      • et al.
      Costs of chronic obstructive pulmonary disease in relation to compliance with guidelines: a study in the primary care setting.
      ) and diabetes (
      • American Diabetes Association
      Economic costs of diabetes in the U.S. in 2012.
      ). It is also greater than the annual cost per person of most other brain disorders considered by the European Brain Council in a series of economic cost estimates (
      • Olesen J.
      • Gustavsson A.
      • Svensson M.
      • Wittchen H.U.
      • Jonsson B.
      • CDBE study group
      • et al.
      The economic cost of brain disorders in Europe.
      ), apart from the neuromuscular condition Guillain–Barré syndrome (which costs approximately €54,000 per person (
      • Olesen J.
      • Gustavsson A.
      • Svensson M.
      • Wittchen H.U.
      • Jonsson B.
      • CDBE study group
      • et al.
      The economic cost of brain disorders in Europe.
      ), about 80% of whom do not have persistent neurological problems (
      • Walling A.D.
      • Dickson G.
      Guillain-Barre syndrome.
      ) – unlike in MS where accumulated disability is mostly irreversible) (
      • Olesen J.
      • Gustavsson A.
      • Svensson M.
      • Wittchen H.U.
      • Jonsson B.
      • CDBE study group
      • et al.
      The economic cost of brain disorders in Europe.
      ).
      As a person with MS becomes more disabled, total societal costs (detailed in Fig. 7) increase significantly. In Europe, the mean annual cost per person with MS has been estimated at €23,000 for EDSS score 0.0–3.5, rising as disability increases to €46,000 for EDSS score 4.0–6.5 and €77,000 for EDSS score 7.0–9.5 (

      Kobelt, G., Kasteng, F., 2009. Access to Innovative Treatments in Multiple Sclerosis in Europe. The European Federation of Pharmaceutical Industry Associations (EFPIA). 〈http://www.comparatorreports.se/Access%20to%20MS%20treatments%20-%20October%202009.pdf〉 (accessed 20.01.15.).

      ). Indirect costs (productivity losses associated with sick leave, incapacity to work and early retirement) – and especially informal care costs – increase dramatically with increasing disability (Fig. 8) (
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Fredrikson S.
      • Jonsson B.
      Costs and quality of life of patients with multiple sclerosis in Europe.
      ). This additional cost burden falls largely outside of the healthcare and social care systems, and a lot of it is borne by people with MS and their families. Medicines (pharmaceuticals) comprise a relatively low proportion of total societal costs, especially at greater levels of disability (Fig. 8) (
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Fredrikson S.
      • Jonsson B.
      Costs and quality of life of patients with multiple sclerosis in Europe.
      ).
      Fig. 8
      Fig. 8As disability progresses, informal care (black) and indirect costs (dark orange) increase dramatically and greatly exceed the cost of pharmaceuticals (medicines; light orange) (
      • Kobelt G.
      • Berg J.
      • Lindgren P.
      • Fredrikson S.
      • Jonsson B.
      Costs and quality of life of patients with multiple sclerosis in Europe.
      ). Average annual costs per person with MS a. in the UK and b. in Germany at EDSS scores 2.0 and 6.5, converted to 2010 euros. Examples of items in each cost category can be found in . Percentages have been independently rounded. EDSS, Kurtzke Expanded Disability Status Scale. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
      Reproduced with permission from Oxford PharmaGenesis Ltd. © 2015 Oxford PharmaGenesis Ltd.
      Relapses also lead to additional costs, only about half of which are borne by the healthcare system (for example, inpatient, outpatient and professional care, consultations, tests and medicines) (
      • Johansson E.
      • Gustavsson A.
      • Miltenburger C.
      • Karampampa K.
      • Rumbach L.
      • Rerat K.
      • et al.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from France.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Mora S.
      • Arbizu T.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from Spain.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Neidhardt K.
      • Lang M.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from Germany.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Teruzzi C.
      • Fattore G.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from Italy.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Tyas D.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from the United Kingdom.
      ). The cost per relapse was estimated at €3400–9600 in a series of recent European studies in people with RRMS and EDSS scores less than 5.0 (
      • Johansson E.
      • Gustavsson A.
      • Miltenburger C.
      • Karampampa K.
      • Rumbach L.
      • Rerat K.
      • et al.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from France.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Kindundu C.M.
      • Selchen D.H.
      Treatment experience, burden, and unmet needs (TRIBUNE) in multiple sclerosis: the costs and utilities of MS patients in Canada.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Mora S.
      • Arbizu T.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from Spain.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Neidhardt K.
      • Lang M.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from Germany.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Teruzzi C.
      • Fattore G.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from Italy.
      ,
      • Karampampa K.
      • Gustavsson A.
      • Miltenburger C.
      • Tyas D.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from the United Kingdom.
      ,
      • Karampampa K.
      • Gustavsson A.
      • van Munster E.T.
      • Hupperts R.M.
      • Sanders E.A.
      • Mostert J.
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in multiple sclerosis study: the costs and utilities of MS patients in The Netherlands.
      ,
      • Karabudak R.
      • Karampampa K.
      • Caliskan Z.
      • Group T.S.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from Turkey.
      ) and at $10,100 (€7600) in members of a US patient support group with RRMS (
      • Oleen-Burkey M.
      • Castelli-Haley J.
      • Lage M.J.
      • Johnson K.P.
      Burden of a multiple sclerosis relapse: the patient's perspective.
      ).
      These data show that the bulk of the additional costs of disability progression and roughly half of the costs of relapses fall outside the healthcare and social care systems. However, in many countries these significant societal costs are not considered when treatments for MS are being assessed (Section 9.1).
      The following sections of this report outline a therapeutic strategy that has the potential to improve outcomes for people with relapsing forms of MS by reducing relapses and disability progression. It could also lead to lower formal and informal care costs and indirect costs, which escalate at higher levels of disability.

      5. Speed up referral and diagnosis

      Key points:
      • The earlier that MS can be diagnosed, the sooner treatment can be initiated.
      • Ideally, people with suspected MS should be referred for diagnosis to a neurologist with a special interest, and expertise, in MS and an experienced team and facilities at their disposal. Such specialists are best placed to diagnose, treat and manage MS.
      • It is currently possible to diagnose MS earlier than ever before – 10 times more rapidly than in the 1980s – by using evidence from magnetic resonance imaging (MRI) brain scans in conjunction with clinical assessments.
      • However, significant delays can still occur between noticing the first symptoms and receiving a diagnosis. Such delays could be reduced by improving awareness of MS among the general public and healthcare professionals who make referrals and by improving access to specialist MS healthcare professionals and diagnostic equipment.

      5.1 Time is critical to preserving brain volume and physical function

      As discussed in Section 4.2.1, many people with CIS (
      • Zivadinov R.
      • Yella V.
      • Dwyer M.G.
      • Hussein S.
      • J.L. C
      Evidence for cortical atrophy in patients with clinically isolated syndrome.
      ) and early MS already experience brain atrophy more rapidly than the general population (Fig. 1) (
      • De Stefano N.
      • Giorgio A.
      • Battaglini M.
      • Rovaris M.
      • Sormani M.P.
      • Barkhof F.
      • et al.
      Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes.
      ). This loss of brain tissue is often subclinical (not accompanied by clinical symptoms), owing to repair mechanisms in the CNS and neurological reserve that enable the brain to reorganize itself and reroute pathways to avoid damaged areas, even when repair is incomplete (
      • Rocca M.A.
      • Mezzapesa D.M.
      • Falini A.
      • Ghezzi A.
      • Martinelli V.
      • Scotti G.
      • et al.
      Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis.
      ,
      • Rocca M.A.
      • Filippi M.
      Functional MRI in multiple sclerosis.
      ). If the brain was not so flexible, clinical symptoms of MS would become apparent sooner; this remarkable ability to compensate means that ongoing damage may go unrecognized until neurological reserve has deteriorated significantly.
      In the absence of a cure for MS, the aim of starting treatment with a DMT should be to reduce subclinical disease activity, preserve brain volume and slow or prevent disability progression (
      • Gold R.
      • Wolinsky J.S.
      • Amato M.P.
      • Comi G.
      Evolving expectations around early management of multiple sclerosis.
      ,
      • Damal K.
      • Stoker E.
      • Foley J.F.
      Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action.
      ). Early diagnosis means that early DMT initiation can be accompanied by other appropriate steps to preserve brain tissue and optimize brain health (for example, exercise, smoking cessation, weight loss and control of comorbidities [other diseases present alongside MS] such as high blood pressure). This approach maximizes the chances of altering the disease course before further relapses or disability progression occur (Section 6).

      5.2 Early referral to a neurologist is essential

      Generally, a person experiencing symptoms compatible with early MS will go initially to their family doctor or primary care physician or to a hospital. From there, they should be referred urgently to a neurologist – a doctor who specializes in diseases of the nervous system.
      Neurology is a wide-ranging discipline that has grown in complexity over the years, resulting in sub-specialization. For example, a world-leading neurology department of a large hospital may offer specialist clinics in the areas of epilepsy, headache, motor neurone disease, movement disorders (such as Parkinson’s disease), peripheral nerve disorders, and MS (sometimes combined with other autoimmune disorders under the term ‘neuroimmunology’) (

      Barts Health NHS Trust, 2015. Barts Health – Neurosciences for Patients. Barts Health NHS Trust. 〈http://www.bartshealth.nhs.uk/our-services/services-a-z/n/neurosciences/for-patients/〉 (accessed 28.01.15.).

      ).

      5.2.1 Referral to an MS neurologist is desirable

      MS is a complex disease, and neurologists who specialize in MS (MS neurologists) (
      • Scolding N.
      • Barnes D.
      • Cader S.
      • Chataway J.
      • Chaudhuri A.
      • Coles A.
      • et al.
      Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis.
      ), together with their multidisciplinary teams (Table 1), are best placed to provide routine diagnosis and an integrated approach to specialist care and management (

      Biogen Idec Inc., 15 August 2014. Plegridy: Prescribing Information (Reference ID: 3608472). Biogen Idec Inc. Cambridge, MA, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125499lbl.pdf〉 (accessed 16.02.15.).

      ;

      Genzyme Corporation, 17 October 2014. Aubagio: Prescribing Information (Reference ID: 3645193). Genzyme Corporation. Cambridge, MA, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202992s001lbl.pdf〉 (accessed 16.02.15.).

      ;
      • De Broe S.
      • Christopher F.
      • Waugh N.
      The role of specialist nurses in multiple sclerosis: a rapid and systematic review.
      ,
      • While A.
      • Forbes A.
      • Ullman R.
      • Mathes L.
      The role of specialist and general nurses working with people with multiple sclerosis.
      ,

      Mynors, G., Perman, S., Morse, M., 2012. Defining the Value of MS Specialist Nurses. Multiple Sclerosis Trust. 〈http://www.mstrust.org.uk/downloads/defining-the-value-of-ms-specialist-nurses-2012.pdf〉 (accessed 12.03.15.).

      ,
      • Adamec I.
      • Barun B.
      • Gabelic T.
      • Zadro I.
      • Habek M.
      Delay in the diagnosis of multiple sclerosis in Croatia.
      ,

      MS Society, 2013. A Lottery of Treatment and Care – MS Services Across the UK. MS Society, London, UK. 〈http://mslottery.mssociety.org.uk/wp-content/uploads/2013/04/UK-ms-lottery.pdf〉 (accessed 20 April 2015).

      ,

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ;

      Novartis Pharma GmbH. Gilenya: EPAR – Product Information (EMEA/H/C/002202-II-26-G). Novartis Pharma GmbH, Revised: 24 July 2014. Nuremberg, Germany. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf〉 (accessed 16.02.15.).

      ;

      Biogen Idec Inc., Revised: 3 December 2014. Tecfidera: Prescribing Information (Reference ID: 3666921). Biogen Idec Inc. Cambridge, MA, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204063s003s008s010lbl.pdf〉 (accessed 16.02.15.).

      ;

      Genzyme Corporation, Revised: 14 November 2014. Lemtrada: Prescribing Information (Reference ID: 3658409). Genzyme Corporation. Cambridge, MA, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/103948s5139lbl.pdf〉 (accessed 16.02.15.).

      ;

      Biogen Idec Ltd., Revised: 18 December 2014. Plegridy: EPAR – Product Information (EMEA/H/C/002827-N/0005). Biogen Idec Ltd. Maidenhead, UK. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002827/WC500170302.pdf〉 (accessed 16.02.15.).

      ,

      Biogen Idec Ltd., Revised: 23 December 2014. Tecfidera: EPAR – Product Information (EMEA/H/C/002601-IB/0008). Biogen Idec Ltd. Maidenhead, UK. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdf〉 (accessed 16.02.15).

      ;

      Genzyme Therapeutics Ltd., Revised: 25 March 2014. Lemtrada: EPAR – Product Information (EMEA/H/C/003718-IB/06). Genzyme Therapeutics Ltd., Oxford, UK. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf〉 (accessed 16.02.15.).

      ;

      Sanofi-aventis Groupe. Aubagio: EPAR – Product Information (EMEA/H/C/002514-PSUV/0005). Sanofi-aventis Groupe, Revised: 28 November 2014. Paris, France. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002514/WC500148682.pdf〉 (accessed 16 February 2015).

      ;

      Novartis Pharmaceuticals Corporation. Gilenya: Prescribing Information (Reference ID: 3494793). Novartis Pharmaceuticals Corporation, Revised: 30 April 2014. East Hanover, NJ, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022527s009lbl.pdf〉 (accessed 16.02.15.).

      ). MS neurologists have broad experience of the long-term management of MS and the fast pace of changes in understanding of the disease, diagnostic criteria, treatment options and monitoring processes.
      Table 1Neurologists with a special interest in MS (described above as MS neurologists) and their multidisciplinary teams have extensive experience, knowledge and facilities at their disposal.
      Specialist aspectDescription
      MS neurologists have access to specialist equipment and personnelMS neurologists have direct access to specialist diagnostic and monitoring equipment (for example, MRI scanners) and often work with experienced and MS-specialized staff, including nurses, physiotherapists, psychologists and others.
      MS neurologists have knowledge of rapidly evolving treatment optionsMS neurologists have in-depth knowledge of the latest techniques and treatment options. In the last 5 years alone, five new DMTs were approved for use in the USA (

      Biogen Idec Inc., 15 August 2014. Plegridy: Prescribing Information (Reference ID: 3608472). Biogen Idec Inc. Cambridge, MA, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125499lbl.pdf〉 (accessed 16.02.15.).

      ;

      Genzyme Corporation, 17 October 2014. Aubagio: Prescribing Information (Reference ID: 3645193). Genzyme Corporation. Cambridge, MA, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202992s001lbl.pdf〉 (accessed 16.02.15.).

      ;

      Biogen Idec Inc., Revised: 3 December 2014. Tecfidera: Prescribing Information (Reference ID: 3666921). Biogen Idec Inc. Cambridge, MA, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204063s003s008s010lbl.pdf〉 (accessed 16.02.15.).

      ;

      Genzyme Corporation, Revised: 14 November 2014. Lemtrada: Prescribing Information (Reference ID: 3658409). Genzyme Corporation. Cambridge, MA, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/103948s5139lbl.pdf〉 (accessed 16.02.15.).

      ;

      Novartis Pharmaceuticals Corporation. Gilenya: Prescribing Information (Reference ID: 3494793). Novartis Pharmaceuticals Corporation, Revised: 30 April 2014. East Hanover, NJ, USA. 〈http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022527s009lbl.pdf〉 (accessed 16.02.15.).

      ) and Europe (

      Novartis Pharma GmbH. Gilenya: EPAR – Product Information (EMEA/H/C/002202-II-26-G). Novartis Pharma GmbH, Revised: 24 July 2014. Nuremberg, Germany. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf〉 (accessed 16.02.15.).

      ;

      Biogen Idec Ltd., Revised: 18 December 2014. Plegridy: EPAR – Product Information (EMEA/H/C/002827-N/0005). Biogen Idec Ltd. Maidenhead, UK. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002827/WC500170302.pdf〉 (accessed 16.02.15.).

      ;

      Biogen Idec Ltd., Revised: 23 December 2014. Tecfidera: EPAR – Product Information (EMEA/H/C/002601-IB/0008). Biogen Idec Ltd. Maidenhead, UK. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002601/WC500162069.pdf〉 (accessed 16.02.15).

      ;

      Genzyme Therapeutics Ltd., Revised: 25 March 2014. Lemtrada: EPAR – Product Information (EMEA/H/C/003718-IB/06). Genzyme Therapeutics Ltd., Oxford, UK. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf〉 (accessed 16.02.15.).

      ;

      Sanofi-aventis Groupe. Aubagio: EPAR – Product Information (EMEA/H/C/002514-PSUV/0005). Sanofi-aventis Groupe, Revised: 28 November 2014. Paris, France. 〈http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002514/WC500148682.pdf〉 (accessed 16 February 2015).

      ); the situation is similar in other geographical regions.
      MS specialist nurses can implement programmes and support people with MSMS specialist nurses are the key staff members in many MS clinical services. Their varied roles include implementation of DMT safety and effectiveness monitoring programmes, support and counselling, case management, symptom screening and management, and provision of education about MS disease and DMTs. There is evidence that MS specialist nurses are highly valued by people with MS (
      • Colhoun S.
      • Wilkinson C.
      • Izat A.
      • White S.
      • Pull E.
      • Roberts M.
      Multiple sclerosis and disease modifying therapies: Results of two UK surveys on factors influencing choice.
      ), can provide emotional support (
      • While A.
      • Forbes A.
      • Ullman R.
      • Mathes L.
      The role of specialist and general nurses working with people with multiple sclerosis.
      ) and can improve their knowledge, confidence and ability to cope (
      • De Broe S.
      • Christopher F.
      • Waugh N.
      The role of specialist nurses in multiple sclerosis: a rapid and systematic review.
      ).
      Involving MS specialist nurses can save moneyThe potential for economic savings has been illustrated in a number of case studies when MS specialist nurses were involved in ongoing care, through reduced numbers of hospital admissions and neurologist appointments (

      Mynors, G., Perman, S., Morse, M., 2012. Defining the Value of MS Specialist Nurses. Multiple Sclerosis Trust. 〈http://www.mstrust.org.uk/downloads/defining-the-value-of-ms-specialist-nurses-2012.pdf〉 (accessed 12.03.15.).

      ).
      Specialist clinics enable rapid diagnosisDiagnosis of MS and CIS was more rapid at a specialist clinic compared with non-specialist options for those suspected of having demyelinating diseases (that is, diseases in which the sheath surrounding the nerves is damaged) (
      • Adamec I.
      • Barun B.
      • Gabelic T.
      • Zadro I.
      • Habek M.
      Delay in the diagnosis of multiple sclerosis in Croatia.
      ).
      Access to MS healthcare professionals increases the likelihood of people with MS taking a DMTPeople with MS were more than twice as likely to be taking a DMT if they had access to an MS neurologist or specialist nurse, according to a 2013 UK survey. In Northern Ireland, a region where people with MS are invited to see a neurologist or MS specialist nurse for a twice-yearly review (unlike in the rest of the UK), 70% more people with MS eligible to receive a DMT were taking one compared with the national average (

      MS Society, 2013. A Lottery of Treatment and Care – MS Services Across the UK. MS Society, London, UK. 〈http://mslottery.mssociety.org.uk/wp-content/uploads/2013/04/UK-ms-lottery.pdf〉 (accessed 20 April 2015).

      ).
      A multidisciplinary team offers an integrated approach to care where different aspects of the disease are managed by specialistsTeam members may include: MS neurologist, MS specialist nurse, physiotherapist, ophthalmologist, pharmacist, clinical psychologist, psychiatrist, occupational therapist, speech therapist, pain management specialist, chiropodist/podiatrist, urologist, continence advisor, social worker, dietician (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ).
      CIS, clinically isolated syndrome; DMT, disease-modifying therapy; MRI, magnetic resonance imaging.
      However, access to MS healthcare professionals, specialist teams and diagnostic facilities varies widely across the globe. There are about 120 times more MRI scanners and neurologists per capita in high-income countries than in low-income countries – and the numbers per capita vary considerably even within high-income countries – according to a 2013 survey (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ). In addition, the existence of multidisciplinary hospital-based teams was reported by respondents from 36 of the 52 countries for which the survey question was completed (

      Multiple Sclerosis International Federation, 2013a. Atlas of MS 2013: Mapping Multiple Sclerosis around the World. Multiple Sclerosis International Federation. 〈http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf〉 (accessed 19.01.15.).

      ). These data indicate that the existence of specialist personnel or facilities does not necessarily imply that they are readily accessible in practice.
      First person account (
      • Colhoun S.
      • Wilkinson C.
      • Izat A.
      • White S.
      • Pull E.
      • Roberts M.
      Multiple sclerosis and disease modifying therapies: Results of two UK surveys on factors influencing choice.
      )
      My MS nurse is my lifeline. Without her I would be lost. She gives me as much or as little as I request.
      Modern technology can be used to address some of the inequalities in access to diagnostic services and ongoing specialist care for people with MS, as indicated by a number of pilot studies in the field of telemedicine (remote diagnosis, treatment or ongoing management using telecommunications technology) (Table 2) (
      • Finkelstein J.
      • Lapshin O.
      • Castro H.
      • Cha E.
      • Provance P.G.
      Home-based physical telerehabilitation in patients with multiple sclerosis: a pilot study.
      ,
      • Kane R.L.
      • Bever C.T.
      • Ehrmantraut M.
      • Forte A.
      • Culpepper W.J.
      • Wallin M.T.
      Teleneurology in patients with multiple sclerosis: EDSS ratings derived remotely and from hands-on examination.
      ,
      • Luccichenti G.
      • Cademartiri F.
      • Pichiecchio A.
      • Bontempi E.
      • Sabatini U.
      • Bastianello S.
      User interface of a teleradiology system for the MR assessment of multiple sclerosis.
      ,
      • Zissman K.
      • Lejbkowicz I.
      • Miller A.
      Telemedicine for multiple sclerosis patients: assessment using Health Value Compass.
      ,
      • Ortiz-Gutierrez R.
      • Cano-de-la-Cuerda R.
      • Galan-del-Rio F.
      • Alguacil-Diego I.M.
      • Palacios-Cena D.
      • Miangolarra-Page J.C.
      A telerehabilitation program improves postural control in multiple sclerosis patients: a Spanish preliminary study.
      ,
      • Wood J.
      • Wallin M.
      • Finkelstein J.
      Can a low-cost webcam be used for a remote neurological exam?.
      ,
      • Turner A.P.
      • Sloan A.P.
      • Kivlahan D.R.
      • Haselkorn J.K.
      Telephone counseling and home telehealth monitoring to improve medication adherence: results of a pilot trial among individuals with multiple sclerosis.
      ,
      • Khan F.
      • Amatya B.
      • Kesselring J.
      • Galea M.P.
      Telerehabilitation for persons with multiple sclerosis. A Cochrane review.
      ). Although telemedicine has proved to be extremely useful for servicing remote populations, it does not solve the problem of a low density of services per capita.
      Table 2Telemedicine can help to improve access to diagnostic services and ongoing specialist care by extending services to remote populations, as indicated by the results of several pilot studies.
      Type of telemedicine resourceOutcome
      Analysis of lesions on MRI scans using software that runs in a web browserSimilar results to those obtained using conventional software (
      • Luccichenti G.
      • Cademartiri F.
      • Pichiecchio A.
      • Bontempi E.
      • Sabatini U.
      • Bastianello S.
      User interface of a teleradiology system for the MR assessment of multiple sclerosis.
      ).
      Remote assessment of disabilityClinically valid information and similar total EDSS scores compared with ‘in-person assessments’ using a videoconference link (
      • Kane R.L.
      • Bever C.T.
      • Ehrmantraut M.
      • Forte A.
      • Culpepper W.J.
      • Wallin M.T.
      Teleneurology in patients with multiple sclerosis: EDSS ratings derived remotely and from hands-on examination.
      ) or low-cost webcam (
      • Wood J.
      • Wallin M.
      • Finkelstein J.
      Can a low-cost webcam be used for a remote neurological exam?.
      ).
      Home-based rehabilitation programmesImprovements in function, such as walking, balance (
      • Finkelstein J.
      • Lapshin O.
      • Castro H.
      • Cha E.
      • Provance P.G.
      Home-based physical telerehabilitation in patients with multiple sclerosis: a pilot study.
      ) and postural control (
      • Ortiz-Gutierrez R.
      • Cano-de-la-Cuerda R.
      • Galan-del-Rio F.
      • Alguacil-Diego I.M.
      • Palacios-Cena D.
      • Miangolarra-Page J.C.
      A telerehabilitation program improves postural control in multiple sclerosis patients: a Spanish preliminary study.
      ). Low-level evidence for reduction in impairments (such as fatigue, pain and insomnia) and improvement in functional activities and participation, based on a systematic review of nine randomized controlled trials (
      • Khan F.
      • Amatya B.
      • Kesselring J.
      • Galea M.P.
      Telerehabilitation for persons with multiple sclerosis. A Cochrane review.
      ).
      Brief telecounselling sessions and home monitoringBetter adherence to medication than that found for people who did not receive these services (
      • Turner A.P.
      • Sloan A.P.
      • Kivlahan D.R.
      • Haselkorn J.K.
      Telephone counseling and home telehealth monitoring to improve medication adherence: results of a pilot trial among individuals with multiple sclerosis.
      ).
      Home monitoringLess severe symptoms than in those who did not receive the service; additionally, two-thirds of those in the telecare home-monitoring group had a decrease in medical costs of at least 35% (
      • Zissman K.
      • Lejbkowicz I.
      • Miller A.
      Telemedicine for multiple sclerosis patients: assessment using Health Value Compass.
      ).
      EDSS, Kurtzke Expanded Disability Status Scale; MRI, magnetic resonance imaging.
      Technology can also provide greater access to specialist training for MS healthcare professionals. For example, 2379 nurses from 30 countries across the globe (

      Winslow, A., 2015. MS Nurse PROfessional. In: Proceedings of European Multiple Sclerosis Platform Conference. 15–16 May 2015. Warsaw, Poland. 〈http://www.emsp.org/attachments/article/304/MS%20Nurse%20PRO%20Summary,%20Anne%20Winslow.pdf〉 (accessed 03.06.15.).

      ) have registered for the MS Nurse Professional course, led by the European Multiple Sclerosis Platform in collaboration with the International Organization of Multiple Sclerosis Nurses and Rehabilitation in MS (

      European Multiple Sclerosis Platform, 2015b. MS Nurse Professional. European Multiple Sclerosis Platform. 〈http://www.msnursepro.org/〉 (accessed 02.04.15.).

      ), in the 2 years to March 2015.

      5.3 Delays in the referral pathway are common

      Delays between the onset of symptoms and MS diagnosis can occur at two key points. Delays between the onset of symptoms and an initial consultation with a healthcare professional are common (
      • Fernandez O.
      • Fernandez V.
      • Arbizu T.
      • Izquierdo G.
      • Bosca I.
      • Arroyo R.
      • et al.
      Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).
      ,
      • Adamec I.
      • Barun B.
      • Gabelic T.
      • Zadro I.
      • Habek M.
      Delay in the diagnosis of multiple sclerosis in Croatia.
      ) and can last more than 1 year (
      • Fernandez O.
      • Fernandez V.
      • Arbizu T.
      • Izquierdo G.
      • Bosca I.
      • Arroyo R.
      • et al.
      Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).
      ). This indicates the need to raise awareness of the symptoms of MS among the general population (
      • Fernandez O.
      • Fernandez V.
      • Arbizu T.
      • Izquierdo G.
      • Bosca I.
      • Arroyo R.
      • et al.
      Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).
      ).
      Further delays may then occur before eventual diagnosis by a specialist healthcare professional (neurologist or MS neurologist). In addition to waiting lists that inevitably occur when the numbers of neurologists per capita are low, such delays can also result from non-availability of diagnostic tools such as MRI scanners and lumbar puncture, from administrative issues (for example, long waiting lists for neurology services after referral) (
      • Kelly S.B.
      • Chaila E.
      • Kinsella K.
      • Duggan M.
      • McGuigan C.
      • Tubridy N.
      • et al.
      Multiple sclerosis, from referral to confirmed diagnosis: an audit of clinical practice.
      ) and from lack of awareness among family or primary care physicians (Fig. 9) (
      • Fernandez O.
      • Fernandez V.
      • Arbizu T.
      • Izquierdo G.
      • Bosca I.
      • Arroyo R.
      • et al.
      Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).
      ,
      • Kelly S.B.
      • Chaila E.
      • Kinsella K.
      • Duggan M.
      • McGuigan C.
      • Tubridy N.
      • et al.
      Multiple sclerosis, from referral to confirmed diagnosis: an audit of clinical practice.
      ,
      • Adamec I.
      • Barun B.
      • Gabelic T.
      • Zadro I.
      • Habek M.
      Delay in the diagnosis of multiple sclerosis in Croatia.
      ).
      Fig. 9
      Fig. 9Delays between the initial onset of MS symptoms and diagnosis are common (
      • Fernandez O.
      • Fernandez V.
      • Arbizu T.
      • Izquierdo G.
      • Bosca I.
      • Arroyo R.
      • et al.
      Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).
      ,
      • Kelly S.B.
      • Chaila E.
      • Kinsella K.
      • Duggan M.
      • McGuigan C.
      • Tubridy N.
      • et al.
      Multiple sclerosis, from referral to confirmed diagnosis: an audit of clinical practice.
      ,
      • Adamec I.
      • Barun B.
      • Gabelic T.
      • Zadro I.
      • Habek M.
      Delay in the diagnosis of multiple sclerosis in Croatia.
      ) and can last more than 2 years (
      • Fernandez O.
      • Fernandez V.
      • Arbizu T.
      • Izquierdo G.
      • Bosca I.
      • Arroyo R.
      • et al.
      Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).
      ). MRI, magnetic resonance imaging.
      Reproduced with permission from Oxford PharmaGenesis Ltd. © 2015 Oxford PharmaGenesis Ltd.
      There is evidence of a relationship between delays in referral to an MS neurologist and disability level at the time of the first visit: the longer the delay, the greater the initial disability level at that time (
      • Kingwell E.
      • Leung A.L.
      • Roger E.
      • Duquette P.
      • Rieckmann P.
      • Tremlett H.
      Factors associated with delay to medical recognition in two Canadian multiple sclerosis cohorts.
      ). The effects of delays between diagnosis and treatment initiation are described in Section 6.
      First-person account (

      Jarvis, N., 2012. The Years of Pain that Lead to a Diagnosis. Multiple Sclerosis Trust. 〈http://www.mstrust.org.uk/mystory/nick-jarvis.jsp#nj〉 (accessed 11.02.15.).

      )
      I started getting a lot of pain in my legs and lower back. Along with the pain, I was getting weird nerve sensations in my legs and my legs felt as though they were getting weaker and weaker. This continued from 2003 to this day. I saw orthopaedic specialists on nine occasions and they put the problems down to the sciatic nerve. In 2010… I registered with a new doctor… He told me he was referring me to a neurosurgeon [sic] to get this checked out properly. In early 2011, I was sent for full body MRI scans and lumbar punctures… finally… [in] February 2012, I was diagnosed with primary progressive MS… I have fought for 9 years to try and work out what was going on in my legs.

      5.4 Magnetic resonance imaging evidence assists early diagnosis

      Symptoms similar to those of MS appear in many other conditions. Therefore, when making a diagnosis, clear differentiation between these other conditions and MS is crucial. Being diagnosed with a chronic, unpredictable, progressive incurable disease such as MS has huge personal implications, including reduced employability, increased anxiety and mental distress, and years of taking medicines (
      • Rolak L.A.
      • Fleming J.O.
      The differential diagnosis of multiple sclerosis.
      ).

      5.4.1 Early diagnostic criteria required two or more acute clinical relapses

      Historically, it was difficult to diagnose MS because lesions in the CNS could only be observed directly on autopsy. The early diagnostic criteria for MS (the Schumacher (
      • Schumacher G.A.
      • Beebe G.
      • Kibler R.F.
      • Kurland L.T.
      • Kurtzke J.F.
      • McDowell F.
      • et al.
      Problems of experimental trials of therapy in multiple sclerosis: report by the panel on the evaluation of experimental trials of therapy in multiple sclerosis.
      ) and Poser (
      • Poser C.M.
      • Paty D.W.
      • Scheinberg L.
      • McDonald W.I.
      • Davis F.A.
      • Ebers G.C.
      • et al.
      New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
      ) criteria, published in 1965 and 1983, respectively) therefore relied on directly observable events: a diagnosis of clinically definite MS required at least two acute clinical relapses. The Poser criteria also incorporated evidence from electrical measurements of brain activity when certain nerves are stimulated (‘evoked potentials’) and lumbar puncture to help to support the clinical diagnosis (
      • Poser C.M.
      • Paty D.W.
      • Scheinberg L.
      • McDonald W.I.
      • Davis F.A.
      • Ebers G.C.
      • et al.
      New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
      ).

      5.4.2 Evidence from brain scans now allows faster and more accurate diagnosis

      With the advent of MRI it became possible to classify lesion patterns in the CNS that are suggestive of MS. As understanding of MRI improved, the McDonald diagnostic criteria were introduced in 2001 (
      • McDonald W.I.
      • Compston A.
      • Edan G.
      • Goodkin D.
      • Hartung H.P.
      • Lublin F.D.
      • et al.
      Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis.
      ) and further refined in 2005 (
      • Polman C.H.
      • Reingold S.C.
      • Edan G.
      • Filippi M.
      • Hartung H.P.
      • Kappos L.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria".
      ,
      • Swanton J.K.
      • Rovira A.
      • Tintore M.
      • Altmann D.R.
      • Barkhof F.
      • Filippi M.
      • et al.
      MRI criteria for multiple sclerosis in patients presenting with clinically isolated syndromes: a multicentre retrospective study.
      ) and 2010 (
      • Polman C.H.
      • Reingold S.C.
      • Banwell B.
      • Clanet M.
      • Cohen J.A.
      • Filippi M.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria.
      ). The McDonald criteria allow a diagnosis of MS to be made in a person who has had just one relapse, by incorporating evidence from MRI scans. The criteria recognize that diagnostic certainty can be increased when lesions are observed in typical locations and when they can be shown to have appeared over a period of time (rather than all at once) (
      • Montalban X.
      • Tintore M.
      • Swanton J.
      • Barkhof F.
      • Fazekas F.
      • Filippi M.
      • et al.
      MRI criteria for MS in patients with clinically isolated syndromes.
      ).
      As a result of incorporation of MRI evidence into the diagnostic criteria, people with MS can have their condition diagnosed more rapidly than was previously possible and in a more sensitive and consistent way (
      • Zipoli V.
      • Portaccio E.
      • Siracusa G.
      • Pracucci G.
      • Sorbi S.
      • Amato M.P.
      Interobserver agreement on Poser's and the new McDonald's diagnostic criteria for multiple sclerosis.
      ). The number of people whose MS is accurately diagnosed within 1 year of their first relapse more than doubles (
      • Dalton C.M.
      • Brex P.A.
      • Miszkiel K.A.
      • Hickman S.J.
      • MacManus D.G.
      • Plant G.T.
      • et al.
      Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis.
      ) or triples (
      • Tintore M.
      • Rovira A.
      • Rio J.
      • Nos C.
      • Grive E.
      • Sastre-Garriga J.
      • et al.
      New diagnostic criteria for multiple sclerosis: application in first demyelinating episode.
      ) using the original McDonald criteria compared with the Poser criteria. In addition, a diagnosis can be established from the earliest MRI scans in about one in five people who have experienced a single relapse using the 2010 McDonald criteria (
      • Runia T.F.
      • Jafari N.
      • Hintzen R.Q.
      Application of the 2010 revised criteria for the diagnosis of multiple sclerosis to patients with clinically isolated syndromes.
      ). It should be noted, however, that the McDonald criteria are not always used consistently in clinical practice (
      • Hawkes C.H.
      • Giovannoni G.
      The McDonald criteria for multiple sclerosis: time for clarification.
      ).

      5.4.3 Greater diagnostic certainty enables earlier treatment

      The McDonald criteria are now widely accepted and used to establish a diagnosis of MS. Of the 105 countries for which data were provided in a 2013 global survey, a version of the McDonald criteria was reported as being used in 92% (

      Multiple Sclerosis International Federation, 2013g. Atlas of MS Database Data Export: Diagnosis, 2013. Multiple Sclerosis International Federation. 〈http://www.atlasofms.org〉 (accessed 27.01.15.).

      ). Real-world evidence from the USA shows that the average delay from symptom onset to diagnosis has fallen 10-fold, from 7.2 years in 1980–1984 to 0.63 years in 2000–2004 (Table 3) (
      • Marrie R.A.
      • Cutter G.
      • Tyry T.
      • Hadjimichael O.
      • Campagnolo D.
      • Vollmer T.
      Changes in the ascertainment of multiple sclerosis.
      ). In the same time period, the proportion of people who had moderate or severe disability (as opposed to mild disability) on their initial visit to a healthcare professional fell from over 50% to about 25% (
      • Marrie R.A.
      • Cutter G.
      • Tyry T.
      • Hadjimichael O.
      • Campagnolo D.
      • Vollmer T.
      Changes in the ascertainment of multiple sclerosis.
      ). Early diagnosis means that early treatment is possible – which will improve the long-term prognosis for people with MS by reducing subsequent damage to the CNS and preventing further unnecessary clinical relapses or disability progression (Section 6).
      Table 3There has been a 10-fold decrease in the delay between the onset of MS symptoms and diagnosis since 1980 in the USA (
      • Marrie R.A.
      • Cutter G.
      • Tyry T.
      • Hadjimichael O.
      • Campagnolo D.
      • Vollmer T.
      Changes in the ascertainment of multiple sclerosis.
      ).
      Onset of symptomsMean (SD) delay (years) from onset of symptoms to diagnosis
      1980–19847.2 (5.7)
      1985–19895.3 (4.4)
      1990–19943.7 (3.2)
      1995–19991.8 (1.7)
      2000–20040.63 (0.8)
      SD, standard deviation.
      The evolution and subsequent implementation of MS diagnostic criteria is an excellent example of the use of an evidence base to improve clinical practice and outcomes for people with MS. Despite clear diagnostic evidence, however, the prescribing guidelines for MS issued by national healthcare authorities in some countries still require a person to experience two clinical relapses, and in some cases disabling relapses, before a DMT can be initiated (Section 6.3.1). This means that further irreversible damage to the CNS can occur, both during the time spent waiting for a second relapse and as a result of the relapse itself.

      5.5 Recommendations

      Delays in the diagnosis of MS should be minimized as these can result in irreversible disability progression.
      • Educate the general public to take prompt action if early symptoms of MS develop, by visiting a healthcare professional. Awareness campaigns that highlight the typical initial symptoms, the negative impact of delaying treatment and the personal and societal costs of the disease would support this.
      • Educate family and primary care physicians about the importance of promptly referring people with suspected MS to a neurologist, and ultimately to a specialist clinic, to speed up diagnosis and treatment initiation.
      • Recommend that general neurologists refer people suspected of having the disease to specialist MS neurologists.
      • Improve access to specialist care for MS: make diagnostic and monitoring procedures more widely accessible, increase the numbers of healthcare professionals who specialize in the management of MS, and ensure that these specialists provide prompt diagnostic and support services for people with suspected MS and those who have been newly diagnosed with the disease.
      • Adopt the latest accepted diagnostic criteria, in order to diagnose MS as early as possible.

      6. Intervene early to maximize lifelong brain health

      Key points:
      • The goal of treating MS should be to preserve brain tissue and maximize lifelong brain health by reducing disease activity.
      • There is a lot of evidence to support the therapeutic strategy of early intervention with a DMT. This should accompany measures to encourage a ‘brain-healthy’ lifestyle as part of a comprehensive approach to treatment.
      • However, initiating treatment with a DMT is often delayed and subject to restrictions in licensing, prescribing guidelines and reimbursement policies.
      • Treatment options are rapidly evolving and many DMTs are now available. They are not all equally effective in all people with MS, and they have a variety of side-effect profiles.
      • The choice to initiate treatment should be an informed, shared decision between the person with MS and their clinician, and should consider all appropriate DMTs. The disease course, values, needs, limitations and lifestyle of the person with MS should all be assessed in parallel with the potential benefits and risks of specific DMTs.

      6.1 Intervention should aim to maximize brain health and physical function

      6.1.1 Early intervention is key

      MS causes irreversible damage to the brain and spinal cord. Although repair mechanisms and remodelling of the CNS can partially compensate for a while, these mechanisms eventually fail to keep up with the damage caused by inflammatory disease activity. Ultimately neurological reserve – the capacity that the CNS has to compensate for injury by remodelling itself – is exhausted (Fig. 2b). The clinical consequences of MS then become clear – steady increases in physical and mental disability without remissions, as seen in people who have transitioned to SPMS.
      Following this transition, the opportunity to change the course of the disease is diminished. No DMTs have been approved worldwide for NRSPMS, and – even if treatment were possible – reversal of persistent disability is highly unlikely. Additionally, the depletion of neurological reserve means that fewer resources remain to combat the cognitive and physical effects of normal age-related brain atrophy (
      • Schwartz C.E.
      • Quaranto B.R.
      • Healy B.C.
      • Benedict R.H.
      • Vollmer T.L.
      Cognitive reserve and symptom experience in multiple sclerosis: a buffer to disability progression over time?.
      ). Effective DMT and lifestyle interventions must, therefore, be initiated as soon as the disease is diagnosed in order to protect neurological reserve and maximize lifelong brain health. This approach is in line with the principles on brain health established by the World Federation of Neurology and promoted across a number of brain and mental health disease areas by the World Brain Alliance (

      World Federation of Neurology, 2015. World Brain Alliance. World Federation of Neurology. 〈http://www.wfneurology.org/world-brain-alliance〉 (accessed 03.06.15.).

      ).

      6.1.2 Treating and managing multiple sclerosis requires a comprehensive approach

      Maximizing lifelong brain health is equivalent to preserving neurological reserve. The results of recent research imply that neurological reserve has two components: brain reserve (brain volume) and cognitive reserve (see Box). Preserving brain volume (
      • Kalincik T.
      • Vaneckova M.
      • Tyblova M.
      • Krasensky J.
      • Seidl Z.
      • Havrdova E.
      • et al.
      Volumetric MRI markers and predictors of disease activity in early multiple sclerosis: a longitudinal cohort study.
      ,
      • Popescu V.
      • Agosta F.
      • Hulst H.E.
      • Sluimer I.C.
      • Knol D.L.
      • Sormani M.P.
      • et al.
      Brain atrophy and lesion load predict long term disability in multiple sclerosis.
      ,
      • Sormani M.P.
      • Arnold D.L.
      • De Stefano N.
      Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis.
      ,
      • Uher T.
      • Horakova D.
      • Bergsland N.
      • Tyblova M.
      • Ramasamy D.P.
      • Seidl Z.
      • et al.
      MRI correlates of disability progression in patients with CIS over 48 months.
      ,
      • Radue E.W.
      • Barkhof F.
      • Kappos L.
      • Sprenger T.
      • Haring D.A.
      • de Vera A.
      • et al.
      Correlation between brain volume loss and clinical and MRI outcomes in multiple sclerosis.
      ) and cognitive reserve (
      • Schwartz C.E.
      • Quaranto B.R.
      • Healy B.C.
      • Benedict R.H.
      • Vollmer T.L.
      Cognitive reserve and symptom experience in multiple sclerosis: a buffer to disability progression over time?.
      ) protects against disability progression, and these two factors independently protect against disease-related cognitive decline (
      • Sumowski J.F.
      • Rocca M.A.
      • Leavitt V.M.
      • Riccitelli G.
      • Comi G.
      • DeLuca J.
      • et al.
      Brain reserve and cognitive reserve in multiple sclerosis: what you've got and how you use it.
      ). The therapeutic strategy in MS should aim to preserve as much brain reserve and cognitive reserve as possible by using DMTs to slow down the disease course and by adopting a ‘brain-healthy’ lifestyle.
      Neurological reserve comprises brain reserve and cognitive reserve
      Brain reserve can be thought of as the physical quantity of brain tissue present. Initial brain volume is genetically and/or congenitally determined (
      • Bartley A.J.
      • Jones D.W.
      • Weinberger D.R.
      Genetic variability of human brain size and cortical gyral patterns.
      ,
      • Tramo M.J.
      • Loftus W.C.
      • Stukel T.A.
      • Green R.L.
      • Weaver J.B.
      • Gazzaniga M.S.
      Brain size, head size, and intelligence quotient in monozygotic twins.
      ), and it is normal for healthy adults to experience some brain atrophy as they age (Fig. 1). It has been shown that elderly people with greater brain reserve (i.e. who have larger brains) experience cognitive impairment later than those with smaller brains (
      • Reynolds M.D.
      • Johnston J.M.
      • Dodge H.H.
      • DeKosky S.T.
      • Ganguli M.
      Small head size is related to low Mini-Mental State Examination scores in a community sample of nondemented older adults.
      ,
      • Tisserand D.J.
      • Bosma H.
      • Van Boxtel M.P.
      • Jolles J.
      Head size and cognitive ability in nondemented older adults are related.
      ,
      • MacLullich A.M.
      • Ferguson K.J.
      • Deary I.J.
      • Seckl J.R.
      • Starr J.M.
      • Wardlaw J.M.
      Intracranial capacity and brain volumes are associated with cognition in healthy elderly men.
      ,
      • Farias S.T.
      • Mungas D.
      • Reed B.
      • Carmichael O.
      • Beckett L.
      • Harvey D.
      • et al.
      Maximal brain size remains an important predictor of cognition in old age, independent of current brain pathology.
      ).
      Cognitive reserve can be viewed as the ability of the brain to process tasks and actively compensate for physical damage (
      • Stern Y.
      What is cognitive reserve? Theory and research application of the reserve concept.
      ). All other things being equal, people with MS who have a high cognitive reserve lose less cognitive function than those with a low cognitive reserve for the same amount of physical damage (measured in terms of brain atrophy (
      • Pinter D.
      • Sumowski J.
      • DeLuca J.
      • Fazekas F.
      • Pichler A.
      • Khalil M.
      • et al.
      Higher education moderates the effect of T2 lesion load and third ventricle width on cognition in multiple sclerosis.
      ,
      • Sumowski J.F.
      • Rocca M.A.
      • Leavitt V.M.
      • Dackovic J.
      • Mesaros S.
      • Drulovic J.
      • et al.
      Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS.
      ,
      • Modica C.M.
      • Bergsland N.
      • Dwyer M.G.
      • Ramasamy D.P.
      • Carl E.
      • Zivadinov R.
      • et al.
      Cognitive reserve moderates the impact of subcortical gray matter atrophy on neuropsychological status in multiple sclerosis.
      ) or lesions (
      • Pinter D.
      • Sumowski J.
      • DeLuca J.
      • Fazekas F.
      • Pichler A.
      • Khalil M.
      • et al.
      Higher education moderates the effect of T2 lesion load and third ventricle width on cognition in multiple sclerosis.
      ,
      • Sumowski J.F.
      • Rocca M.A.
      • Leavitt V.M.
      • Dackovic J.
      • Mesaros S.
      • Drulovic J.
      • et al.
      Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS.
      )).
      Cardiovascular fitness correlates with brain volume and cognitive reserve (processing speed) in people with MS (
      • Prakash R.S.
      • Snook E.M.
      • Motl R.W.
      • Kramer A.F.
      Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis.
      ), and improving it through aerobic exercise should be part of managing MS. Avoidance of smoking should be another component of a ‘brain-healthy’ lifestyle. Cigarette smoking is associated with decreased brain volume in people with MS (
      • Kappus N.
      • Weinstock-Guttman B.
      • Hagemeier J.
      • Kennedy C.
      • Melia R.
      • Carl E.
      • et al.
      Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis.
      ), as well as with higher relapse rates (
      • D'Hooghe M.B.
      • Nagels G.
      • Bissay V.
      • De Keyser J.
      Modifiable factors influencing relapses and disability in multiple sclerosis.
      ), increased disability progression (
      • Pittas F.
      • Ponsonby A.L.
      • van der Mei I.A.
      • Taylor B.V.
      • Blizzard L.
      • Groom P.
      • et al.
      Smoking is associated with progressive disease course and increased progression in clinical disability in a prospective cohort of people with multiple sclerosis.
      ,
      • D'Hooghe M.B.
      • Nagels G.
      • Bissay V.
      • De Keyser J.
      Modifiable factors influencing relapses and disability in multiple sclerosis.
      ), increased cognitive impairment (
      • Ozcan M.E.
      • Ince B.
      • Bingol A.
      • Erturk S.
      • Altinoz M.A.
      • Karadeli H.H.
      • et al.
      Association between smoking and cognitive impairment in multiple sclerosis.
      ) and reduced survival (
      • Jick S.S.
      • Li L.
      • Falcone G.J.
      • Vassilev Z.P.
      • Wallander M.A.
      Epidemiology of multiple sclerosis: results from a large observational study in the UK.
      ) compared with not smoking. Additionally, smokers with CIS are nearly twice as likely as non-smokers with CIS to develop further inflammatory lesions and, thus, MS (
      • Di Pauli F.
      • Reindl M.
      • Ehling R.
      • Schautzer F.
      • Gneiss C.
      • Lutterotti A.
      • et al.
      Smoking is a risk factor for early conversion to clinically definite multiple sclerosis.
      ). Limiting the use of alcohol is also important, because there is evidence that unsafe levels of drinking (currently or in the past) lead to reduced survival in people with MS (
      • Jick S.S.
      • Li L.
      • Falcone G.J.
      • Vassilev Z.P.
      • Wallander M.A.
      Epidemiology of multiple sclerosis: results from a large observational study in the UK.
      ).
      Activities that enhance cognitive reserve by being intellectually enriching (such as education, reading, hobbies and creative expression) have been shown to protect against cognitive impairment in MS when pursued over a lifetime (
      • Sumowski J.F.
      • Chiaravalloti N.
      • Wylie G.
      • Deluca J.
      Cognitive reserve moderates the negative effect of brain atrophy on cognitive efficiency in multiple sclerosis.
      ,
      • Sumowski J.F.
      • Wylie G.R.
      • Chiaravalloti N.
      • DeLuca J.
      Intellectual enrichment lessens the effect of brain atrophy on learning and memory in multiple sclerosis.
      ,
      • Pinter D.
      • Sumowski J.
      • DeLuca J.
      • Fazekas F.
      • Pichler A.
      • Khalil M.
      • et al.
      Higher education moderates the effect of T2 lesion load and third ventricle width on cognition in multiple sclerosis.
      ,
      • Sumowski J.F.
      • Rocca M.A.
      • Leavitt V.M.
      • Dackovic J.
      • Mesaros S.
      • Drulovic J.
      • et al.
      Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS.
      ,
      • Modica C.M.
      • Bergsland N.
      • Dwyer M.G.
      • Ramasamy D.P.
      • Carl E.
      • Zivadinov R.
      • et al.
      Cognitive reserve moderates the impact of subcortical gray matter atrophy on neuropsychological status in multiple sclerosis.
      ) and should be prioritized day-to-day.
      Minimizing comorbidities (other diseases present alongside MS) will help to reduce their negative effect on the MS disease course and to limit the potential for disability unrelated to MS, which can add to the overall impairment burden.
      • In people with MS, high blood pressure and heart disease are both associated with lower brain volume, and obesity is associated with higher lesion numbers (
        • Kappus N.
        • Weinstock-Guttman B.
        • Hagemeier J.
        • Kennedy C.
        • Melia R.
        • Carl E.
        • et al.
        Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis.
        ).
      • High blood pressure, type 2 diabetes, dyslipidaemia (high levels of cholesterol and/or fat in the blood) and peripheral artery disease (narrowing of the arteries outside of the heart and brain) are all associated with greater disability progression if they co-exist at any time in the MS disease course (
        • Tettey P.
        • Simpson Jr., S.
        • Taylor B.V.
        • van der Mei I.A.
        Vascular comorbidities in the onset and progression of multiple sclerosis.
        ); so too are vascular diseases in general (those affecting the blood vessel system) (
        • Marrie R.A.
        • Rudick R.
        • Horwitz R.
        • Cutter G.
        • Tyry T.
        • Campagnolo D.
        • et al.
        Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis.
        ).
      • Heart disease, influenza, pneumonia, urinary tract infections and cancer are all predictors of reduced survival among people with MS (
        • Jick S.S.
        • Li L.
        • Falcone G.J.
        • Vassilev Z.P.
        • Wallander M.A.
        Epidemiology of multiple sclerosis: results from a large observational study in the UK.
        ).
      To summarize, maximizing lifelong brain health in MS involves a comprehensive approach that incorporates lifestyle measures such as aerobic exercise, avoidance of smoking and excessive alcohol consumption, activities that enhance cognitive reserve, and steps to minimize comorbidities, in addition to intervention with a DMT (the focus of the remainder of this section).

      6.2 A lot of evidence supports early intervention with a disease-modifying therapy

      Long-term studies clearly show that early intervention with a DMT is more likely than late intervention to lead to a better outcome in people with CIS and RRMS (Fig. 10) (
      • Miller J.R.
      The importance of early diagnosis of multiple sclerosis.
      ). There are three main components to the body of evidence supporting this.
      • In people with a diagnosis of CIS, treatment with a DMT increases the time to a second relapse (that is, conversion to RRMS under any diagnostic criteria) and improves MRI outcomes, including brain atrophy rate (Table B.1) (
        • Jacobs L.D.
        • Beck R.W.
        • Simon J.H.
        • Kinkel R.P.
        • Brownscheidle C.M.
        • Murray T.J.
        • et al.
        Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
        ,
        • Comi G.
        • Filippi M.
        • Barkhof F.
        • Durelli L.
        • Edan G.
        • Fernandez O.
        • et al.
        Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study.
        ,
        • O'Connor P.
        The effects of intramuscular interferon beta-Ia in patients at high risk for development of multiple sclerosis: a post hoc analysis of data from CHAMPS.
        ,
        • Filippi M.
        • Rovaris M.
        • Inglese M.
        • Barkhof F.
        • De Stefano N.
        • Smith S.
        • et al.
        Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial.
        ,
        • Kappos L.
        • Polman C.H.
        • Freedman M.S.
        • Edan G.
        • Hartung H.P.
        • Miller D.H.
        • et al.
        Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes.
        ,
        • Comi G.
        • Martinelli V.
        • Rodegher M.
        • Moiola L.
        • Bajenaru O.
        • Carra A.
        • et al.
        Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
        ,
        • Comi G.
        • De Stefano N.
        • Freedman M.S.
        • Barkhof F.
        • Polman C.H.
        • Uitdehaag B.M.
        • et al.
        Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial.
        ,
        • Miller A.E.
        • Wolinsky J.S.
        • Kappos L.
        • Comi G.
        • Freedman M.S.
        • Olsson T.P.
        • et al.
        Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial.
        ).
      • In people with a diagnosis of CIS, initiating treatment with a DMT early in the disease course is associated with better long-term outcomes than delaying treatment (Table B.2) (
        • Kinkel R.P.
        • Dontchev M.
        • Kollman C.
        • Skaramagas T.T.
        • O'Connor P.W.
        • Simon J.H.
        Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: a 10-year follow-up of the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance.
        ,
        • Comi G.
        • Martinelli V.
        • Rodegher M.
        • Moiola L.
        • Leocani L.
        • Bajenaru O.
        • et al.
        Effects of early treatment with glatiramer acetate in patients with clinically isolated syndrome.
        ,
        • Edan G.
        • Freedman M.
        • Montalban X.
        • Miller D.
        • Hartung H.
        • Hemmer B.
        • et al.
        Long-term impact of early MS treatment with interferon beta-1b (IFNB-1b): clinical, MRI, employment, and patient-reported outcomes (PROs) at the 11-year follow-up of BENEFIT (BENEFIT 11).
        ).
      • In people with a diagnosis of RRMS, initiating treatment with a DMT early in the disease course is associated with better long-term outcomes than delaying treatment (Table B.3) (
        • Prisms Study Group and University of British Columbia MS/MRI Analysis Group
        PRISMS-4: long-term efficacy of interferon-beta-1a in relapsing MS.
        ,
        • Johnson K.P.
        • Ford C.C.
        • Lisak R.P.
        • Wolinsky J.S.
        Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data.
        ,
        • Kappos L.
        • Traboulsee A.
        • Constantinescu C.
        • Eralinna J.P.
        • Forrestal F.
        • Jongen P.
        • et al.
        Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS.
        ,
        • Rovaris M.
        • Comi G.
        • Rocca M.A.
        • Valsasina P.
        • Ladkani D.
        • Pieri E.
        • et al.
        Long-term follow-up of patients treated with glatiramer acetate: a multicentre, multinational extension of the European/Canadian double-blind, placebo-controlled, MRI-monitored trial.
        ,
        • Trojano M.
        • Pellegrini F.
        • Fuiani A.
        • Paolicelli D.
        • Zipoli V.
        • Zimatore G.B.
        • et al.
        New natural history of interferon-beta-treated relapsing multiple sclerosis.
        ,
        • Trojano M.
        • Pellegrini F.
        • Paolicelli D.
        • Fuiani A.
        • Zimatore G.B.
        • Tortorella C.
        • et al.
        Real-life impact of early interferon beta therapy in relapsing multiple sclerosis.
        ,
        • Bermel R.A.
        • Weinstock-Guttman B.
        • Bourdette D.
        • Foulds P.
        • You X.
        • Rudick R.A.
        Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study.
        ,
        • Ebers G.C.
        • Traboulsee A.
        • Li D.
        • Langdon D.
        • Reder A.T.
        • Goodin D.S.
        • et al.
        Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial.
        ,
        • Goodin D.S.
        • Ebers G.C.
        • Cutter G.
        • Cook S.D.
        • O'Donnell T.
        • Reder A.T.
        • et al.
        Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNbeta-1b study.
        ,
        • Goodin D.S.
        • Reder A.T.
        • Ebers G.C.
        • Cutter G.
        • Kremenchutzky M.
        • Oger J.
        • et al.
        Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNbeta-1b trial.
        ,
        • Agius M.
        • Meng X.
        • Chin P.
        • Grinspan A.
        • Hashmonay R.
        Fingolimod therapy in early multiple sclerosis: an efficacy analysis of the TRANSFORMS and FREEDOMS studies by time since first symptom.
        ,
        • Kappos L.
        • O'Connor P.
        • Radue E.W.
        • Polman C.
        • Hohlfeld R.
        • Selmaj K.
        • et al.
        Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial.
        ).
      Fig. 10
      Fig. 10Early intervention with a DMT in MS and CIS is thought to give the best long-term prognosis. CIS, clinically isolated syndrome; DMT, disease-modifying therapy.
      Reproduced with permission from Oxford PharmaGenesis Ltd. © 2015 Oxford PharmaGenesis Ltd.
      It is important to note that, nowadays, many of the participants in the CIS trials summarized in Table B.1, Table B.2 would have been diagnosed with RRMS according to the 2010 revision of the McDonald diagnostic criteria (

      Costello, K., Halper, J., Kalb, R., Skutnik, L., Rapp, R., 2015. The Use of Disease-modifying Therapies in Multiple Sclerosis: Principles and Current Evidence. Multiple Sclerosis Coalition. 〈http://www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color〉 (accessed 13.05.15).

      ). Therefore, this evidence also supports early treatment in RRMS.
      In the majority of studies summarized in Table B.2, Table B.3, participants were randomly chosen to receive either a DMT or placebo (a ‘dummy’ treatment with no therapeutic effect) for an initial period, followed by a DMT for an extended period. These ‘placebo-switch’ studies therefore show the difference between initiating a DMT early in the disease course and later.
      Further evidence that DMTs are most effective early in the disease course is provided by a recent meta-analysis of published randomized clinical trials in RRMS. This showed that DMTs are more effective at slowing disability progression from MS in younger people than in older people; they also reduce the relapse rate most effectively in younger people (rather than older people), in patients with low EDSS scores (rather than high scores) and in those with active lesions (i.e. lesions that are currently inflamed) rather than no active lesions (
      • Signori A.
      • Schiavetti I.
      • Gallo F.
      • Sormani M.P.
      Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials.
      ).
      Support for early treatment in RRMS is also provided by real-world evidence from databases and registries (Table B.3) (
      • Trojano M.
      • Pellegrini F.
      • Fuiani A.
      • Paolicelli D.
      • Zipoli V.
      • Zimatore G.B.
      • et al.
      New natural history of interferon-beta-treated relapsing multiple sclerosis.
      ,
      • Trojano M.
      • Pellegrini F.
      • Paolicelli D.
      • Fuiani A.
      • Zimatore G.B.
      • Tortorella C.
      • et al.
      Real-life impact of early interferon beta therapy in relapsing multiple sclerosis.
      ). In addition, for people with CIS, an analysis of data from an international registry shows that the greater the length of time spent taking a DMT within 12 months of onset, the lower the risk of a sustained increase of at least 1 point on the EDSS in the same time period (
      • Jokubaitis V.G.
      • Spelman T.
      • Kalincik T.
      • Izquierdo G.
      • Grand'Maison F.
      • Duquette P.
      • et al.
      Predictors of disability worsening in clinically isolated syndrome.
      ). Furthermore, data from the Swedish registry indicate that earlier treatment with a DMT is associated with slower disability progression (from diagnosis of MS to EDSS score≥4.0) than later treatment (
      • Kavaliunas A.
      • Stawiarz L.
      • Hedbom J.
      • Glaser A.
      • Hillert J.
      The influence of immunomodulatory treatment on the clinical course of multiple sclerosis.
      ).
      Initiating treatment with a DMT “as early as possible in eligible patients” is also recommended in the 2015 guidelines from the Association of British Neurologists (ABN) (
      • Scolding N.
      • Barnes D.
      • Cader S.
      • Chataway J.
      • Chaudhuri A.
      • Coles A.
      • et al.
      Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis.
      ). Once a transition from RRMS to SPMS has occurred, however, DMTs become ineffective at preventing disability progression (
      • Secondary progressive efficacy clinical trial of recombinant interferon-beta-1a in MS study group
      Randomized controlled trial of interferon- beta-1a in secondary progressive MS: clinical results.
      ,
      • Cohen J.A.
      • Cutter G.R.
      • Fischer J.S.
      • Goodman A.D.
      • Heidenreich F.R.
      • Kooijmans M.F.
      • et al.
      Benefit of interferon beta-1a on MSFC progression in secondary progressive MS.
      ,
      • Panitch H.
      • Miller A.
      • Paty D.
      • Weinshenker B.
      Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study.
      ), although some clinical trials have demonstrated significant effects on the relapse rate (