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Leutmezer: Multiple sclerosis – an overview on epidemiology, pathogenesis and diagnosis


Multiple sclerosis (MS) is one of the most common neurological diseases in young adults in Europe and North America, with around 2.5 million people worldwide affected by this chronic inflammatory disease of the central nervous system (CNS). MS has often been viewed as a ‘white man’s disease’ and, indeed, the disease is not evenly distributed across continents and ethnicities. One of the first systematic epidemiological studies, conducted by Davenport in 1922, described a higher frequency of MS in men drafted to the US army from northern states than from southern states, and noted the high risk in people of Scandinavian ancestry.1 Davenport suggested a latitudinal effect as well as a possible racial effect to account for this difference. One of the most comprehensive reviews of the distribution of MS in the second half of the twentieth century was conducted by Kurtzke.2,3 Kurtzke distinguished between high-risk regions (i.e. northern parts of Europe and North America), with prevalence rates of > 30 per 100 000 population, and low-risk regions (i.e. southern parts of Europe and North America, and South America and Asia), with prevalence rates of < 5 per 100 000. Although incidence and prevalence data published in modern epidemiological studies are liable to stochastic variation, differences in diagnostic criteria, the inclusion of possible MS cases, ascertainment errors, selection bias and age and sex adjustment, the existence of continental differences is beyond controversy, with prevalence rates of up to 220 per 100 000 population (median 108 per 100 000) in Western Europe and up to 300 per 100 000 (median 140 per 100 000) in the USA. Corresponding prevalence rates in Asia, Africa and South America are < 50 per 100 000.4 Moreover, according to the Multiple Sclerosis International Federation’s Atlas of MS 2013,5 the global median prevalence of MS has increased from 30 per 100 000 in 2008 to 33 per 100 000 in 2013.

A constantly increasing women-to-men ratio in patients with MS has been reported in recent decades in some studies but disputed in others.6

Causes and risk factors

Disease susceptibility in MS seems to depend on a complex interplay between genetic and environmental risk factors. This view is supported by studies of twins: in genetically different, dizygotic twins the risk of developing the disease is around 5% in both siblings (compared with 0.1% in the general population).7 In contrast, in genetically identical, monozygotic twins, the probability is much higher, at around 30%.7 This difference underlines the importance of both genes and additional (environmental) factors in disease risk, as even in identical twins the disease concordance is far from complete. But which are the genes that contribute to MS predisposition? Clearly, there is no single ’disease gene’ as there is in the case of monogenic diseases such as cystic fibrosis. Instead, there are many gene variants that can increase (or decrease) disease risk.8 That predisposition to MS is linked to the human leucocyte antigen (HLA) gene complex, which encodes the major histocompatibility complex proteins and controls antigen recognition by T-lymphocytes, has been well established. Specifically, the HLA DR2 variant increases MS risk significantly, while another variant – HLA A2 – is protective. HLA genes are the strongest risk genes, but they are not the only ones. Recent genome-wide association studies have identified more than 150 MS-associated gene variants outside the HLA gene complex.9 Interestingly, most of these genes encode or regulate structure and functions of the immune system, lending further support to the immune concept of MS.

More than 50 environmental risk factors with a possible association to MS have been studied in recent years, including Epstein–Barr virus (EBV), human herpesvirus type 6, mycoplasma pneumonia, vaccination, smoking, vitamin D deficiency, exposure to ultraviolet radiation, diet, traumatic events, surgery, exposure to environmental agents and comorbid diseases. Infectious agents have attracted particular attention, as foreign agents may have a nuclear antigen that is structurally homologous with myelin sheet components such as myelin basic protein (MBP) or myelin-associated glycoprotein. Thus, when immune cells are activated by such pathogens, ’collateral’ damage to the myelin sheet could occur.10

Smoking is another putative environmental factor, as it produces nitric oxide and carbon monoxide, both of which are critical players in lipid peroxidation and mitochondrial damage, leading to oligodendrocyte apoptosis, axonal degeneration and demyelination.11

Vitamin D deficiency is also discussed as an environmental risk factor, as its metabolism is dependent on ultraviolet B radiation and the prevalence and incidence of MS are dramatically lower in areas with high sun exposure. Vitamin D plays an important role in cell proliferation and differentiation as well as gene expression and regulation of immunity, thus probably influencing the origin and course of MS.12

However, to date there is no robust evidence about a particular environmental factor in the pathogenesis of MS, as most studies in this field include caveats that cast doubt on their validity. A recent meta-analysis found only immunoglobulin G antibodies to EBV, a history of infectious mononucleosis and smoking to have a consistent association with the appearance of MS.13


According to the currently prevailing pathogenic concept of MS as an inflammatory disease, MS is caused by an autoimmune attack, primarily directed against the myelin sheet of CNS neurons. T-cells with receptors for myelin determinant are regular components of the healthy immune repertoire. On pathological activation, these cells cross the blood–brain barrier (BBB), enter the CNS parenchyma and trigger a cascade of events that culminate in the histological hallmark of an active MS lesion, including infiltrations of T-cells, macrophages and B-cells; degradation of myelin and, to a lesser extent, axons; and reactive changes in astrocytes and microglia. Autoimmune T-cells recognize ‘their’ autoantigen presented on local antigen-presenting cells and become activated. They secrete proinflammatory mediators, which may act on neurons directly but, more importantly, recruit and activate accessory macrophages. Macrophages have an important role in creating acute neuronal dysfunction. First, they attack myelin sheaths and myelin-forming oligodendrocytes and, hence, are responsible for demyelination. Second, they can attack the denuded axons, causing direct disruption and indirect neuronal degeneration. T-cells also interact as helper cells with autoimmune B-lymphocytes, which produce myelin-specific autoantibodies. Certain autoantibodies bind to the surface of myelin sheaths and destroy them together with complement and/or macrophages.14

This autoimmune concept is based on investigations using human CNS samples, mainly post mortem, and experimental animal models. The fact that only atypical MS cases undergo brain biopsy or postmortem analysis at early disease stages, as well as the fact that animal models can reproduce only in part disease processes in humans, have raised some concerns about this concept of MS.

Other, perhaps less likely, possibilities are that the inflammatory reaction is primarily directed against an unknown infectious agent, or that the inflammatory changes are secondary to a primary degenerative process.14 These two fundamentally different concepts precipitate two different hypotheses.

According to the outside-in hypothesis,15 activated T-lymphocytes from the peripheral blood pass the BBB and cause focal inflammation within the CNS. Subsequently, inflammation is driven not only by T-lymphocytes but also by B-lymphocytes, macrophages and microglia, leading to focal demyelination as the histological hallmark of the disease, with relapses evident both radiologically – T2 lesions revealed by magnetic resonance imaging (MRI) – and clinically. After cessation of the inflammation, patients can be clinically stable for months or years until a new wave of T-lymphocytes invade the CNS, culminating in the next clinical attack. The outside-in hypothesis is strongly supported by the fact that all effective immunomodulatory treatments thus far act mainly on the peripheral immune system. In addition, it has been observed that the transfusion of purified, activated MBP-specific CD4 T-cells into healthy syngeneic animals can induce experimental autoimmune encephalomyelitis (EAE) – ‘transfer EAE’ – in recipients with clinical similarities to MS. This supports the hypothesis that there is an inflammatory component to the disease. On the other hand, no antigen has been identified to date that causes this peripheral immune activation with subsequent influx of inflammatory cells into the CNS.

The inside-out hypothesis argues that a primary CNS trigger (infection, metabolic defect) initiates a secondary immune cascade, leading to histologically confirmed inflammatory CNS lesions.16 Patients with cortical atrophy preceding demyelinating lesions and (rare) histologically confirmed cases of early MS without lymphocyte infiltrates within the CNS would support this hypothesis. However, similar to an ’MS antigen’, a key defect in the CNS that could give rise to a subsequent inflammatory cascade has yet to be identified.

Despite these two fundamentally different hypotheses, convincing evidence exists to support the concept that MS is an autoimmune disease in which inflammatory demyelinating processes in early stages of the disease trigger a cascade of events that lead to subsequent neurodegeneration and that are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden. The later course of the disease, with its clinical counterpart of a secondary progressive course, is characterized by change in the inflammatory repertoire. Waves of inflammatory events driven by lymphocytes constantly decrease in frequency and intensity. At the same time, the inflammation is trapped behind an increasingly closed BBB. This leads to more diffuse inflammatory activity that most probably emerges from subpial meningeal B-cell follicles and mainly affects the grey matter of the brain with diffuse axonal damage and neurodegeneration, leading to diffuse brain atrophy. Although inflammatory components dominate the early phase of the disease, later stages are characterized by microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons and age-related iron accumulation in the brain. Altered mitochondrial function in axons might be of particular importance. This process leads to chronic cell stress and imbalance of ionic homoeostasis, resulting in axonal and neuronal death.17

Clinical presentation

The onset of the disease peaks at around the age of 30 years, with an age at onset of < 20 years in around 10% of patients and > 40 years in around 20% of patients.18 The disease shows female predominance, apparent in all representative studies, with sex ratios (female to male) of up to 3:1.

About 85% of MS patients initially present with relapsing–remitting MS (RRMS).19 In the majority of cases, this converts over time to secondary chronic progressive MS (SPMS) after a median of 15–20 years. Some patients, particularly directly after the transition from RRMS to SPMS, still have (so-called ‘superimposed’) relapses. About 15% of cases present with a primary progressive MS disease course. A small percentage of these patients have a progressive relapsing MS disease course. The clinical hallmark of RRMS is the relapse, defined as new symptoms or an aggravation of pre-existing symptoms that last > 24 hours. The most common clinical symptoms associated with the initial relapse are weakness in one or more limbs, optic neuritis, paraesthesia, diplopia, vertigo and bladder dysfunction. With longer disease duration, gait disturbances, chronic fatigue, cognitive decline, pain, bowel and bladder disturbances and sexual dysfunction become more prominent clinical features.

Diagnosis and diagnostic criteria

The diagnostic process has been summarized with the so-called McDonald criteria.20 These have been amended multiple times, with the latest refinement in 2010, and another amendment is expected in late 2017 or early 2018.

The diagnostic hallmark of the disease is the patient’s clinical presentation, with typical signs and symptoms related to demyelinating lesions, usually accompanied by imaging that is consistent with MS, disseminated in both space and time. At the same time, there should not be a better explanation for the symptoms, stressing the need for careful examination for a possible or probable alternative disease process.

Dissemination in space (DIS) refers to the requirement that lesions affect at least two areas of the CNS typically affected by MS. This can be demonstrated clinically, such as in a patient with a prior history of optic neuritis who now presents with a brainstem syndrome. In this case, DIS is satisfied if there is objective clinical evidence of these two separate lesions or if there is objective clinical evidence of one lesion with a reasonable historical account of the other. However, often a patient will present after only a single event, which is termed a clinically isolated syndrome (CIS). In this case, DIS may be satisfied if the clinician detects on neurological examination evidence for another separate lesion; however, DIS may also be satisfied with clinical evidence for only one lesion by incorporating the patient’s MRI data. MRI criteria for DIS require the presence of at least one T2 lesion in at least two of the four areas of the CNS typically affected by MS: periventricular, juxtacortical, infratentorial and spinal cord areas. If the patient has a brainstem or spinal cord syndrome, the symptomatic lesion has presumably already been ‘counted’ and, therefore, does not count towards the MRI criteria for DIS.21

Dissemination in time (DIT) refers to the requirement that CNS lesions have developed over time, reducing the misdiagnosis of monophasic illness as MS. DIT can easily be clinically satisfied in a patient with two clinical attacks, again with objective clinical evidence for both attacks or for one with a reasonable historical account of the other. However, DIT can also be satisfied with a single clinical episode by the application of MRI criteria. With the patient’s initial MRI results, DIT can be satisfied by demonstration of the presence of both gadolinium-enhancing and non-enhancing lesions on the same scan, as this illustrates that the lesions presumably developed at different points in time. However, the enhancing lesion may not be the symptomatic lesion, which has already been counted. In addition, DIT may be satisfied by the development of any new T2 and/or gadolinium-enhancing lesions with reference to the baseline scan, regardless of the time interval between them.21

Cerebrospinal fluid analysis is no longer a requirement for the diagnosis of RRMS according to the McDonald criteria. However, it is recommended as an additional diagnostic step to increase the rate of correct diagnosis, particularly after a patient’s very first clinical attack and in cases in which diagnosis is not entirely clear.

The category CIS was recently added to the McDonald classification scheme,20 although the term has been used for many years in both research and clinical practice. CIS represents a patient’s initial presentation with clinical symptoms typical of a demyelinating event. A patient is classified as having CIS when there is clinical evidence of a single exacerbation and the MRI results do not fully meet RRMS criteria. From a practical standpoint, there is little difference in approach for a patient with CIS and a patient with RRMS as multiple studies have now demonstrated that patients with a typical CIS, especially those with brain lesions consistent with MS as established by MRI, have a high likelihood of going on to meet RRMS criteria in the future and early treatment is effective at preventing additional relapses.2125

As the use of MRI has become increasingly widespread in cases of headache, trauma and other conditions, abnormalities suggestive of MS have been noted in patients who have not previously experienced clinical symptoms of the disease. The term radiologically isolated syndrome (RIS) was introduced in 2009 and requires that lesions are ovoid and well circumscribed, are not consistent with a vascular pattern and meet three out of four Barkhof criteria: one gadolinium-enhancing lesion or at least nine total T2 lesions, one juxtacortical lesion, one infratentorial lesion and three periventricular lesions.26 The findings must be incidental, meaning that there must be no history of neurological symptoms suggestive of a demyelinating event and the lesions must not account for functional impairment. The risk of converting from RIS to a first clinical symptom suggestive of MS was 34% after a mean follow-up of 4.4 years.27 Younger age, male sex and the presence of spinal cord lesions were predictive of a conversion to CIS.

Differential diagnosis

Multiple sclerosis still relies on clinical diagnosis as no specific biomarker for the disease has been identified. Diagnosis depends on appropriate interpretation of MRI data in patients with the appropriate history and neurological examination suggestive of demyelination. Despite well-validated diagnostic criteria, misdiagnosis remains a significant problem, with implications for patients, their providers and health-care systems.28,29 In a recent multicentre study of 110 misdiagnosed patients, 22% suffered from migraine alone or in combination with other diagnoses, 15% from fibromyalgia, 12% from non-specific or non-localizing neurological symptoms with abnormal MRI results, 11% from conversion or psychogenic disorders and 6% from neuromyelitis optica spectrum disorder. Duration of misdiagnosis was ≥ 10 years in 33% of patients. A total of 70% of misdiagnosed patients received disease-modifying therapy, with 31% experiencing unnecessary morbidity due to misdiagnosis and incorrect treatment.30

The differential diagnosis of MS should include other demyelinating syndromes, diseases typically causing multiple lesions in the brain and often following a relapsing–remitting course, isolated or monophasic syndromes, systematized diseases with symmetrical manifestation and a progressive course, and non-organic symptoms.31

Common diseases that should be incorporated in an accurate diagnostic work-up are listed below.

Other demyelinating syndromes

  • Isolated demyelinating syndromes

    • acute haemorrhagic leucoencephalomyelitis (Hurst disease)

    • acute disseminated encephalomyelitis (ADEM)

    • autoimmune encephalitis

    • paraneoplastic encephalitis

    • paraneoplastic syndrome

    • optic neuritis

    • spinal cord lesions

    • acute necrotizing myelitis

    • transverse myelitis

    • chronic progressive myelopathy

    • radiation myelopathy

    • HTLV-1-associated myelopathy.

  • Multiple sclerosis variants

    • Marburg variant

    • Balo’s concentric sclerosis.

  • Neuromyelitis optica and neuromyelitis optica spectrum disorders.

  • Myelin oligodendrocyte glycoprotein-associated syndromes.

  • Leucodystrophies

    • adrenoleucodystrophy

    • metachromatic leucodystrophy

    • Krabbe disease

    • Canavan disease

    • Alexander disease

    • Pelizaeus–Merzbacher disease

    • vanishing white matter disease

    • oculodentodigital syndrome.

  • Central pontine myelinolysis.

Diseases causing multiple lesions with possible relapsing–remitting course

  • Acute disseminated encephalomyelitis

    • relapsing ADEM

    • autoimmune encephalitis

    • paraneoplastic encephalitis

    • acute haemorrhagic encephalomyelitis

    • post-vaccination encephalomyelitis.

  • Systemic lupus erythematosus.

  • Antiphospholipid antibody syndrome.

  • Primary Sjögren syndrome.

  • Behçet’s disease.

  • Central nervous system vasculitis.

  • Non-inflammatory vascular disorders.

  • Sarcoidosis.

  • Chronic infections

    • Lyme disease

    • meningovascular syphilis

    • human immunodeficiency virus encephalitis

    • progressive multifocal leucencephalopathy

    • subacute sclerosing panencephalitis

    • Whipple disease.

  • Central nervous system lymphoma.

  • Mitochondrial diseases.

Systematized CNS diseases

  • Hereditary ataxias and paraplegias.

  • Leucodystrophies.

  • Vitamin B12 deficiency.

  • Cerebrotendinous xanthomatosis.

  • Phenylketonuria.

  • Leucencephalopathy related to glue-sniffing.

  • Multiple system atrophy.

  • Paraneoplastic syndrome.

  • Coeliac disease.

  • Myeloneuropathy from acquired copper deficiency.

  • Motor neuron disease and variants.

Isolated or monosymptomatic CNS syndromes

  • Spinal cord

    • compression

    • cervical spondylotic myelopathy

    • Chiari malformation

    • spinal dural arteriovenous malformation

    • HTLV-1 myelopathy

    • primary lateral sclerosis

    • spinal cord stroke

    • transverse myelitis

    • other myelitides.

  • Optic nerve

    • anterior ischaemic optic neuropathy

    • Leber’s hereditary optic neuropathy

    • central serous retinopathy

    • neuroretinitis

    • chronic relapsing optic neuritis

    • paraneoplastic optic neuritis

    • amblyopia associated with tobacco or alcohol abuse.

Non-organic psychiatric diseases

Overall, a diagnosis of MS should be made only if the clinical history, neurological examination results and MRI results are consistent with MS, suggesting dissemination in space and time either clinically or radiologically. Moreover, there should not be a better explanation for the patient’s presentation.



Compston A, Lassmann H, McDonald I. The story of multiple sclerosis. In: Compston A, Confavreux C, Lassman H, et al. (eds.). McAlpine’s Multiple Sclerosis, 4th edn. Philadelphia: Churchill Livingstone Elsevier; 2006. pp. 3–67.


Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Acta Neurol Scand 1975; 51:137–57.


Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Part one. Acta Neurol Scand 1975; 51:110–36.


Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010; 9:520–32.


Multiple Sclerosis International Federation. Atlas of MS 2013. 2013. URL: (accessed 23 March 2017).


Boström I, Landtblom AM. Does the changing sex ratio of multiple sclerosis give opportunities for intervention? Acta Neurol Scand 2015; 132:42–5.


Compston A, Coles A. Multiple sclerosis. Lancet 2008; 372:1502–17.


Wekerle H. Nature plus nurture: the triggering of multiple sclerosis. Swiss Med Wkly 2015; 145:w14189.


International Multiple Sclerosis Genetics Consortium (IMSGC), Beecham AH, Patsopoulos NA, et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 2013; 45:1353–60.


Ghasemi N, Razavi S, Nikzad E. Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy. Cell J 2017; 19:1–10.


Mitrovic B, Ignarro LJ, Vinters HV, Akers MA, Schmid I, Uittenbogaart C, Merrill JE. Nitric oxide induces necrotic but not apoptotic cell death in oligodendrocytes. Neuroscience 1995; 65:531–9.


VanAmerongen BM, Dijkstra CD, Lips P, Polman CH. Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr 2004; 58:1095–109.


Belbasis L, Bellou V, Evangelou E, Ioannidis JPA, Tzoulaki I. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol 2015; 14:263–73.


Wekerle H. Immune pathogenesis of multiple sclerosis. Neurol Sci 2005; 26(Suppl. 1):s1–s2.


Hohlfeld R, Wekerle H. Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: from pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci USA 2004; 101(Suppl. 2):14599–606.


Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008; 31:247–69.


Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol 2015; 14:183–93.


Amato MP, Ponziani G. A prospective study on the prognosis of multiple sclerosis. Neurol Sci 2000; 21(Suppl. 2):S831–8.


Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46:907–11.


Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69:292–302.


Katz Sand I. Classification, diagnosis, and differential diagnosis of multiple sclerosis. Curr Opin Neurol 2015; 28:193–205.


Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357:1576–82.


Comi G, Martinelli V, Rodegher M, 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. Lancet 2009; 374:1503–11.


Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, Comi G. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:1489–96.


Miller AE, Wolinsky JS, Kappos L, 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. Lancet Neurol 2014; 13:977–86.


Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 2009; 72:800–5.


Okuda DT, Siva A, Kantarci O, et al. Radiologically isolated syndrome: 5-year risk for an initial clinical event. PLOS ONE 2014; 9:e90509.


Herndon RM. Multiple sclerosis mimics. Adv Neurol 2006; 98:161–6.


Rudick RA, Miller AE. Multiple sclerosis or multiple possibilities: the continuing problem of misdiagnosis. Neurology 2012; 78:1904–6.


Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology 2016; 87:1393–9.


Miller D, Compston A. The differential diagnosis of multiple sclerosis. In: Compston A, Confavreux C, Lassman H, et al. (eds.). McAlpine’s Multiple Sclerosis, 4th edn. Philadelphia: Churchill Livingstone Elsevier; 2006. pp. 389–437.

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