Multiple sclerosis Primer Nature.pdf

PRIMER Corrected: Author Correction Multiple sclerosis Massimo Filippi1,2*, Amit Bar-​Or3, Fredrik Piehl4,5,6, Paolo Pr...

PRIMER Corrected: Author Correction Multiple sclerosis Massimo Filippi1,2*, Amit Bar-​Or3, Fredrik Piehl4,5,6, Paolo Preziosa1,2, Alessandra Solari7, Sandra Vukusic8 and Maria A. Rocca1,2 Abstract | Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. This disorder is a heterogeneous, multifactorial, immune-​mediated disease that is influenced by both genetic and environmental factors. In most patients, reversible episodes of neurological dysfunction lasting several days or weeks characterize the initial stages of the disease (that is, clinically isolated syndrome and relapsing–remitting MS). Over time, irreversible clinical and cognitive deficits develop. A minority of patients have a progressive disease course from the onset. The pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which can be associated with neuro-​axonal damage. Focal lesions are thought to be caused by the infiltration of immune cells, including T cells, B cells and myeloid cells, into the central nervous system parenchyma, with associated injury. MS is associated with a substantial burden on society owing to the high cost of the available treatments and poorer employment prospects and job retention for patients and their caregivers. Multiple sclerosis (MS) is a chronic, inflammatory, Diagnosis is based on the demonstration of the dissem­ demyelinating and neurodegenerative disease of the ination of demyelinating lesions to different regions of central nervous system (CNS). MS is a heterogen­ the CNS (dissemination in space (DIS)) and over time eous, multifactorial, immune-​mediated disease that is (dissemination in time (DIT)), which can be demon­ caused by complex gene–environment interactions. strated using clinical evaluation or paraclinical tools The pathological hallmark of MS is the accumula­ once MS-​mimicking disorders have been excluded. tion of demyelinating lesions that occur in the white MRI has a high sensitivity for detecting disease-​related matter and the grey matter of the brain and spinal abnormalities, including the presence of demyelinat­ cord. The clinical manifestations and course of MS are ing lesions and, accordingly, the use of this imaging hetero­geneous; in most patients, reversible episodes of modality has substantially changed the diagnosis of neurological deficits (known as relapses) that usually MS. Additionally, MRI is helpful for monitoring dis­ last for days or weeks characterize the initial phases ease activity and the response to disease-​modifying of the disease (that is, clinically isolated syndrome treatments (DMTs). Combined with improved under­ (CIS) and relapsing–remitting MS (RRMS); Fig. 1). standing of the immunological and neurobiological Over time, the development of permanent neurologi­ disease processes underlying MS, improvements in cal deficits and the progression of clinical disability diagnosis have led to the development of many new become prominent (known as secondary progressive treatments that can substantially reduce disease activ­ MS (SPMS); Fig. 1). A minority of patients have a pro­ ity in many patients and delay, at least partially, the gressive disease course from onset, which is referred progression of MS. to as primary progressive MS (PPMS); Fig. 1). Each In this Primer, we review current knowledge on subtype of MS can be classified as active or not active the epidemiology and pathophysiology of MS and on the basis of clinical assessment of relapse occur­ describe the clinical presentations and the classification rence or lesion activity detected using MRI1; more­ of clinical phenotypes. The current diagnostic tools over, patients with PPMS or SPMS, can be classified and their prognostic value are discussed, in addition according to whether disability has progressed over a to how treatment of the disease has evolved. Finally, given time1,2. key outstanding questions in the field are considered, MS typically affects young adults, with an onset including the identification of features specific to the between 20 years and 40 years of age and has a higher pathological substrates of MS, the development of bio­ *e-​mail: [email protected] prevalence in women, although some patients experi­ markers sensitive to disease-​related changes, the opti­ https://doi.org/10.1038/ ence their initial demyelinating event during child­ mization of treatment at an individual patient level and s41572-018-0041-4 hood or adolescence, typically with an RRMS form3,4. the assessment of the impact of comorbidities. Nature Reviews | Disease Primers | Article citation ID: (2018) 4:43 1 0123456789(); Primer a systematic review estimated an overall incidence of Author addresses 3.6 per 100,000 person-​years in women and 2.0 per 1 Neuroimaging Research Unit, Institute of Experimental Neurology, Division of 100,000 person-​years in men10 and demonstrated an Neuroscience, San Raffaele Scientific Institute, Vita-​Salute San Raffaele University, increased female to male ratio over time from an esti­ Milan, Italy. mated 1.4 in 1955 to 2.3 in 2000 (ref.10). The increased 2 Department of Neurology, Institute of Experimental Neurology, Division of female preponderance of MS suggests a possible role of Neuroscience, San Raffaele Scientific Institute, Vita-​Salute San Raffaele University, Milan, Italy. environmental risk factors that mainly affect women 3 Department of Neurology and Center for Neuroinflammation and Experimental (for example, occupation, increased cigarette smoking, Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, obesity, birth control and childbirth)9,11. PA, USA. MS symptoms are the main direct cause of death 4 Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden. in >50% of patients with MS, although infections and 5 Department of Neurology, Karolinska University Hospital, Stockholm, Sweden. suicide are substantially increased compared with the 6 Neuroimmunology Unit, Center for Molecular Medicine, Karolinska University Hospital, general population12. The life expectancy of patients is Karolinska Institute, Stockholm, Sweden. reduced by 7–14 years, but this decreased life expectancy 7 Unit of Neuroepidemiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, is less evident in recent estimates12. Excess standardized Milan, Italy. mortality values are higher in men than women, in 8 Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Fondation Eugène Devic EDMUS Contre la Sclérose en Plaques, patients with PPMS than those with RRMS and in those Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon, France. with higher disability13–16. Risk factors Epidemiology The causes of MS are still unknown, although this disease MS is one of the most widely studied neurological dis­ is known to result from interplay of genetic susceptibility eases in terms of epidemiology and it is the primary and environmental risk factors. cause of non-​traumatic disability in young adults. RRMS typically has an onset between 20 years and 35 years of Lifestyle and environmental factors. Many environmen­ age, whereas PPMS typically begins at ~40 years of age, tal factors can contribute to the risk of MS and might although up to 10% of patients experience their initial be present and therefore increase disease risk during demyelinating event during childhood or adolescence4. a particular time frame. Substantial evidence supports a Approximately 2.3 million people have MS5 worldwide, period of susceptibility to environmental risk factors for and this disease is associated with a high societal eco­ MS during adolescence17 (Table 1), although exposure to nomic burden, which has increased over time. The some factors might be relevant during other phases of economic burden of MS was estimated as ~14.6 billion life (such as low vitamin D level during pregnancy)18. euros in 2010 within Europe and 4.3 billion dollars in the Identifying the role of lifestyle or environmental risk fac­ United States in 2013 (refs6,7). tors of MS is difficult and large prospective studies are, The prevalence of MS varies between countries with few exceptions, rare. The most well-​established risk (Fig. 2). MS is mainly found in individuals of European factors are Epstein–Barr virus (EBV) infection in ado­ descent and is rare in Asian, black, Native Americans lescence and early adulthood, tobacco exposure through and Māori individuals8. Prevalence estimates range from active or passive smoking, a lack of sun exposure, 2 per 100,000 individuals in Asia to ~1 per 1,000 indi­ low vitamin D levels and obesity during adolescence viduals in Western countries, although a prevalence of (Table 1). Other, less-​established risk factors include 1 per 400 individuals has been reported in some countries night work, excessive alcohol or caffeine consumption with a high latitude9. Indeed, in many studies, a higher and history of infectious mononucleosis17. latitude correlates with increased prevalence and inci­ Owing to the immune-​mediated pathogenesis of dence of MS, mainly in Europe and North America9,10. MS, infectious diseases have been suggested as possi­ Genetic factors, in particular the distribution of the ble triggers for disease onset. Of the different pathogens HLA-​DRB1 haplotype, might account in part for the lati­ investigated, EBV infection is the most consistently and tudinal gradient, but environmental risk factors that vary robustly associated17,19. To this end, it is noteworthy that with latitude might also be involved. Of these factors, up to 100% of patients with MS are seropositive for EBV low vitamin D levels owing to a lack of sun exposure is according to epidemiological studies20. The mechanism the most likely candidate (see Risk factors, below). by which EBV infection increases the risk of MS is not The prevalence of MS has increased since the 1950s, clear, but molecular mimicry leading to the generation especially in women9; this finding might represent a true of cross-​reactive T cells and antibodies has been pro­ increase in disease burden but might also be attributed posed17,19. Despite data supporting an increased risk to improved access to medical facilities, better diag­ of MS with EBV infection, a direct causal relationship nostic accuracy and increased life expectancy owing to remains difficult to establish. improved management. However, these reasons cannot Smoking has been consistently demonstrated as a explain the female preponderance. The female to male risk factor for MS and has an odds ratio (OR) of ~1.6 ratio of MS, which seems to decrease with higher lati­ (ref.17). The risk of MS and smoking is dose-​dependent: a tude, has increased to ~3:1 in the 2010s from a 2:1 ratio higher amount of smoking and cumulative smoking are in the 1950s, despite no difference in the incidence of both associated with increased risk. Passive exposure to disease in males and females in some regions (such smoking has also been associated with increased risk of as Norway, the United States and Italy)9,11. In 2008, MS17. Moreover, smoking has also been linked to faster 2 | Article citation ID: (2018) 4:43 www.nature.com/nrdp 0123456789();  Primer disability progression and to higher risk of conversion as polymorphisms in genes encoding human leukocyte from RRMS to SPMS21. A direct toxic effect of some antigen (HLA), to confer a higher risk of MS. As some smoke components (promoting lung irritation) and of the environmental factors are modifiable, preventive an indirect systemic effect (mediated by the peribron­ strategies might be possible in the future; this strategy chial lymphatic tissue) have been proposed to explain might also be relevant after disease onset, as some of the association. these risk factors have an influence on disease course Sun exposure, particularly exposure to ultraviolet-​B and prognosis (see below). radiation, is the major determinant of vitamin D levels and tends to decrease with increasing latitudes. Thus, Genetic factors vitamin D levels have been proposed to underlie the ‘lati­ The prevalence of familial MS is ~13% for all MS pheno­ tude effect’ in MS prevalence. Several studies suggest an types23. The risk of recurrence within families increases association between low vitamin D levels and increased with the percentage of genetic sharing24; for example, risk of MS and an increased disease activity (in terms of the age-​adjusted risk in monozygotic twins is 35%, as clinical relapses and MRI activity)17,22, suggesting a pro­ compared with 6% in dizygotic twins and 3% in sib­ tective effect of normal vitamin D levels throughout the lings24. The heritability of MS is polygenic and involves disease course. Although the mechanisms of action of polymorphisms in several genes, each of which is asso­ vitamin D are not fully clear, some data suggest that the ciated with a small increase in disease risk. Among these, active form of vitamin D (1,25-dihydroxycholecalciferol) polymorphisms in HLA class I and HLA class II genes has a role in the modulation of immune function17,22. convey the highest risk of MS17,24. Interestingly, some of these risk factors, notably Genome-​w ide association studies have identi­ EBV infection, obesity during adolescence and smok­ fied >200 genetic risk variants for MS; each variant has ing, can interact with genetic risk factors for MS, such a small effect on risk of disease, and different combi­ nations of these variants likely contribute to genetic susceptibility in different patients25. Most of these vari­ Pre-symptomatic Relapsing–remitting CIS Secondary progressive ants encode molecules involved in the immune system (such as the HLA genes on chromosome 6, including Inflammatory relapses HLA-​DRB1*15:01 polymorphisms, and polymorphisms Clinical in IL2 and IL7R) and are associated with a higher risk disability of other systemic immune disorders. Polymorphisms (RRMS and in genes involved in T cell activation and proliferation SPMS) Clinical (such as IL2 and IL7R) are a major feature of the disease, Clinical disability disability together with polymorphisms in other components of (PPMS) adaptive and innate immunity (such as genes that modu­ late tumour necrosis factor (TNF))26–28. Risk genes of MS Clinical threshold do not overlap with those of other neurodegenerative diseases, whereas mutations in only a few genes that have clear functions in the nervous system have been associated with an increased risk of MS (for example, MANBA and GALC). As previously mentioned, some polymorphisms, particularly those in HLA genes, might interact with environmental risk factors (Table 1). For Time example, the HLA-​DRB1*15:01 allele, which conveys Fig. 1 | Clinical course of MS. The National Multiple Sclerosis Society Advisory an increased risk of MS, but not the protective HLA-​ Committee on Clinical Trials in multiple sclerosis (MS)316 defined four clinical A*02 allele, confers a significantly higher risk of MS in courses of MS: relapsing–remitting MS (RRMS), secondary progressive MS (SPMS), smokers (OR 13.5)29, in individuals with EBV infec­ primary progressive MS (PPMS) and progressive relapsing MS (PRMS)316. RRMS accounts tion (OR 16.0)30 and in those with adolescent obesity for ~85% of patients and is characterized by the occurrence of relapses at irregular (OR 16.2)31. Moreover, polymorphisms in genes involved intervals with complete or incomplete neurological recovery133,317,318; the average relapse frequency is ~1.1 per year early in the disease course but seems to decrease with in vitamin D metabolism (such as GC and CYP24A1)32 advancing disease, increasing neurological dysfunction and age319. Most patients are associated with an increased risk of MS17. Further with RRMS will develop SPMS, which is characterized by progressive, irreversible efforts are required to elucidate how environmental risk disability that occurs independently of the presence of relapses316. Conversion to SPMS factors interact with MS susceptibility genes to contrib­ occurs in ~2–3% of patients per year316. Approximately 10–15% of patients present with ute to early disease mechanisms in the immune system PPMS, which is characterized by disease progression from the onset, resulting in gradual, and the CNS. progressive and permanent neurological deficits for >1 year without relapses159,316. PRMS is rare and is characterized by progressive disease from the onset, with acute Mechanisms/pathophysiology relapses (with or without full clinical recovery) and periods of continuing progression Pathology between relapses316. A revision of these phenotypes has been proposed1 and includes The pathological hallmark of all MS phenotypes is clinically isolated syndrome (CIS)1 to denote those patients whose first clinical presentation has characteristics of inflammatory demyelination that could be MS but focal plaques (also known as lesions), which are areas who do not fulfil its diagnostic criteria1. Within each subtype, disease can be classified as of demyelination that are typically located around post-​ active or not active, which are defined by the occurrence of relapses or lesions detected capillary venules and are characterized by breakdown using MRI. Another important modifier of the progressive stages is the inclusion of of the blood–brain barrier (BBB). The mechanisms of whether disability has progressed over a given time period. BBB breakdown are incompletely understood but seem Nature Reviews | Disease Primers | Article citation ID: (2018) 4:43 3 0123456789(); Primer Patients with MS (per 100,000 individuals) 0.00–5.00 5.01–20.00 20.01–60.00 60.01–100.00 >100.00 Data not provided Fig. 2 | Worldwide prevalence of MS. The prevalence of multiple sclerosis (MS) varies between countries. In general, the prevalence of MS is higher in countries of higher latitude and in Western countries. The MS International Federation’s Atlas of MS, 2013. to involve direct effects of pro-​inflammatory cytokines are less frequent in patients with PPMS and SPMS owing and chemokines (such as TNF, IL-1β and IL-6) prod­ to a reduced frequency of inflammatory events in these uced by resident cells and endothelial cells, as well as patients. PPMS and SPMS are mainly characterized by indirect cytokine-​dependent and chemokine-​dependent inactive lesions. Inactive lesions are sharply circum­ leukocyte-​mediated injury33,34. The dysregulation of the scribed, hypocellular and have well-​defined demyelin­ BBB increases the trans-​endothelial migration of acti­ ation, reduced axonal density, reactive astrocyte gliosis, vated leukocytes, including macrophages, T cells and variable microglial activation only in the periplaque B cells, into the CNS, which leads to further inflammation white matter (without macrophages) and a lower den­ and demyelination, followed by oligodendrocyte loss, sity of lymphocytes than active lesions42–46. However, reactive gliosis and neuro-​axonal degeneration35,36. inflammatory mechanisms still have a role in PPMS Plaques occur in both white matter and grey matter and SPMS44,45,47–49; indeed, active or mixed (inactive and and are typically found throughout the CNS, including active) lesions represented up to 57% of all lesions in in the brain, optic nerve and spinal cord37–39. Although patients with progressive MS in one study, and active the anatomical location of white matter lesions is asso­ lesions correlated with a more-​severe disease course49. ciated with specific clinical manifestations of MS, the Other forms of plaques include chronic active plaques total volume of these lesions is only moderately cor­ and slow expanding lesions. Chronic active plaques are related with overall clinical disability and cognitive more frequent in patients with MS with a longer dis­ impairment40,41 owing to the involvement of other patho­ ease duration and in SPMS and are characterized by physiological mechanisms, such as the occurrence of macrophages at the edge of the lesion, with fewer macro­ grey matter lesions and normal-​appearing brain tissue phages in the lesion centre (Fig. 3). Slow expanding damage, which affect both grey matter and white matter. lesions, which are typically found in patients with SPMS, are characterized by an inactive centre with demyelin­ White matter lesions ation, activated microglia at the lesion edge and few The earliest phases of MS (CIS and RRMS) are typically macrophages containing myelin debris, but transected characterized by active demyelinating lesions. These axons are also observed, suggesting a very slow rate of lesions have heavy lymphocyte infiltration (mainly CD8+ ongoing demyelination and axonal damage42,44–46. T cells and CD20+ B cells, with fewer CD4+ T cells), acti­ vated microglia (particularly at the lesion edge and con­ Normal-​appearing white matter. In addition to the taining myelin debris), macrophages (containing myelin focal lesions typically observed in patients with MS, debris) and large, reactive (sometimes multinucleated) macroscopically normal white matter (that is, normal-​ astrocytes42,43. By contrast, active demyelinating plaques appearing white matter (NAWM)) often shows signs 4 | Article citation ID: (2018) 4:43 www.nature.com/nrdp 0123456789();  Primer Table 1 | Lifestyle and environmental risk factors for MS Risk factor Odds HLA gene Combined Effect during Immune Level of ratio interaction odds ratioa adolescence system implied evidence Smoking ~1.6 Yes 14 No Yes +++ EBV infection (seropositivity) ~3.6 Yes ~15 Yes Yes +++ Vitamin D level 27 at 20 years of age). Adapted from ref.17, Springer Nature Limited. of diffuse inflammation and neuro-​axonal damage45,50. formation is supposed to be promoted by pro-​inflam­ Abnormalities of NAWM have been observed in patients matory media­tors released from the meninges or with RRMS but are more severe in those with progres­ present in the cerebrospinal fluid60. Compared with sive disease and include decreased fibre density owing white matter lesions, cortical lesions typically display to axonal degeneration and demyelination, small round less BBB breakdown, less oedema, a lower degree of cell infiltration (mainly lymphocytes), macrophage inflammation (characterized by fewer infiltrating acti­ infiltration, widespread microglia activation and glio­ vated micro­glia and macro­phages61) and more efficient sis50. NAWM was previously considered secondary to myelin repair occurring after demyelination, suggest­ the axonal damage within focal lesions, although these ing that different mechanisms determine lesion for­ diffuse changes poorly correlate with the number, size, mation in the white matter and the grey matter62,63. location and destructiveness of focal white matter lesions Cortical lesions are associated with variable degrees of in the brain50 and spinal cord, suggesting that they might transected neurites, neuronal apoptosis and loss of neu­ occur independently51. rons, neuro-​axons and glial cells, together with a sub­ stantial loss of synapses61,64,65 (Fig. 3). Decreased synaptic Grey matter lesions. Extensive cortical demyelina­ density has also been described in the normal-​appearing tion is observed in the forebrain50,52 and cerebellum53 cortex in patients with MS without cortical lesions, sug­ in patients with MS, occurs from the earliest phases gesting that synaptic loss might be in part independent of the disease (that is, also in patients with radiolog­ from focal demyelination in the cortex65. ically isolated syndrome54 (see below) and CIS55) and According to their location within the grey matter, is more widespread in patients with PPMS and SPMS, four different types of cortical lesions have been identi­ in extreme cases of which >60% of the cortex can be fied in patients with MS61,66: type I lesions are located at affected. Lesions can also occur within deep grey mat­ the cortico-​subcortical border and affect both the grey ter nuclei56,57 and in the grey matter of the spinal cord, matter and the white matter; type II lesions are small in which grey matter demye­lination is more extensive perivenous intracortical lesions that do not affect white and widespread than in the white matter37,39. Although matter or the pial surface of the brain; type III lesions the mechanisms underlying the differences in the extent extend inward from the subpial layers of the cortex of demyelination in the grey matter and white matter (subpial lesions); and type IV lesions extend through have not been clarified, it could be due to differences the whole width of the cortex but without passing the in the mechanisms of promoting demyelination and border between the cortex and the white matter. Type III the presence of pro-​demyelinating soluble factors in the cortical lesions are the most frequent in patients with cerebrospinal fluid37,39. MS and are characterized by subpial areas of demye­ Cortical lesions are predominantly found in corti­ lination, which involve the cortical ribbon of several cal sulci and in deep invaginations of the brain surface gyri and are often related to meningeal inflammatory and are often topographically related to inflamma­ infiltrates58,59 usually not extending beyond layers 3 and tory infiltrates in the meninges58,59. Moreover, their 4 of the cortex. Nature Reviews | Disease Primers | Article citation ID: (2018) 4:43 5 0123456789(); Primer a b c d e f g h i Fig. 3 | Post-​mortem histopathological findings in MS. a | A tissue block from the superior frontal gyrus (SFG) showing normal-​appearing grey and white matter (upper rectangle) and a macroscopically visible mixed grey and white matter lesion (lower rectangle) was obtained from a 70-year-​old patient with secondary progressive multiple sclerosis (MS) with a disease duration of 33 years who died owing to euthanasia, with a post-​mortem delay of 6 hours. b–e | Stained sections of normal-​appearing grey and white matter are shown. f–i | Stainined sections of a mixed grey and white matter lesion are shown. Proteolipid protein labelling (parts b,f) to quantify myelin confirmed the presence of a mixed grey and white matter lesion (part f). In the same lesion, Bielschowsky (part g) and NeuN (part h) staining revealed axonal injury and neuronal shrinkage and loss, respectively. Compared with normal-​appearing grey and white matter (part e), sections stained for ionized calcium binding adaptor molecule 1, a marker of microglia, showed a higher density of microglia in the rim of the lesion (part i), mainly in the white matter edge. The patient donor gave written informed consent for the use of his tissue and medical records for research purposes, and he was registered at the Netherlands Brain Bank, Amsterdam, Netherlands. Remyelination and degeneration. Remyelination can astrocytes72. Together with peripheral immune cells, occur in MS62,63,67, has been suggested as a mechanism CNS-​resident cells secrete a range of inflammatory of clinical recovery after a relapse and could represent mediators that can recruit inflammatory cells into the a target for future therapies68. Remyelination gives rise CNS, lead to neuronal demyelination and induce inflam­ to the so-​called shadow plaques that are characterized mation within the CNS parenchyma. In addition, both by global or patchy remyelination, a sharp demarcation peripheral and CNS-​compartmentalized inflammatory from the surrounding NAWM and axons with thin mye­ mechanisms are involved in MS pathophysiology. In lin sheaths and shortened internodes62,63,69,70. The extent particular, CNS-​resident cells that sense homeostatic of remyelination is very heterogeneous, although it disturbances, mainly microglia and astrocytes, can also is generally limited and restricted to the lesion border or is produce neurotoxic inflammatory mediators (such as patchy, and has been demonstrated in ~40–50% of white cytokines, chemokines and reactive oxygen species) matter lesions and in up to 90% of grey matter lesions, that can promote and sustain neuro-​axonal damage and although different values have been reported in some neurodegeneration in MS47 (Fig. 4). Despite the notion studies62,63,67. The variability in remyelination depends on that CNS-​compartmentalized inflammation likely con­ several factors, including patients’ age, disease duration, tributes to CNS injury, it is poorly targeted by currently lesion location, the presence of oligodendrocyte progeni­ available treatments73 and needs further study48,74. tor cells and axonal integrity48; substantial remyelination is frequently observed during the earlier phases of MS T cell involvement. The historical view of MS, on the basis and in younger individuals, whereas it is more sparse or of studies of patients and studies using the most com­ absent in PPMS and SPMS71. monly used animal model of MS (that is, experimental Of the neuropathological findings in MS, neuro-​axonal autoimmune encephalomyelitis (EAE)), is that relapses loss is of particular interest, as it corresponds to neuro­ are principally mediated by aberrantly activated and/or degeneration. In MS, neurodegeneration occurs from the insufficiently regulated pro-​inflammatory CNS-​specific earliest phases of disease and might contribute to irre­ effector T cells, including CD4+ T cells and CD8+ T cells, versible clinical disability45. Whether the degree of axonal that traffic to the CNS parenchyma and cause perivascu­ loss correlates with the severity of MS is unknown and lar demyelination, glial cell activation and neuro-​axonal requires further study. Different mechanisms occurring injury47,75. One potential cause of aberrant effector T cell at different stages of MS might drive n ­ eurodegeneration activation is an insufficiency in the function of regu­ as a primary and/or secondary phenomenon45,48. latory T (Treg) cells and resistance of CNS-​specific effector T cells to Treg cell-​mediated regulation76,77. Indeed, several Immune pathophysiology abnormalities in circulating Treg cells have been observed Our understanding of the underlying immunopatho­ and implicated in MS, including decreased expression physiology of MS has evolved. The traditional view of forkhead box protein P3 (FOXP3) by Treg cells and/or of T cell-​mediated MS relapses has been altered to deficient regulatory capacity of FOXP3-expressing include the involvement of key bidirectional inter­ CD25hiCD127low natural Treg cells (which arise in the thy­ actions between several immune cell types, includ­ mus and are a separate lineage to induced Treg cells)78–80. ing T cells, B cells and myeloid cells in the periphery, In addition, decreased numbers or deficient regulatory and resident cells of the CNS such as microglia and responses have also been suggested for CD46-expressing 6 | Article citation ID: (2018) 4:43 www.nature.com/nrdp 0123456789();  Primer induced type 1 regulatory cells, CD39-expressing thought to contribute to effector T cell trafficking from Treg cells, IFNγ-​expressing Treg cells and follicular Treg cells lymphoid structures and blood to the CNS in the EAE in blood in patients with MS, which could promote model and possibly in patients with MS99,100. In addition, ­aberrant ­effector T cell function81–83. junctional adhesion molecule-​like (JAML) has a role in The most widely implicated pro-​inflammatory effec­ the migration of CD8+ T cells and monocytes across the tor T cells are IL-17-expressing CD4+ T cells (known as brain endothelium, whereas MUC18 is used by CD8+ T helper 17 cells (TH17 cells)) and CD8+ T cells that might T cells and CD4+ T cells to access the CNS, and nin­ be increased in the periphery and in the CNS in patients jurin 1 is selectively implicated in the CNS migration of with MS. These cells are speculated to contribute to myeloid cells99,101. Also of note, in addition to the post-​ direct injury of oligodendrocytes and neurons (although capillary venule BBB endothelial cells (which are the site the exact mechanisms that direct injury have not been of the classical perivascular MS lesions), immune cells defined) and to indirect tissue injury through the acti­ might enter the CNS via the subarachnoid space and the vation of other cells, such as macrophages84–87. Other blood–CSF barrier. Identifying the molecules that are effector T cell subsets with a role in MS include IFNγ-​ involved in the trafficking of subsets of immune cells secreting CD4+ T cells (TH1 cells) and granulocyte– across distinct CNS barriers might guide development of macrophage colony-​stimulating factor (GM-​CSF)- more selective therapeutic targeting. The earliest molec­ expressing CD4+ and CD8+ T cells; the role of GM-​CSF ular mechanisms underlying new inflammatory lesion is not fully defined in MS, but GM-​CSF has been shown formation in MS might involve abnormalities in these to activate myeloid cells and CD8+ mucosal-​associated barriers, which enable immune cell infiltration from invariant T (MAIT) cells in the EAE model88–90. the periphery102–104. The aberrant T cell activation in MS requires anti­ The biology underlying remission in MS is not well gen presentation to T cells by antigen-​presenting cells understood, but it is unlikely to merely represent a pas­ (APCs) such as B cells and myeloid cells (macrophages, sive decline in the pro-​inflammatory effector cell activity dendritic cells and microglia) in the periphery and the and is likely to involve mechanisms that downregulate CNS, although the responsible antigens have not been immune responses, such as Treg cell activity76. In addi­ routinely identified91 (Box 1). Myelin-​related antigens are tion, remission is likely to involve activation-​induced suspected to be involved, although there is no consen­ cell death wherein activated pro-​inflammatory cells sus, and some studies have suggested antigens on the might have upregulated surface molecules that make neuronal or glial cell surface. Important bidirectional them more susceptible to killing by other immune interactions between T cells and myeloid cells that can cells105. Indeed, several studies have suggested that shape their effector responses (both pro-​inflammatory apoptosis of immune cells (such as myelin-​reactive or anti-​inflammatory responses) have long since T cells) could exert positive effects by switching off been recognized75,92. Pro-​inflammatory APCs such as CNS inflammation106. B cells and myeloid cells can drive TH1 cell and TH17 cell responses, which might have a role in immune cell inter­ B cell involvement. A role for B cells in the development actions and the trafficking that underlies relapses in MS. of MS relapses has emerged on the basis of impressive To this end, circulating myeloid cells in patients with results of selective B cell-​targeting therapies (such as anti-​ MS have an overly pro-​inflammatory profile, includ­ CD20 antibodies) in MS107. The role of a small subset ing the expression of the microRNA miR-155 and pro-​ of CD20-expressing T cells (which are also depleted with inflammatory cytokines such as TNF, IL-12, IL-6, IL-23 anti-​CD20 therapy) remains of interest, although this and IL-1β, which are involved in TH1 cell and TH17 cell subset has not been ascribed a particular pathogenetic differentiation93–95. function in MS108. How aberrantly activated immune cells access Healthy individuals typically have low levels of the CNS in MS is of ongoing interest and therapeutic antibodies in the CNS (the normal ratio is ~1:300 importance. Despite the fact that the CNS was con­ of CNS to periphery); patients with MS have an abnor­ sidered immune privileged, with the BBB thought to mally increased production of antibodies within the restrict entry of cells and macromolecules from the CNS, which can be detected, for example, as increased circulation, as previously mentioned, BBB breakdown immunoglobulin synthesis rates and the presence of has been observed in patients with MS, which is specu­ cerebrospinal fluid-​restricted oligoclonal bands (OCBs). lated to facilitate the migration of pro-​inflammatory This finding was the basis for anti-​B cell therapies in cells into the CNS parenchyma. In addition, a lymphatic MS, although interestingly, the reduction in relapse drainage system has been demonstrated in the CNS96. rate with anti-​CD20 therapy was associated with little The immune system can interact continuously with the or no change to the cerebrospinal fluid immunoglob­ CNS as part of normal immune surveillance and, in MS, ulin profile in patients109,110, suggesting an antibody-​ bidirectional trafficking likely takes place during the independent role of B cells in MS relapses. These course of disease97,98. After activation in the periphery, antibody-​independent functions are likely to be the immune cells upregulate cell surface molecules such as contribution of B cells to cascades of cellular immune chemokine receptors and adhesion molecules, which interaction in the periphery and/or their ability to attract enables efficient tissue infiltration, including to the CNS. and activate T cells and myeloid cells in the CNS72. Indeed, chemokine receptors, such as CC-​chemokine Indeed, B cells from patients with MS have an abnor­ receptor 6 (CCR6), CCR2 and CCR5, and cell surface mal propensity to produce pro-​inflammatory cytokines glycoprotein MUC18 (also known as MCAM) are (including IL-6, GM-​CSF, TNF and lymphotoxin-α Nature Reviews | Disease Primers | Article citation ID: (2018) 4:43 7 0123456789(); Primer Meningeal SAS Astrocyte Early disease vessel Pial basement membrane Glia limitans CNS parenchyma Soluble mediators recruit immune cells Soluble mediators promote inflammation CD8+ at distal sites T cell Perivascular DC or macrophage Perivascular immune Oligodendrocyte T cell cell accumulation reactivation Myelin sheath Antibody Vessel Neuron CD4+ activation Degraded T cell CD8+ TH1 cell IFNγ myelin MAIT protein IL-17 cell Demyelination TH17 cell Monocyte GM-CSF Cerebrospinal fluid Phagocytosis Complement proteins Ependyma B cell Choroid plexus Microglial Capillary Pericyte cell Plasma cell Choroid plexus macrophage T cell reactivation by choroid plexus and meningeal APCs Late disease Meningeal tertiary lymphoid-like structures promote glia limitans damage and astrocyte dysfunction Follicular DC Oligodendrocyte progenitor Clonally CCL2 Metabolic expanded GM-CSF stress B cells Osteopontin NO ROS Ionic Glutamate RNS Energy accumulation imbalance deficiency Neuro-axonal and oligodendrocyte damage and death Neurodegenerative processes promote further damage at distal sites (LTα)) and are deficient in regulatory cytokines such profile of B cells from patients with MS can induce as IL-10 (refs111–116). One subset of pro-​inflammatory aberrant TH1 cell and TH17 cell responses through TNF B cells, CD27+ GM-​CSF-expressing memory B cells, and IL-6 and can induce pro-​inflammatory myeloid cell which produce high levels of TNF and IL-6 but do not responses (principally through GM-​CSF), which could express IL-10, is found in increased numbers in the contribute to the cellular immune cascades involved circulation of patients with MS and has an exaggerated in relapses111–116. In line with this finding, anti-​CD20 response profile112. The abnormal cytokine response B cell-​depleting therapy reduces the pro-​inflammatory 8 | Article citation ID: (2018) 4:43 www.nature.com/nrdp 0123456789();  Primer ◀ Fig. 4 | Immune system dysregulation within the central nervous system in early against myelin antigens, such as myelin basic protein and late MS. Immune cells are believed to enter the central nervous system (CNS) in (MBP) or myelin-​oligodendrocyte glycoprotein (MOG) multiple sclerosis (MS) through the blood vessels of the blood–brain barrier (BBB), the and the inward rectifying potassium channel Kir4.1 (also subarachnoid space (SAS) and the choroid plexus (dashed arrows). In MS relapses, which known as KCNJ10)119–121, have not led to the same patho­ are more prominent in the early phases of disease, underlying mechanisms involve the genetic implications for specific CNS-​directed antibodies infiltration of cells of the innate and adaptive immune systems, such as CD4+ and CD8+ T cells, B cells and myeloid cells, into the CNS parenchyma with perivascular distribution as those observed in other conditions, such as anti-​ around post-​capillary venules of the BBB. These immune cells, together with resident aquaporin 4 antibodies in neuromyelitis optica spectrum activated microglia and astrocytes, are thought to contribute to oligodendrocyte injury, disorders (NMOSDs) and anti-​N-methyl-​d-aspartate demyelination and neuro-​axonal injury through cell contact-​dependent mechanisms (NMDA) antibodies in NMDA encephalitis. In addition, and the secretion of soluble factors. In later stages of the disease, the episodic infiltration the presence of circulating anti-​MOG antibodies in a of immune cells into the CNS is diminished. Mechanisms contributing to ongoing tissue subset of patients with CNS inflammatory demyelinat­ injury (and the clinical manifestations of progressive disease) are thought to include ing disease, including NMOSD122, has been associated neurodegeneration, in terms of neuro-​axonal, astrocyte and oligodendrocyte damage, with clinical and imaging features that are not typical owing to acute or chronic oxidative stress promoted by innate and adaptive immune cell of MS123,124 (even if they have been also described in activation, mitochondrial dysfunction, extracellular free iron accumulation, loss of myelin up to 5% of patients with MS), which are mainly charac­ trophic support, hypoxia, altered glutamate homeostasis and a pro-​inflammatory environment, with possible involvement of cytotoxic factors and complement activation. terized by severe brainstem and spinal cord involvement, Chronic inflammation is potentially mediated by ongoing CNS-​compartmentalized a severe disease course with high relapse rates and failure inflammation involving meningeal immune cell infiltrates (for example, B cells) that can in response to several DMTs125. form lymphoid-​like structures and by CNS-​resident innate cells (for example, microglia). For example, CC-​chemokine ligand 2 (CCL2) and granulocyte–macrophage colony-​ Progressive MS. In addition to cascades of the cellular stimulating factor (GM-​CSF) produced by astrocytes can promote microglia recruitment immune interactions in the periphery that contribute to and activation, and astrocytes can limit remyelination by preventing the differentiation MS relapses, ongoing inflammation in the CNS might of oligodendrocyte progenitor cells into mature oligodendrocytes. APC, antigen-​ contribute to the propagation of injury in patients with presenting cell; DC, dendritic cell; MAIT, mucosal-​associated invariant T; NO, nitric oxide; PPMS and SPMS (Fig. 4). In particular, inflammation RNS, reactive nitrogen species; ROS, reactive oxygen species; TH1, T helper 1; TH17, may differ in individuals with progressive MS compared T helper 17. Adapted from ref.47, Springer Nature Limited. with RRMS and is characterized by a lower frequency of inflammatory relapses (waves of infiltration of activated responses of TH1 cells and TH17 cells and reduces mye­ immune cells into the CNS in a perivascular distrib­ loid cell pro-​inflammatory responses in the periphery of ution). Additionally, a CNS-​compartmentalized inflam­ patients with MS111,112. By contrast, the (largely naive) mation is evident, involving, for example, CD8+ T cells B cells that re-​emerge after discontinuation of anti-​CD20 and plasma cells that survive and persist in the CNS treatment111,112,114 have reduced secretion of GM-​CSF, or surrounding meninges and possibly also involving IL-6 and TNF but increased IL-10 secretion; whether microglia and astrocyte inflammatory responses43,45,47,48. these cells have an immune-​regulatory effect in a subset CD8+ T cells might be quiescent memory cells that of patients that potentially contributes to the durabil­ promote further tissue damage when exposed to and ity of the treatment effect and whether the treatment activated by their target antigen43. The different inflam­ effect lasts until the re-​emergence of pro-​inflammatory matory mechanisms in PPMS and SPMS might contrib­ memory B cells are of interest. ute to the lack of efficacy of DMTs, which typically have MS relapses might also be driven by alterations systemic anti-​inflammatory activity45,48. in the balance between pro-​inflammatory and anti-​ Ongoing questions relate to how relapse biology is inflammatory B cells. This is supported by the obser­ involved in the initiation and maintenance of CNS-​ vation that, aside from anti-​CD20 therapies, all other compartmentalized inflammation, which, at least at approved therapies for MS affect memory B cell some point in the disease process, is maintained in the responses (reviewed previously72). In addition, the absence of obvious relapses. The subpial demyelinating finding that atacicept (a recombinant fusion protein that cortical injury that is present from the earliest phase inhibits B cells) exacerbated MS relapses in clinical trials of the disease and is more widespread in patients with lends further support to this hypothesis117. Atacicept progressive MS reportedly involves a graded pattern of leads to selective loss of several subsets of B cells (includ­ neuronal loss and microglial activation45,126,127, which ing plasmablasts and plasma cells) but spares memory could be consistent with a ‘surface-​in’ process, such as B cells, which might result in a more pro-​inflammatory that mediated by one or more toxic substances in the cere­ B cell profile, therefore, aggravating disease. brospinal fluid. In this regard, the extent of meningeal The antibody-​independent functions of B cells do not inflammation is associated with the extent of subpial cor­ preclude a role for antibodies in MS pathophysiology. tical injury126 and with higher levels of pro-​inflammatory However, antibody levels in the CNS do not substantially cytokines such as IFNγ, TNFα, LTα and IL-6 in the cere­ change following anti-​CD20 treatment118, suggesting brospinal fluid of patients60. The potential for meningeal that antibodies are unlikely to be critically involved in immune cells to contribute to CNS injury has also been triggering relapses. It is possible that antibodies could noted above in the context of cytotoxic CD8+ T cells that persist in the CNS for a long period of time after treat­ may enter the CNS through the meninges to respond ment; however, if the antibodies were relevant, the effects to local (potentially EBV-​infected) B cells60,128 (Box 1). of treatment would not be quick or substantial while the In addition, B cells from patients with MS can secrete antibodies do not change. Studies of circulating antibod­ unidentified factors that are toxic to oligodendrocytes and ies in patients with MS, including antibodies directed neurons in vitro129,130. The CNS inflammation in patients Nature Reviews | Disease Primers | Article citation ID: (2018) 4:43 9 0123456789(); Primer might, in turn, foster B cell persistence and propagation to brainstem and/or cerebellar syndromes) or the cere­ of CNS-​compartmentalized inflammation131. Future bral hemispheres (cerebral hemispheric syndrome; research will aim to elucidate whether and how bidire­c­ Fig. 5; Table 2). During the disease course of RRMS, tional interactions between meningeal immune cells further clinical episodes can occur (known as relapses); and underlying brain cells contribute to the propaga­ these episodes last for ≥24 hours and occur in the tion of non-​relapsing inflammation and progressive absence of fever, infection or clinical features of enceph­ injury to CNS structures adjacent to the cerebrospinal alopathy (for example, altered consciousness or epilep­ fluid and how such processes could interact with and/or tic seizures)132. Symptoms of a clinical attack typically respond to the degenerative mechanisms described show an acute or sub-​acute onset, worsen over days or above (reviewed previously45). weeks, reach a peak severity within 2–3 weeks and remit Despite occurring at early disease stages, neuro-​ to a variable degree, ranging from minimal resolution to axonal degeneration is common in progressive disease. complete recovery normally 2–4 weeks after reaching The mechanisms of neuro-​axonal degeneration include maximum deficit133. neuronal apoptosis owing to acute or chronic oxida­ Optic neuritis is the first neurological episode in tive stress promoted by innate and adaptive immune ~25% of patients and is associated with a conver­ cell activation, mitochondrial dysfunction and extra­ sion to clinically definite MS in 34–75% of patients cellular free iron accumulation, loss of myelin trophic between 10 years and 15 years after clinical onset134–136. support, hypoxia, altered glutamate homeostasis and a Approximately 70% of patients with MS have optic neu­ pro-​inflammatory environment, with possible cytotoxic ritis during the course of the disease134–136. Optic neuritis factors and complement activation45,48. is characterized by a partial or total visual loss in one eye with a central scotoma (a blind spot in the visual field), Diagnosis, screening and prevention dyschromatopsia (deficiency of colour vision) and pain Clinical presentation within the orbit that is worsened by eye movement134–136 The clinical presentation of MS is heterogeneous and (Table 2). During fundus oculi examination using ophthal­ depends on the location of demyelinating lesions within moscopy, the optic nerve head appears normal if inflam­ the CNS. Although no clinical findings are unique to mation is limited to the retrobulbar portion of the MS, some are highly characteristic of the disease. nerve, but approximately one-​third of patients might Typically, the onset of MS is characterized by an ini­ have inflammation of the optic disc (papillitis) and disc tial clinical attack (defined as CIS) in ~85% of patients, oedema owing to anterior optic neuritis. Patients with­ which consists of an unpredictable episode of neuro­ out visual complaints with suspected MS should be eval­ logical dysfunction owing to demyelinating lesions in uated for more subtle manifestations of optic neuritis, the optic nerve (leading to optic neuritis), spinal cord such as an afferent pupillary defect or abnormalities at (leading to myelitis), brainstem or cerebellum (leading paraclinical tests (for example, visual evoked potentials, optical coherence tomography (OCT) or MRI). Sensory symptoms are the first clinical manifesta­ Box 1 | Autoantigens in MS tion in up to 43% of patients with MS and are mainly The antigenic targets of the aberrant immune cell activation in multiple sclerosis (MS) caused by myelitis or brainstem syndromes137. Sensory remain incompletely defined. Historically, the focus of investigation was on myelin symptoms include paresthesia (commonly described proteins that are commonly used to induce autoimmune encephalomyelitis (EAE) in as numbness, tingling, pins-​and-needles feeling, tight­ experimental models, such as myelin basic protein (MBP), proteolipid protein and ness, coldness and/or swelling of the limbs or trunk), myelin-​oligodendrocyte glycoprotein75,92. Indeed, several studies in patients support a Lhermitte sign138 (a transient symptom described as role for myelin-​reactive T cells in MS owing to the increased frequency, stability and/or an electric shock radiating down the spine or into the pro-​inflammatory response profiles of these cells in patients compared with controls92,299. However, most healthy individuals also have T cells (and B cells) that are limbs with flexion of the neck), impairment of vibra­ reactive to the same myelin antigens as patients with MS, therefore, the mere presence tion and joint position sensation, and reduced pain and of such autoreactive cells is insufficient to induce disease. Non-​myelin antigens might light touch perception. These symptoms can temporar­ be relevant in early MS pathogenesis, such as axo-​glial apparatus molecules that have ily worsen with increased body temperature (known as been implicated in paediatric-​onset MS300. T cell activation by an infectious agent that Uhthoff phenomenon). has similarities with central nervous system (CNS) antigens (known as molecular Motor manifestations are the initial symptoms in mimicry) has been postulated as a mechanism for triggering MS and MS relapses. 30–40% of patients and affect almost all patients during In particular, a strong epidemiological association has been demonstrated between the course of the disease139. Motor symptoms are charac­ Epstein–Barr virus (EBV) infection and risk of MS in the earliest phases of MS, close to its terized by pyramidal signs (such as Babinski sign, more-​ biological onset301,302; EBV shares a molecular sequence with MBP, and aberrant CD4+ pronounced reflexes and clonus), paresis and spasticity. and CD8+ T cell responses to EBV have been reported in patients with MS303,304. Moreover, EBV can transform and activate B cells in vivo, and it is plausible that, in Brainstem and cerebellar symptoms are present in up to patients with MS, EBV contributes to pro-​inflammatory B cell activation in the 70% of patients with MS139, which include impairment in periphery and, in turn, mediates aberrant activation of CNS-​reactive T cells that are ocular movements (such as nystagmus (involuntary eye involved in MS relapses. In addition, some studies have demonstrated EBV-​infected movement), oscillopsia (a visual phenomenon in which B cells and plasma cells in patients with MS, which are located adjacent to CD8+ T cells items in the visual field seem to move) and diplopia expressing cytotoxic molecules, such as perforin and granzyme128,305. The process by (double vision)), ataxia and gait imbalance, dysmetria which immune cell activation to additional CNS antigens might be triggered as a (poor coordination) and decomposition of complex consequence of CNS injury and exposure of additional antigenic targets has been movements, slurred speech and dysphagia (difficulty referred to as epitope spreading. This process is well demonstrated in EAE, with limited swallowing). The extent of sphincter and sexual dysfunc­ studies suggesting this might also occur in patients with MS92,306. tion often parallels the degree of motor impairment in the 10 | Article citation ID: (2018) 4:43 www.nature.com/nrdp 0123456789();  Primer a b c d e Fig. 5 | Radiological examples of demyelinating events in MS. 3T MRI sequences from five patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), within 5 days from clinical onset, are shown. Focal lesions (arrows) can be observed in: the right optic nerve in a patient with acute optic neuritis (part a); the left pons and the right middle cerebellar peduncle in a patient with diplopia (part b); the cerebellar hemispheres in a patient with vertigo (part c); the cervical spinal cord in a patient with paresthesia and Lhermitte sign (part d); and the left cerebral hemisphere in a patient with right sensorimotor hemisyndrome (part e). lower extremities, and the dysfunction usually becomes Affective disturbance occurs in up to two-​thirds of permanent late in the disease course, affecting 34–99% patients, of which depression is the most common mani­ of patients140. The most common symptom of bladder festation146. Pain is reported in up to 43% of patients and dysfunction is urinary urgency, but hesitancy, frequency can include trigeminal neuralgia, dysesthetic pain, back and urge incontinence can also occur140. Constipation is pain, visceral pain and painful tonic spasms147. Typically, more common than faecal incontinence, and men with the prevalence and the severity of all clinical manifesta­ MS often have erectile dysfunction and impotence. tions previously described are higher in patients with Other symptoms include cognitive impairment, PPMS and SPMS than in those with RRMS. fatigue and affective disturbance. Overall, 40–70% of Several qualitative and semi-​quantitative scales have patients with MS have cognitive impairment, which can been proposed to grade the clinical manifestations start in the earliest phases of the disease41. Cognitive of MS. Of these, the Expanded Disability Status Scale deficits can predict conversion to clinically definite MS (EDSS)148 is the most widely accepted measure of clin­ in patients with CIS141, are more frequent and more-​ ical disability. The EDSS is a scale that ranges from 0 pronounced in chronic progressive MS, worsen over (a completely normal neurological examination) to 10 time and affect patients’ daily life activities41. Common (death owing to MS) and provides 8 subscale measure­ cognitive symptoms include impairment in information ments (functional system scores) that include the main processing speed, episodic memory, attention, efficiency functional domains affected by MS, including pyra­ of information processing and executive function41. Up midal, cerebellar, brainstem, sensory, bowel and bladder, to 95% of patients experience fatigue142. Several mech­ visual, mental and other domains. anisms have been suggested to promote the occurrence of fatigue in patients with MS. Fatigue can be associated Diagnostic criteria with relapses and can persist after the attack has sub­ The diagnosis of MS is primarily based on clinical cri­ sided, but it can also be a feature of daily life and can teria; in most patients, the occurrence of two or more be present for years. Several strings of evidence support clinically distinct episodes of CNS dysfunction with the hypothesis of a central origin of MS-​related fatigue at least partial resolution is sufficient for diagnosis of owing to a dysfunction of cortico-​subcortical circuits, RRMS. Although the diagnosis can be made on the mainly involving structural damage in fronto-​parietal basis of clinical criteria alone, MRI can support, sup­ regions and the basal ganglia143. Sleep disorders (for plement or replace some clinical criteria owing to the example, insomnia, obstructive sleep apnoea and restless sensitivity and specificity of this imaging modality in legs syndrome) are found in up to 54% of patients with demonstrating demyelinating lesions, as well as DIS and MS144 and might also promote fatigue145. DIT149 (Box 2). Nature Reviews | Disease Primers | Article citation ID: (2018) 4:43 11 0123456789(); Primer Table 2 | Typical and atypical clinical presentations of MS Presentation Typical or Onset Involvement Signs or symptoms Recovery atypical presentation Optic neuritis Typical Sub-​acute Unilateral Afferent pupillary defect Gradual to chronic Central visual blurring or scotoma recovery within (hours to Reduced visual acuity 2–4 weeks after days) Dyschromatopsia (colour blindness) reaching peak Normal optic disc or optic disc swelling severity Mild unilateral orbital pain that is worsened by eye movements Atypical Acute Bilateral Peripheral visual loss Progressive (seconds Altitudinal visual loss worsening or no to minutes) Retinal haemorrhages or exudates recovery Severe optic disc swelling No light perception No or severe orbital pain Photophobia Brainstem Typical Sub-​acute Unilateral and localized Unilateral or bilateral internuclear ophthalmoplegia Gradual and/or and/or Multidirectional nystagmus recovery cerebellar chronic Sixth cranial nerve palsy starting within syndromes (hours to Ataxia or gait imbalance 2–4 weeks after days) Vertigo reaching peak Facial numbness or sensory loss severity Dysmetria and decomposition of complex movements Dysarthria and slurred speech Dysphagia Hearing loss Nausea Atypical Acute Alternating syndromes Vascular territory signs Progressive (seconds Isolated trigeminal neuralgia worsening or no to minutes) Fluctuating ocular or bulbar weakness recovery Fever Meningism Myelitis Typical Sub-​acute Incomplete transverse Sensory involvement: paresthesias (numbness, Gradual and/or myelitis tingling, pins-​and-needles feeling, tightness, recovery chronic Asymmetric involvement coldness and/or swelling of the limbs or trunk), starting within (hours to Lhermitte sign, impairment of vibration and joint 2–4 weeks after days) position sense, decreased pain and light touch reaching peak perception and Uhthoff phenomenon severity Motor deficits: pyramidal signs (Babinski sign, bright reflexes and clonus), spastic paresis and/or weakness (asymmetric) and spasticity Sphincter dysfunction: urinary urgency, hesitancy, urge incontinence, constipation and faecal incontinence Sexual dysfunction: erectile dysfunction and impotence Atypical Acute Complete transverse Progressive and symmetrical spastic paraparesis Progressive (seconds myelitis Progressive sensory ataxia (posterior column worsening or no to minutes) Complete Brown-​ involvement) recovery Séquard syndrome Sharp level to all sensory modalities Cauda equina syndrome Segmental loss of pain and temperature sensation Anterior spinal artery Areflexia and/or spinal shock territory lesion Acute urinary retention Localized or radicular Severe pain spinal pain Cerebral Typical Sub-​acute Unilateral Hemisyndrome (corticospinal tract involvement): Gradual hemispheric and/or hemiparesis and hemisensory deficits recovery syndromes chronic Campimetric deficits (optic radiation involvement) starting within (hours to 2–4 weeks after days) reaching peak severity Atypical Acute Bilateral Encephalopathy Progressive