Multiple Sclerosis PDF

The n e w e ng l a n d j o u r na l of m e dic i n e Review Article Dan L. Longo, M.D., Editor Multiple Sclerosis...

The n e w e ng l a n d j o u r na l of m e dic i n e Review Article Dan L. Longo, M.D., Editor Multiple Sclerosis Daniel S. Reich, M.D., Ph.D., Claudia F. Lucchinetti, M.D., and Peter A. Calabresi, M.D.​​ M ultiple sclerosis is the most prevalent chronic inflammatory From the Translational Neuroradiology disease of the central nervous system (CNS), affecting more than 2 million Section, National Institute of Neurologi­ cal Disorders and Stroke, National Insti­ people worldwide (at least 400,000 in the United States),1 and it is currently tutes of Health, Bethesda (D.S.R.), and the incurable. It is punctuated by fully or partially reversible episodes of neurologic Departments of Neurology and Neuro­ disability, usually lasting days or weeks. Typical syndromes at presentation include, science, Johns Hopkins School of Medi­ cine, Baltimore (P.A.C.) — both in Mary­ but are not limited to, monocular visual loss due to optic neuritis, limb weakness land; and the Department of Neurology, or sensory loss due to transverse myelitis, double vision due to brain-stem dysfunc- Mayo Clinic, Rochester, MN (C.F.L.). Ad­ tion, or ataxia due to a cerebellar lesion.2 After typically 10 to 20 years, a progres- dress reprint requests to Dr. Reich at the National Institute of Neurological Dis­ sive clinical course develops in many of the persons affected, eventually leading to orders and Stroke, 10 Center Dr., MSC impaired mobility and cognition; approximately 15% of patients have a progressive 1400, Bldg. 10, Rm. 5C103, Bethesda, MD course from onset. More than a dozen disease-modifying medications are available 20892, or at ­daniel​.­reich@​­nih​.­gov. to reduce the frequency of transient episodes of neurologic disability and limit the N Engl J Med 2018;378:169-80. accumulation of focal white-matter lesions on magnetic resonance imaging (MRI). DOI: 10.1056/NEJMra1401483 Copyright © 2018 Massachusetts Medical Society. No medication fully prevents or reverses the progressive neurologic deterioration, characterized most commonly by impaired ambulation, loss of bladder control, and slowed cognitive processing, but the question of whether disease-modifying medications can delay clinical progression is controversial.3-5 The annual economic cost of multiple sclerosis in the United States is approximately $10 billion.6 Pathol o gy The idea that multiple sclerosis is a disseminated plaque-like sclerosis was estab- lished approximately 150 years ago; indeed, the demonstration of dissemination — in space (disease-related changes in multiple regions of the CNS, including white matter, gray matter, brain stem, spinal cord, and optic nerve) (Fig. 1) and time — forms the cornerstone of diagnosis of the disease. Our understanding of the details of that pathology, and especially how it evolves over time, has been revolutionized with modern techniques such as immunohistochemical staining and MRI. Multiple sclerosis lesions can appear throughout the CNS and are most easily recognized in the white matter as focal areas of demyelination, inflammation, and glial reaction. Evidence from MRI and pathological assessment (biopsies and au- topsies) indicates that the earliest stages of white-matter demyelination (known as early active white-matter lesions) are heterogeneous7 and evolve over the course of months. Regardless of the particular immunologic pattern of early demyelination (Fig. 2), analysis of active lesions, over both time and space, suggests that a single immune-effector mechanism dominates in each person.8 Consistent with this notion are the observations that plasma exchange, which removes pathogenic antibodies from the circulation, ameliorates relapses that are refractory to initial treatment with glucocorticoids in patients whose active lesions contain immunoglobulin and complement9 and that cerebrospinal fluid (CSF) profiles differ according to lesion n engl j med 378;2 nejm.org January 11, 2018 169 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  The n e w e ng l a n d j o u r na l of m e dic i n e A B G C E F D Thalamus Pons Figure 1. Topography of Multiple Sclerosis Lesions. Shown is a schematic of lesion location, calling out imaging and pathological examples, in the periventricular white matter (inset A), subpial cortex (B), leptomeninges (C), thalamus and pons (D), spinal cord (E), optic nerve (F), and retina (G). Insets A, B, and D show a 7­tesla MRI of a 40­year­ old woman with relapsing–remitting multiple sclerosis, with similar pathological findings (in different patients) highlighted by immunohisto­ chemical staining directed against myelin proteolipid protein. Inset C shows a 3­tesla MRI after the administration of gadolinium in a 35­year­old woman with secondary progressive multiple sclerosis, with corresponding pathological findings in the meninges of a different patient (hematox­ ylin and eosin staining). Inset E shows a 3­tesla MRI of a 60­year­old woman with relapsing–remitting multiple sclerosis and corresponding path­ ological findings in a different patient (Luxol fast blue–periodic acid Schiff staining). Inset F shows a 3­tesla MRI of a 31­year­old woman with re­ lapsing–remitting multiple sclerosis and corresponding pathological findings in a different patient (anti–proteolipid protein immunohistochemical staining). Inset G shows a spectral­domain optical coherence tomographic reconstruction illustrating thinning of the peripapillary retinal nerve fiber layer. The normal range of retinal thickness is shown in green, and for this particular patient (black line), the retina is thinner than in 99% of control eyes. The bottom panel of the inset shows corresponding pathological findings in a different patient (immunohistochemical staining for Iba­1, a macrophage and microglial marker, with hematoxylin counterstaining). In all insets, lesions are indicated with arrowheads or circles. 170 n engl j med 378;2 nejm.org January 11, 2018 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  Multiple Sclerosis Acute white-matter lesions — immunologic patterns Chronic white-matter lesions I Microglia Oligodendrocyte Macrophage T cell Smoldering II Complement Subpial cortical lesions ? Antibody Blood vessel T cell Apoptotic Chronic inactive Macrophage III oligodendrocyte B cell Microglia Region of demyelination Degeneration of inner myelin loops Remyelinated Figure 2. Lesions of the White Matter and Gray Matter. Early active white­matter demyelination falls into three major categories. The most common types (patterns I and II) show a background of mononuclear phagocytes with perivascular and parenchymal T­cell infiltration. Pattern II is further distinguished by immunoglobulin and complement deposition. In approximately 25% of biopsied active lesions (pattern III), oligodendrocyte apoptosis is accompanied by a “dying­back” oligodendrogliopathy, starting at the portion of myelin closest to the axon. These lesions resemble viral, toxic, and ische­ mic processes and can be destructive. After the acute phase, factors that remain poorly understood determine whether surviving axons in a lesion are invested by a thin myelin sheath (remyelinated), whether inflammation resolves without remyelination (chronic inactive), or whether inflammation and slow myelin degeneration persist (smoldering). Smoldering lesions are most common in progressive multiple sclerosis. The subpial cortical lesion, which is also more common in progressive multiple sclerosis, is characterized by demyelination of the superficial cortex, possibly in association with inflammation in the overlying leptomeninges and sparse macrophages and microglia at the border between demyelinated and myelinated neuropil. pattern.10 The identification of noninvasive bio- more effectively,11 a finding consistent with markers that correlate with active lesion pat- preclinical work indicating that age strongly terns will facilitate the design of personalized modulates immune-mediated regenerative pro- therapeutic strategies for multiple sclerosis, cesses.12,13 What remains unclear is whether since current treatment algorithms may not ade- lesions can remyelinate years after a smolder- quately address the underlying pathogenic hetero- ing lesion is established and whether remyelin- geneity of this complex disease. ated lesions have heightened susceptibility to What determines the long-term fate of a recurrent demyelination. High-resolution, ultra- given lesion — whether the inflammation re- high-field (7-tesla) MRI shows promise as a tool solves or “smolders” or whether it remyelinates for noninvasive staging of lesions,14 and it will — is not well understood. Recent data from be important for future studies to investigate longitudinal imaging studies suggest that le- the relationship between lesion outcomes and sions that form in younger people may repair clinical status. n engl j med 378;2 nejm.org January 11, 2018 171 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  The n e w e ng l a n d j o u r na l of m e dic i n e Myelin is not exclusive to white matter, and derived from retinal ganglion cells and which demyelination in multiple sclerosis also involves succumb to a dying-back process after retrobul- gray matter.15-17 Approximately half of cortical bar inflammatory demyelination in acute optic lesions are perivascular. In some cortical lesions, neuritis. Studies have clearly shown concomitant the inflamed vessel may be located near the retinal ganglion-cell loss27 even in the absence of leukocortical junction, in which case demyelin- clinical optic neuritis, presumably reflecting ei- ation also affects the juxtacortical white matter. ther subclinical inflammation of the optic nerve Sometimes, a small penetrating cortical vein is or retrograde transsynaptic degeneration. involved and only central cortical layers are af- fected. Cortical lesions are less inflammatory Epidemiol o gy than their white-matter counterparts and have substantially less permeability of the blood–brain It is not known whether multiple sclerosis has a barrier.18 single or multiple causes, and rarely (if ever) has The remaining cortical lesions do not arise a specific etiologic trigger been identified. None- from a single cortical vessel but rather appear to theless, various genetic and environmental risk proceed inward from the pial surface of the factors have been found (Fig. 3).28 For unknown brain. In autopsies conducted after decades of reasons, approximately three quarters of people disease, most such lesions are found to be inac- with multiple sclerosis are women, as is common tive, in contrast to subpial lesions in early mul- in diseases that are considered autoimmune. tiple sclerosis, which are inflammatory and to- People with an affected first-degree relative have pographically associated with diffuse and focal a 2 to 4% risk of multiple sclerosis (as compared leptomeningeal inflammatory aggregates (espe- with approximately 0.1% risk in the general cially when observed in biopsy specimens).17 Sub- population), and concordance in monozygotic pial lesions can be extensive and are often found twins is 30 to 50%. Genomewide association on flanking cortical banks within a sulcus, studies, based on samples assembled from thou- which strongly suggests a leptomeningeal origin. sands of patients with multiple sclerosis and Leptomeningeal inflammation can organize into matched controls, have identified more than 200 self-sustaining structures akin to tertiary lym- gene variants that raise the risk of the disease, phoid follicles.19 Although findings on MRI sup- of which the most significant remains the HLA port an association between leptomeningeal in- DRB1*1501 haplotype (with an odds ratio of ap- flammation and subpial cortical demyelination,20 proximately 3). Most risk alleles are associated robust detection methods are lacking, and the with immune-pathway genes, a finding consis- natural history of such lesions — and their re- tent with the notion that autoimmune mecha- sponsiveness to therapy — remain unknown. nisms are paramount in the development of Spinal cord lesions are a major source of clinical multiple sclerosis. We are currently un- clinical disability. Perivascular and circumferen- aware of any validated genetic risk factor that tial demyelination is often highly inflammatory strongly influences the clinical course of the and can involve gray matter.21 Spinal cord atro- disease; this limitation reflects the difficulty phy results from focal inflammatory demyelin- of measuring disease severity in a disease that ation and remote neuroaxonal degeneration.22 It evolves over a period of decades. is detectable by MRI, and the cross-sectional Major environmental risk factors include geo- area of the spinal cord is therefore a promising graphic latitude (with a higher incidence in more outcome measure for clinical trials.23,24 temperate climates), which may reflect seasonal As part of the CNS, the optic nerve is also a changes in sunlight exposure influencing vita- major target in multiple sclerosis, and loss of the min D levels or pathogens prevalent in these contiguous retinal ganglion cells is well docu- regions, although a genetic contribution is pos- mented.25 Retinal damage can be assessed in sible as well. Tobacco exposure, obesity, and vivo by means of optical coherence tomogra- mononucleosis are also associated with an en- phy,26 which reveals substantial thinning of the hanced risk of multiple sclerosis. Mononucleosis retinal nerve-fiber and ganglion-cell layers de- results from infection with Epstein–Barr virus in spite their lack of myelin. Thinning results from the postpubertal population, and multiple scle- injury to axons in the optic nerve, which are rosis eventually develops in only a minority of 172 n engl j med 378;2 nejm.org January 11, 2018 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  Multiple Sclerosis people with a history of mononucleosis (and a tiny minority of all those infected with the nearly EBV and mononucleosis ubiquitous Epstein–Barr virus). Viruses other Other viruses than Epstein–Barr virus have been suggested as Risk genes Temperate latitude potential causes of multiple sclerosis or of mul- Fibrinogen tiple sclerosis–related disease activity, but none Toxins have been definitively proved. Some of these vi- Trauma ruses may act as molecular mimics, whereas Low vitamin D others may interfere with mechanisms that nor- Smoking Obesity mally limit self-reactive cells. Differential sus- Early adulthood ceptibility is reflected in the mouse model of Female sex multiple sclerosis, experimental autoimmune en- cephalomyelitis (EAE), such that specific myelin antigens are required to induce EAE in different strains of mice.29 Along these lines, an interest- ing set of experiments showed that components of the intestinal microbiome can also strongly influence the propensity for the development of Demyelination Axonal loss EAE, especially in genetically predisposed mouse strains with transgenes for myelin recognition by B cells and T cells,30 and evidence for a similar phenomenon in patients with multiple sclerosis Low inflammation, High or chronic inflammation, many spinal cord and cortical lesions, is beginning to emerge.31,32 Overall, the mecha- few spinal cord lesions, poor endogenous repair, good endogenous repair, VS. nisms by which genetic polymorphisms and preserved axons and synapses, mitochondrial dysfunction, extensive axon and synapse loss, environmental exposures raise the risk of mul- early treatment, delayed treatment, younger age tiple sclerosis remain the subject of intense older age investigation. Low Intermediate High Patho gene sis Chance of progression Tissue damage in multiple sclerosis results from a complex and dynamic interplay between the Figure 3. Risk Factors, Triggers, Modifiers, and Disease Courses. immune system, glia (myelin-making oligoden- It is unlikely that multiple sclerosis will ultimately be attributed to a single drocytes and their precursors, microglia, and cause. Rather, the genetic and environmental factor or combination of fac­ tors that result in a predisposition to multiple sclerosis, initiate the disease, astrocytes), and neurons (Fig. 4). Although there and modify its course are highly diverse from one person to the next. The is debate about whether the root cause of mul- top portion of the figure shows the funneling of proposed factors, for which tiple sclerosis is intrinsic or extrinsic to the CNS, varying levels of evidence exist, into the development of inflammatory, de­ studies in animal models, particularly EAE in myelinating lesions with heterogeneous axonal loss (middle portion). The mice and marmosets, together with analysis of bottom portion of the figure lists features of the lesions and their conse­ quences that are generally salutary or deleterious and that modify the risk immune cells and their products in CSF and of progression. EBV denotes Epstein–Barr virus. blood of humans, have disclosed a critical role for adaptive immunity.29 However, despite the fact that some of the disease-modifying thera- the innate immune system (as described below). pies that were first shown to ameliorate EAE Moreover, although some animal models have eventually reached clinical practice, differences clinical progression, none recapitulate the spec- between EAE and multiple sclerosis are myriad trum of critical pathologic features of multiple and have a variety of causes, including the genetic sclerosis.33 Genetic data suggest that the patho- and environmental heterogeneity of humans genesis of multiple sclerosis shares important relative to laboratory mouse strains, as well as a features with a variety of non-CNS autoimmune complex immune process in multiple sclerosis diseases.34 that clearly involves T cells (the major driver of Both helper (CD4+) and cytotoxic (CD8+) T cells EAE) as well as B cells, antibodies, and cells of have been described in multiple sclerosis lesions: n engl j med 378;2 nejm.org January 11, 2018 173 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  The n e w e ng l a n d j o u r na l of m e dic i n e Periphery Cortex Alemtuzumab Daclizumab Oligodendrocyte Dimethyl fumarate precursor cell Fingolimod Glatiramer acetate Interferon beta Lesion Mitoxantrone CD8+ Ocrelizumab T cell Microglia Teriflunomide Glucocorticoids Dalfampridine Complement Oligodendrocyte Neuroprotection Na+ channel Complement Mitochondrial K+ Astrocyte abnormalities channel Macrophage Blood Ocrelizumab vessel CD4+ T cell T cell Natalizumab B cell Figure 4. Cells, Molecules, and Therapies. Shown is a simplified schematic depiction of major cell types within white­matter multiple sclerosis lesions, along with several current and promising therapeutic targets in the central nervous system and in the periphery. CD4+ T cells are more concentrated in the peri- response to B-cell depletion (as early as 8 to 12 vascular cuff, whereas CD8+ T cells are widely weeks), even before the reduction of circulating distributed within the parenchyma.35 Drugs that immunoglobulin, it seems more likely that other limit T-cell access to the CNS can reduce or functions of B cells, including antigen presenta- eliminate new multiple sclerosis lesions. How- tion to helper T cells and cytokine production, are ever, T cells that are reactive to myelin antigens more relevant. have been observed in similar proportions in Cells of the innate immune system are espe- people with and people without multiple sclero- cially important in the pathogenesis of multiple sis, which suggests either that these cells are sclerosis.37 Bloodborne macrophages infiltrate ac- dysfunctional in multiple sclerosis or that other tive multiple sclerosis lesions and remove myelin immune factors also play critical roles. debris and inflammatory by-products; classically Because of the dramatic success of B-cell– and alternatively activated macrophages, as well depleting antibodies in limiting multiple sclero- as mixed populations, have been described in sis lesion formation and clinical disease activity, these lesions. Microglia, the primary endogenous there is renewed attention on the role of B cells.36 phagocytes of the CNS, are abundant in multiple It has long been known that the CSF of most sclerosis lesions, but whether their role is patho- patients with multiple sclerosis harbors unique genic or protective — or both — remains uncer- antibodies (oligoclonal bands) that are produced tain.38 Microglial activation, often remote from within the CNS. There is evidence that the anti- established lesions, has been found in the white body-producing function of B-lineage cells is matter of autopsy specimens from patients with important in some multiple sclerosis lesions.7 multiple sclerosis39 and may represent the earli- However, because of the rapidity of the clinical est stage of lesion development (as is the case in 174 n engl j med 378;2 nejm.org January 11, 2018 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  Multiple Sclerosis animal models40). Once activated, microglia and up glutamate, providing metabolic support to macrophages are pathologically indistinguish- axons, and maintaining the blood–brain barrier.49 able, but progress with the use of gene-expres- An underemphasized but surprisingly common sion technology has opened the door to unraveling cell (approximately 5% of all CNS cells) is the their separate contributions, potentially enabling oligodendrocyte precursor cell, which expresses the development of targeted therapy.41 Studies in the proteoglycan NG2.50 Oligodendrocyte pre- animals have suggested that monocyte and mac- cursor cells can differentiate into oligodendro- rophage populations strongly influence myelin cytes and are present even late in life,51 but in regeneration.13,42 patients with multiple sclerosis they are often Disturbance in the blood–brain barrier is an arrested at the plaque edge, or they may differ- important step in the development of white- entiate into premyelinating oligodendrocytes but matter lesions, which show evidence of gado- fail to wrap myelin.52 Thus, promoting oligoden- linium extravasation on MRI early in their devel- drocyte precursor-cell differentiation is an attrac- opment. Abnormal vascular permeability precedes tive strategy to enhance endogenous remyelin- inflammatory demyelination in EAE40 and po- ation, but such a strategy must be balanced tentially in multiple sclerosis.43 Studies in mice against the potential of oligodendrocyte precur- have shown that leakage of a key plasma protein sor cells to respond to cytokines and thereby (fibrinogen),44 or even secretion of a bacterial participate in inflammation themselves.53,54 Fur- toxin,45 can trigger inflammatory demyelination thermore, oligodendrocytes may become dysfunc- by a cascade that involves microglial activation tional even without dying, causing tissue dam- and subsequent adaptive immunity. In early mul- age through loss of trophic support to axons; tiple sclerosis lesions, vessels near the lesion whether such dysfunctional oligodendrocytes can center become permeable to gadolinium, which participate in repair is unclear. then diffuses passively into enlarged interstitial spaces; days later, the central breach in the Axon Biology blood–brain barrier begins to repair, while small Although relative axonal sparing in the face of capillaries at the lesion edge become permeable profound demyelination is a hallmark of multi- — perhaps as part of the early wound-healing ple sclerosis pathology, axonal transections are process.46 Leptomeningeal inflammation can also frequent, especially acutely.55 Studies with two- contribute to vascular permeability, but this ap- photon microscopy in animal models have be- pears to be a chronic process.20 gun to elucidate relevant cellular and molecular processes, some of which are potentially revers- Glial-Cell Biology ible.56 In chronically demyelinated lesions, denud- Acute multiple sclerosis plaques show activation of ed axons remain vulnerable and can degenerate astrocytes and microglia and sometimes caspase- slowly; possible mechanisms include impaired independent oligodendrocyte apoptosis.7 Microg- axonal transport, mitochondrial dysfunction, and lia are prominent in white-matter lesions but are increased energy demands related to the up- less activated in gray matter.18 Importantly, mi- regulation of ion channels.57 Adaptive immunity croglia play dual roles, sometimes mediating — which is critical for the formation of new inflammation but in other circumstances pro- white-matter lesions — is much less prominent moting repair through clearance of myelin de- in the slow neurodegeneration of progressive bris.47 In gray matter, microglia may limit dam- multiple sclerosis, which highlights the impor- age through pruning of dysfunctional synapses tance of glial activation and secondary mecha- that express classical complement cascade pro- nisms of injury. teins (C1q and C3). This pruning process may become pathologic if activated astrocytes promote Biom a r k er s aberrant expression of complement at synapses, thereby accelerating degeneration.48 Since astro- Magnetic Resonance Imaging cytes are a major component of the multiple The slow rate of disease progression in time sclerosis plaque, they are well positioned to en- frames that are relevant for clinical monitoring hance inflammation by releasing effector mole- or clinical trials, together with heterogeneous cules, but they may also limit damage by taking pathogenic mechanisms and the impracticality n engl j med 378;2 nejm.org January 11, 2018 175 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  The n e w e ng l a n d j o u r na l of m e dic i n e of directly sampling CNS tissue (as opposed to not shown a strong correlation with clinical blood or CSF), have limited the development of status at the population level, probably because biomarkers for progressive multiple sclerosis. The of the heterogeneous presentation and course of most important diagnostic and prognostic tech- multiple sclerosis and the inherent variability of nique for assessing multiple sclerosis — particu- clinical measures, there has been a trend toward larly early in the disease course — is MRI, which the use of imaging to investigate multiple scle- is currently the only technique that can interro- rosis pathology and pathogenesis, including peri- gate the entire CNS in vivo. vascular inflammation, the development of cor- Inflammatory demyelination is easily visible on tical and spinal cord lesions, myelin loss and MRI, as are changes in the blood–brain barrier regeneration, innate immune activation, lepto- that accompany its early development. Figure 1 meningeal inflammation, and network func- shows the in vivo appearance on MRI of lesions tion.14 Such research has been facilitated by the in the periventricular white matter, thalamus and advent of 7-tesla MRI and, to a lesser extent, brain stem, spinal cord, and optic nerve. Since molecular tracers detectable by positron-emission 2000, MRI has been the key diagnostic test when tomography. A particularly exciting innovation patients present with a clinical syndrome that is has been the use of optical coherence tomography suggestive of multiple sclerosis, and the most to rapidly assess the retina at micron-level reso- recent criteria58 — when applied carefully59 — lution. Retinal ganglion-cell axon loss results in allow for accurate diagnosis with a single scan. easily detectable retinal thinning, which tracks MRI diagnostic criteria are revised as new data with MRI changes in the brain74 and can predict accumulate, and standardized protocols for rou- the evolution of disability at the cohort level.75 tine use have been proposed.60,61 MRI is also critical in the development of new disease-modi- Blood and CSF fying therapies, because new lesions are an order Clonal expansion of immunoglobulin-secreting of magnitude more frequent than clinical re- B cells and plasma cells in the CNS results in the lapses.62 Indeed, the effect of a therapy on the characteristic finding of CSF-specific oligoclonal formation new lesions, as detected by MRI, in bands.76 Although the targets of these immuno- small proof-of-concept studies strongly predicts globulins are probably multifaceted, their pres- the effect of the therapy on rates of relapse in ence implies a CNS-restricted immune response. definitive trials.63 Furthermore, MRI findings that However, the specificity of oligoclonal bands for are consistent with multiple sclerosis have been multiple sclerosis is poor, and infections can observed in healthy people who underwent scan- cause the same pattern. Currently, no externally ning for other purposes (such as research), and validated blood immune marker has adequate clinical multiple sclerosis develops in up to 50% sensitivity and specificity to be used for the di- of people with this so-called radiologically isolat- agnosis of multiple sclerosis, which probably re- ed syndrome, sometimes with a primary progres- flects the genetic and environmental heterogene- sive course.64,65 ity of the disease. CSF and serum neurofilament Neurodegeneration in multiple sclerosis is best light chains are promising in their ability to re- captured on MRI by measuring the size of the flect axonal pathologic processes in the CNS at brain or spinal cord. An abnormally low brain the cohort level,77 and there is ongoing interest parenchymal fraction — a measure of brain size in various types of noncoding RNA molecules relative to intracranial capacity — can be taken that can affect gene expression.78 The extent to as surrogate evidence of previous disease-related which these approaches will be useful in pa- atrophy of the brain. In cohort studies, CNS at- tients remains unclear. rophy has been documented even before clinical presentation.66,67 Atrophy complements lesion- Ther a pie s based biomarkers,68 and proof-of-concept clini- cal trials using atrophy as the primary outcome As of December 2017, the Food and Drug Ad- have been published.69,70 Studies of CNS atrophy ministration has approved 15 medications for have focused on specific gray-matter structures modifying the course of multiple sclerosis: (the neocortex and thalamus).71-73 5 preparations of interferon beta; 2 preparations Because conventional MRI biomarkers have of glatiramer acetate; the monoclonal antibodies 176 n engl j med 378;2 nejm.org January 11, 2018 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  Multiple Sclerosis natalizumab, alemtuzumab, daclizumab, and specific inhibition, clonal deletion, or induction ocrelizumab (the first B-cell–targeted therapy); of immunotolerance. Previous attempts at target- the chemotherapeutic agent mitoxantrone; and the ing cytokines have been unsuccessful85 or even small-molecule oral agents fingolimod, dimethyl deleterious,86 probably because of an incomplete fumarate, and teriflunomide. Dalfampridine has understanding of the roles of different forms of been approved as a symptomatic therapy to im- cytokines and their receptors, as well as com- prove walking speed. It is beyond the scope of pensatory pathways. The innate immune system this article to discuss the relative benefits, risks, has not been specifically targeted in large-scale modes of action, and routes of administration of trials of treatment for multiple sclerosis, and these various medications (although some tar- given the high likelihood that this system can be gets are shown in Fig. 4), except to say that all both protective and deleterious, such efforts must are approved for relapsing–remitting multiple be approached cautiously. Nonetheless, the ubiqui- sclerosis and reduce, to various extents, the like- ty of innate immune cells in and around mul- lihood of the development of new white-matter tiple sclerosis lesions underscores the need for lesions, clinical relapses, and stepwise accumu- further research. lation of disability. On the basis of the ability of Beyond the immune system, a great deal of several of these medications to delay a formal work has revolved around tissue repair and pro- diagnosis of multiple sclerosis after an initial tection. On the repair side, small studies have attack, there has been a general move toward preliminarily reported mixed results for therapies early treatment, although, as discussed above, that promote endogenous remyelination through the long-term value of this approach with re- various pathways.87 On the basis of preclinical spect to preventing progressive multiple sclero- data, including in vitro screens and testing in sis remains uncertain. The recent approval of models such as EAE, several approved drugs ocrelizumab for primary progressive multiple (targeting, e.g., nuclear hormone receptor, hista- sclerosis is a promising step, but the reasons for minic, cholinergic [muscarinic], and adrenergic the ability of ocrelizumab to slow progression79 pathways) are being tested for remyelination or remain uncertain. Another important trend has myelin protection. Transplantation of neural or been to escalate treatment with a target of “no oligodendrocyte precursor cells into the brain evidence of disease activity,” as evidenced by the is effective in animal models, but well-designed absence of new lesions, relapses, disability pro- clinical trials involving patients with multiple gression and, more recently, tissue atrophy80,81; sclerosis have not been undertaken, and it is however, it is doubtful that multiple sclerosis likely that promotion of endogenous remyelin- can be fully arrested with current therapies. ation will prove more fruitful and feasible, espe- Several incipient multicenter studies will com- cially if the inhibitory factors inherent in the pare early intensive treatment with more conven- multiple sclerosis plaque can be overcome.52 A tional treatment-escalation approaches. challenge for remyelination trials is the lack of a Small-scale studies have shown that immuno- robust, easily deployable biomarker of success. ablation followed by autologous hematopoietic Visual evoked potentials have been used in small stem-cell transplantation may be a highly dura- studies, but standardization is difficult and tech- ble and effective — and increasingly safe — nical variability high. The specificity of high- therapy.82 The favorable side-effect profile and resolution imaging-based markers for myelin re- high efficacy of B-cell–inhibiting therapies is generation remains questionable. Nevertheless, likewise a welcome development, although op- MRI is highly sensitive to changes in myelin, portunistic infections can occur in rare cases, and such sensitivity can be exploited in early and postmarketing studies will need to monitor proof-of-concept trials.88 long-term side effects. There are early-stage ef- Axonal protection is actively being examined. forts to interfere with specific T-cell populations Results from initial clinical trials of a wide vari- that are thought to drive multiple sclerosis, stem- ety of drugs have been published or reported, ming from data indicating that certain key sub- with several medium-to-large studies currently sets of helper T cells, including those that ex- under way.89 There is an emerging consensus press both interferon gamma and interleukin-17, that slowing the rate of cerebral or spinal cord are important.83,84 Such approaches may involve atrophy is a feasible goal, which, at the proof-of- n engl j med 378;2 nejm.org January 11, 2018 177 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved.  The n e w e ng l a n d j o u r na l of m e dic i n e concept stage, can be undertaken in several have sometimes strayed too far from the caus- hundred people over a period of a few years.90 ative biology. The richest conception of multiple However, definitive proof of neuroprotection — sclerosis will allow appreciation of common pa- an elusive goal in many neurologic conditions thology, which, in the context of variable triggers — awaits larger studies with clinical end points. and clinical courses, makes multiple sclerosis among the most remarkable of all neurologic disorders. C onclusions a nd F u t ur e Dir ec t ions Dr. Reich reports having cooperative research and develop- ment agreements with Vertex Pharmaceuticals, holding a patent Meaningful advances in basic immunology, my- (US9607392) on a system and method of automatically detect- ing tissue abnormalities, and having a pending patent (PCT/ elin biology, and neuroscience, together with a US2013/033334) on a method of analyzing multisequence MRI global focus on halting progressive accumula- data for analyzing brain abnormalities in a patient; Dr. Lucchinetti, tion of disability,91 have opened the promise of a receiving grant support from Novartis, Sanofi-Synthelabo, Biogen, Mallinkrodt, and Alexion; and Dr. Calabresi, receiving grant multipronged understanding of, and therapeutic support, paid to his institution, and consulting fees from Biogen attack on, multiple sclerosis. At the same time, Idec, grant support paid to his institution from Novartis, Med- a renewed focus on lesion development and re- Immune, Teva, and Annexon, and consulting fees from AbbVie, Merck, Vaccinex, Vertex, and Disarm Therapeutics. No other po- pair — more broadly conceived to include lesions tential conflict of interest relevant to this article was reported. in white matter, gray matter, and leptomeninges Disclosure forms provided by the authors are available with — should ultimately unify lines of research, the full text of this article at NEJM.org. We thank Ms. Erina He for drafting earlier versions of the particularly on the side of fluid and imaging- figures and Drs. Martina Absinta, Carlos Pardo, and Yong Guo related biomarkers and clinical outcomes, which for providing radiologic and histopathological images. References 1. GBD 2015 Neurological Disorders cal changes in multiple sclerosis and re- cortical multiple sclerosis lesions. Ann Collaborator Group. 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Is it 2008;​7:​796-804. multiple sclerosis: the International Col- time to target no evident disease activity 86. The Lenercept Multiple Sclerosis Study laborative on Progressive MS. Mult Scler (NEDA) in multiple sclerosis? Mult Scler Group, the University of British Columbia 2012;​18:​1534-40. Relat Disord 2015;​4:​329-33. MS/MRI Analysis Group. TNF neutraliza- Copyright © 2018 Massachusetts Medical Society. images in clinical medicine The Journal welcomes consideration of new submissions for Images in Clinical Medicine. Instructions for authors and procedures for submissions can be found on the Journal’s website at NEJM.org. At the discretion of the editor, images that are accepted for publication may appear in the print version of the Journal, the electronic version, or both. 180 n engl j med 378;2 nejm.org January 11, 2018 The New England Journal of Medicine Downloaded from nejm.org at AUCKLAND UNIVERSITY OF TECHNOLOGY on January 28, 2019. For personal use only. 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