REVIEW ARTICLE Multiple Sclerosis: New Insights and Trends
`
`M. Inglese
`
`The past few years have witnessed major advancements in
`
`our ability to diagnose multiple sclerosis (MS) and begin
`treatments that can favorably modify the course of the disease.
`In addition, there is now a much better understanding of the
`pathogenesis of the disease and an increasing interest in “de-
`coding” the complex genetic factors responsible for, not only
`the susceptibility to the disease, but also different clinical phe-
`notypes and disease progression.
`In this update on MS, the main clinical aspects and the
`basic features of the diagnosis, including the new McDonald
`criteria, will be discussed. Next, new insights into the genetics,
`immunology, and pathology, with emphasis on MS as a dis-
`ease with early axonal injury, will be reviewed. Finally, a brief
`description of the available treatments will be presented.
`
`Symptoms and Clinical Course
`MS is the most common inflammatory-demyelinating disease
`of the central nervous system (CNS) and the most frequent
`cause of nontraumatic neurologic disability in young and
`middle-age adults.1 MS is estimated to affect 400,000 persons
`in the United States and 2 million people worldwide.2 Women
`are affected twice as frequently as men, between the ages of 20
`and 40, and whites are especially vulnerable, particularly those
`of northern European extraction. Though clearly not inher-
`ited in a simple Mendelian pattern, MS tends to cluster within
`families, because there is a 1%–5% risk of developing MS if a
`parent or sibling has the disease and ⱖ25% concordance
`among monozygotic twins.3
`Variability and diversity characterize the symptoms and
`presentation of MS. There is virtually no neurologic complaint
`that has not been ascribed to MS. In a significant number of
`patients who later develop typical MS, the clinical onset is with
`an acute or subacute episode of neurologic disturbance due to
`monoregional involvement of the CNS. This form of presen-
`tation is known as clinically isolated syndrome (CIS). These
`may consist of optic neuritis, isolated brain stem, partial spinal
`cord syndrome, or hemispheric syndromes. In a review of all
`published work, McAlpine4 found that the incidence of the
`initial symptoms was weakness in one or more limbs (40%),
`optic neuritis (22%), paraesthesiae (21%), diplopia (12%),
`vertigo (5%), disturbance of micturition (5%), or other (5%).
`Likewise at onset, deficits of sensory, motor, cerebellar,
`brain stem, and autonomic functions are the most common
`clinical manifestations in the more advanced stage of MS.
`There does not seem to be any predictable pattern in the tim-
`ing or location of lesions. Some clinical presentations are dis-
`tinctive of MS, for example, the presence of bilateral internu-
`
`Editor’s Note: This is the first in a 2-part series of Review Articles on the topic of multiple
`sclerosis. The second installment will appear in the June-July issue.
`From the Department of Radiology, New York University School of Medicine, New York,
`NY.
`This work was supported by NIH grants R37 NS 29029–11, RO1 NS051623–01.
`Address correspondence to Matilde Inglese, MD, PhD, Department of Radiology, New York
`University School of Medicine, 650 First Ave, 6th floor, New York, NY 10016.
`
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`clear ophthalmoplegia. Fatigue has been described as the most
`common complaint in 80% of patients and the worst com-
`plaint in 40%5 Neuropsychologic investigations demonstrated
`that cognitive dysfunctions are common in MS patients, af-
`fecting 40%– 65% of them.6
`Most MS patients (85%) experience a relapsing-remitting
`(RRMS) course of the disease characterized by the episodic
`onset of symptoms followed by residual deficits or by a full
`recovery within a few weeks, especially in the early stage of the
`disease.7 Most definitions of a relapse require that new symp-
`toms or signs be present for at least 24 hours and that they not
`be associated with a fever, because elevated body temperature
`can unmask subclinical lesions. Approximately 20% of pa-
`tients with RRMS will remain clinically stable or nearly stable
`for at least 2 decades (benign MS). Specifically, benign MS is
`when a patient remains fully functional in all neurologic sys-
`tems 15 years after disease onset. Within 25 years, however,
`most untreated RRMS patients will evolve into a secondary
`progressive phase (SPMS) characterized by a chronic and
`steady increase of physical symptoms and disability.7 Approx-
`imately 10%–15% of MS patients experience a primary pro-
`gressive (PPMS) course. PPMS differs from the RRMS subtype
`in that it affects both men and women at equal rates, occurs in
`older individuals, exhibits lower levels of inflammatory mark-
`ers and myelopathic features, and is unresponsive to immu-
`nomodulatory agents.8 Progressive relapsing MS, which is de-
`fined as progressive disease from onset, with clear acute
`relapses, with or without recovery, and with periods between
`relapses characterized by continuing progression is quite un-
`common. Although MS is not a fatal disease, very rarely it may
`exhibit a malignant course leading to significant disability in
`multiple neurologic systems or death within a short time after
`disease onset.9
`
`Diagnosis
`MS is a clinical diagnosis, dependent on a detailed history,
`careful neurologic examination, and supportive paraclinical
`investigations, including MR imaging scans, CSF, evoked po-
`tentials, and blood tests to exclude confounding diagnoses.
`The classic MS diagnostic criteria are the evidence of lesions in
`the CNS disseminated in time and space (ie, more than one
`clinical episode involving more than one area of the CNS
`[brain, spinal cord, and optic nerves]). The use of MR imag-
`ing, since its introduction by Young et al,10 has had a major
`impact on the early and more precise diagnosis of the disease.
`In patients with clinically definite MS, brain MR imaging re-
`veals multifocal cerebral white matter (WM) lesions in more
`than 95% of patients and in 75%– 85% there are focal spinal
`cord lesions. About two thirds of patients experiencing a single
`episode of suspected demyelination or CIS have cerebral WM
`lesions indistinguishable from those seen in definite MS.11 Be-
`cause the presence of such lesions increases the likelihood of
`developing clinically definite MS, it is not surprising that for-
`mal MR imaging features for dissemination in space and time
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`REVIEW ARTICLE
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`have been incorporated within the diagnostic criteria for MS
`by an international panel in 2001.12 The previous diagnostic
`criteria for MS by Poser13 were established for use in clinical
`trials of MS and included clinically definite MS, laboratory
`(CSF)–supported definite MS, probable MS (either clinically
`or laboratory supported), and possible MS. Because MR im-
`aging scanning was relatively new at the time of these criteria,
`it was included as a paraclinical element but was not further
`defined.
`According to the new McDonald criteria, the diagnosis of
`MS requires objective evidence of lesions disseminated in time
`and space: MR imaging findings may contribute to the deter-
`mination of dissemination in time or space; other supportive
`investigations include CSF and visual evoked potentials
`(VEPs); diagnostic categories are possible MS, MS, or not MS.
`For dissemination in space, McDonald criteria include the
`Barkhof-Tintore MR imaging criteria,11,14 which require 3 of
`the following 4 elements: (1) at least one gadolinium-enhanc-
`ing lesion or 9 T2 hyperintense lesions; (2) at least one infra-
`tentorial lesion; (3) at least one juxtacortical lesion; (4) at least
`3 periventricular lesions. A spinal cord lesion can substitute
`for any of the above brain lesions. If there are immunoglobulin
`abnormalities in the CSF, the MR imaging criteria are relaxed
`to only 2 T2 lesions typical of MS. For dissemination in time,
`the MR imaging can be equally useful. If an MR imaging scan
`of the brain performed at ⱖ3 months after an initial clinical
`event demonstrates a new gadolinium-enhancing lesion, this
`would indicate a new CNS inflammatory event, because the
`duration of gadolinium enhancement in MS is usually less
`than 6 weeks. If there are no gadolinium-enhancing lesions
`but a new T2 lesion (presuming an MR imaging at the time of
`the initial event), a repeat MR imaging scan after another 3
`months is needed with demonstration of a new T2 lesion or
`gadolinium-enhancing lesion.
`Subsequent application of these criteria in several natural
`history or treatment trial cohorts indicated that they were ro-
`bust in allowing an earlier diagnosis and predicting an in-
`creased likelihood of conversion to clinically definite MS when
`there was MR imaging evidence for dissemination in space and
`time in patients with a CIS.15–17 Specificity was high, and in
`particular this was the case when dissemination in time was
`present: dissemination in space per se was less specific. The
`requirement for a gadolinium-enhancing lesion to fulfill dis-
`semination in time after 3 months had poor sensitivity, but it
`was noted that allowing a new T2 lesion instead overcame this
`limitation.18 In the light of subsequent studies, and in view of
`the criticism—from the Therapeutics and Technology Assess-
`ment Subcommittee of the American Academy of Neurology,
`which recommended 1–3 lesions per se as sufficient evidence
`for diagnosing MS19—the 2001 criteria were revised by a re-
`convened international panel during 2005.20 A constant fea-
`ture in both 2001 and 2005 is the use of the Barkhof-Tintore
`criteria. They differ in the extent to which a spinal cord lesion
`can also assist with fulfillment of dissemination in space: in
`2001, only one cord lesion could substitute for one brain le-
`sion, whereas in 2005 any number of cord lesions can substi-
`tute for brain lesions and a cord lesion is also assigned the same
`status as an infratentorial lesion. This change may have been
`based on a study in 107 early but definite MS patients, where
`cord lesions substantially increased the proportions with dis-
`
`semination in space from 67% by using brain MR imaging
`alone to 94% by using all available cord lesions to complement
`brain lesions.21 Also cord MR imaging allows the exclusion of
`alternative pathology in patients with cord syndromes and the
`higher specificity for MS than brain MR imaging findings
`when comparison is made with other neurologic disorders
`and with older healthy controls who frequently have WM le-
`sions due to small vessel disease.22
`In time, the 2005 criteria for dissemination were more sub-
`stantially revised to include a new T2 lesion occurring more
`than 1 month after clinical onset. This should increase the
`sensitivity while retaining specificity in making an earlier di-
`agnosis of MS in CIS patients. In PPMS, the presence of CSF
`oligoclonal bands is no longer required, though in their ab-
`sence it is necessary to have at least 2 spinal cord lesions and
`either 9 brain lesions or 4 – 8 brain lesions plus abnormal
`VEPs.
`Although MR imaging is the most sensitive investigational
`technique for MS, it is important to keep in mind that the
`appearance of multiple lesions on MR imaging is not specific
`for MS. In the clinical setting, however, this appearance pro-
`vides an important ancillary diagnostic tool that may establish
`the multifocality of CNS involvement. MR imaging is also
`used to assess MS disease activity, disease burden, and the
`temporal, dynamic evolution in these parameters. Finally, MR
`imaging is 4 –10 times more sensitive than the clinical evalua-
`tion in capturing CNS lesions, and serial studies have demon-
`strated that clinically apparent changes reflect only a minor
`component of disease activity. Lesions in the cerebrum are
`much more likely to be clinically silent compared with lesions
`in the brain stem or spinal cord.
`
`Pathogenesis
`The etiology of MS is still unknown, but according to current
`data the disease develops in genetically susceptible individuals
`and may require additional environmental triggers. According
`to the pathogenesis, derived from the experimental autoim-
`mune encephalomyelitis, autoreactive peripherally activated
`CD4⫹ T cells recognize autoantigens within the CNS paren-
`chyma in the context of class II molecules of the major histo-
`compatibility complex (MHC) expressed by both local glial
`antigen-presenting cells and dendritic cells,23 which commit T
`cells toward a TH1 phenotype.24 Activated TH1 cells cause my-
`elin disruption and the release of new potential CNS autoan-
`tigens. Secreted proinflammatory cytokines, such as interfer-
`on-␥ and tumor necrosis factor (TNF)-␣,25 and chemokines
`recruit additional unspecific inflammatory cells and specific
`antimyelin antibody-forming B cells that amplify tissue injury.
`Finally, the apoptotic death of T cells and their conversion
`toward a TH2 phenotype positively modulate the outcome of
`the lesion.25 Additional cells are necessary for the typical MS
`lesions to occur such, as the CD8⫹ cells, which show a more
`prominent clonal expansion within MS plaques and better
`than CD4⫹ correlate with the extent of acute axonal inju-
`ry.26,27 The pre-existing autoreactive T cells are activated out-
`side the CNS by foreign microbes, self-proteins, or microbial
`superantigens. The activated T cells cross the blood-brain bar-
`rier through a multistep process. First, activated T cells that
`express integrins can bind to adhesion molecules on the sur-
`face of the endothelium. Then the T cells must pass through a
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`barrier of extracellular matrix (ECM) in a step that involves
`matrix metalloproteases, enzymes that play a role in both the
`degradation of ECM and the proteolysis of myelin compo-
`nents in MS. Antimyelin antibodies—activated macrophages
`or microglial cells— complement and TNF-␣ are believed to
`cooperate in producing demyelination. In the neurodegenera-
`tive phase of the disease, excessive amounts of glutamate are
`released by lymphocytes, microglia, and macrophages.27 The
`glutamate activates various glutamate receptors (AMPA and
`kainate receptors), and the influx of calcium through ion
`channels associated with different glutamate receptors may
`cause necrotic damage to oligodendrocytes and axons.
`It is clear that genetic factors play a prominent role in sus-
`ceptibility to MS.3 Both genetic and nongenetic environmen-
`tal factors may be involved in susceptibility as well as outcome.
`Any environmental factor is likely to be ubiquitous and act on
`a population-basis rather than within the family microenvi-
`ronment. It is likely that there are several independent or in-
`teracting polymorphic genes, each exerting a small, or at most
`moderate, effect to the overall risk. It is also likely that genetic
`heterogeneity exists, meaning that specific genes influence
`susceptibility and pathogenesis in some individuals but not in
`others. Concordance in families for early and late clinical fea-
`tures has been observed as well, which indicates that, in addi-
`tion to susceptibility, genes influence disease severity or other
`aspects of the clinical phenotype. Therefore, some genes may
`be involved in the initial pathogenic events, whereas others
`could influence the development and progression of the dis-
`ease. The strongest and most consistently replicated evidence
`for an MS susceptibility gene has been localized to the MHC.
`The proportion of the total genetic susceptibility explained by
`the MHC locus is estimated to range between 20% and 50%.3
`
`Pathology
`The pathologic hallmarks of MS are demyelinated plaques
`within the WM combined with inflammatory infiltrates con-
`sisting of lymphocytes (T cells and B cells) and activated mac-
`rophages/microglia.26 Demyelination, followed by a variable
`degree of remyelination, is associated with oligodendrocyte
`loss during the chronic stage of the disease. Axonal loss and
`gliosis with astrocyte proliferation and glial fiber production
`are important pathologic features of MS. Recent histopatho-
`logic studies of MS lesions, however, have revealed a great
`variability within lesions of different subjects with respect to
`the extent of inflammation, oligodendrocyte pathology, and
`neuroaxonal injury.28 Four different patterns of pathology
`with resulting demyelination have been observed in MS le-
`sions: Type 1 are T cell-mediated and account for 19% of le-
`sions where demyelination is macrophage-mediated, either
`directly or by macrophage toxins. Type II lesions are both T
`cell and antibody mediated and, at 53%, are the most common
`pathology observed in MS lesions. This pattern results in de-
`myelination via specific antibodies and complement. Type III
`represent the 26% of lesions and are related to distal oligoden-
`dropathy; degenerative changes in distal processes occur that
`are followed by apoptosis. Type IV is responsible for only 2%
`of lesions and results from primary oligodendrocyte damage
`followed by secondary demyelination. This latter pattern was
`observed only in a small subset of PPMS patients.29 Of note,
`the pattern of demyelination found in type III lesions mimics
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`that found in the early stages of WM ischemia and may there-
`fore reflect hypoxic WM damage. A pathologic process similar
`to ischemia could be induced in inflammatory conditions by 2
`mechanisms: vascular impairment leading to defective micro-
`circulation or local production of toxins that alter the mitho-
`condrial energy metabolism.30
`There is increasing evidence that neuroaxonal damage is a
`key feature in MS lesions and that it has a major impact on
`permanent neurologic deficits.31 Axonal damage occurs
`within both acute and chronic plaques, as well as in normal-
`appearing WM, and it is already present in the early stage of
`the disease.32 It may occur either in parallel with myelin de-
`struction or during a second phase, when the axon is demyeli-
`nated and more susceptible to damage. The immunologic at-
`tack, triggered by myelin-reactive T cells, leads to the release of
`free oxygen radicals and nitric oxide (NO) by microglial cells,
`causing myelin breakdown. The increased concentration of
`NO in MS lesions can mediate axonal injury possibly by mi-
`tochondrial injury and subsequent energy depletion, which
`can be prevented by sodium channel blockers.33 The increase
`of glutamate in MS lesions is another potential mechanism of
`cell-mediated cytotoxicity.34 In the later phase, microglia and
`T cell activation are less important, whereas the up-regulation
`of sodium and calcium channels along degenerating axons
`may play an important role in the disease process.35
`In addition to axonal injury, the presence of cortical
`plaques has long been described in MS.36 A systematic descrip-
`tion of these lesions identified 7 plaque types depending on the
`topography within the cortex.37 Cortical plaques are charac-
`terized by less lymphocyte infiltration and predominant mi-
`croglial activation.38 The involvement of neuroaxonal struc-
`tures in the disease process is characterized by neuronal
`apoptosis, loss of dendritic arborization, and transected and
`demyelinated axons.39
`
`Therapy
`The most important goal of MS therapy is to prevent perma-
`nent neurologic disability. Acute relapses of MS are usually
`treated with corticosteroids that shorten symptoms, reduce
`inflammation, seal the blood-brain barrier, enhance nerve
`conduction, and alter the immune system, all of which are
`potentially beneficial in treating MS. Five drugs are currently
`approved by the Food and Drug Administration as disease-
`modifying agents that alter the natural history of RRMS. The 4
`self-administered drugs are intramuscular beta-interferon-la
`(Avonex), subcutaneous beta-interferon-1a (Rebif), subcuta-
`neous beta-interferon-1b (Betaseron), and glatiramer acetate
`(Copaxone). These medications reduce the number of attacks
`in RRMS. These therapies, however, appear to be ineffective
`against the purely progressive form of the disease. Further-
`more, longitudinal brain MR imaging data indicate that the
`accumulation of focal lesions early in the course of MS is as-
`sociated with late progressive disability. Because available dis-
`ease-modifying drugs can reduce the formation of such focal
`lesions, these data support the early institution of disease
`modifying therapy, especially in patients who are at high risk
`for future attacks and significant disability. Nevertheless, these
`treatments seem to have little effect once the disease has en-
`tered a secondary progressive phase. For SPMS, the most con-
`vincing data favors mitoxantrone (Novantrone) as most likely
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`to retard progression and delay disability.40 Several symptom-
`atic treatments are also available to alleviate spasticity, bladder
`disturbances, neuropathic pain, and fatigue.
`
`Conclusion
`The past few years have seen increasing improvement in the
`development of laboratory and imaging approaches to study
`MS, leading to a better understanding of the immunopatho-
`genesis, pathology, and genetics of the disease. In addition,
`MR imaging criteria have been incorporated, for the first time,
`into formal clinical diagnostic criteria for MS and a few dis-
`ease-modifying therapies are currently available. These treat-
`ments, however, are less effective in the progressive stage of the
`disease. There is hope that ongoing research will identify ap-
`propriate molecular targets of intervention and novel diag-
`nostics and, more importantly, will enable the development of
`new and more effective therapies.
`
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