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Clinical Course of Multiple Sclerosis

Sylvia Klineova and Fred D. Lublin

The CGD Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, New York 10029

Correspondence: [email protected]

The 1996 originally established multiple sclerosis (MS) subtypes, based solely on clinicalimpression and consensus, were revised in 2013 to review potential imaging and biologicalcorrelates and to reflect recently identified clinical aspects of MS. As a result, potential newdisease phenotypes, radiologically isolated syndrome, and clinically isolated syndromewereconsidered along with the addition of two new descriptor subtypes: activity and progressionapplied to relapsing remitting and progressive MS phenotypes. In this way, the description ofan individual patient’s disease course is refined and provides temporal information about theongoing disease process. There is still a lack of imaging and biological markers that woulddistinguish MS phenotypes and prognosticate the disease course on an individual patient’slevel, creating a pressing need for large collaborative research efforts in this field.

Multiple sclerosis (MS), a chronic, inflam-matory disease of the central nervous

system (CNS) with hallmarks of demyelinationand axonal degeneration, is characterized byheterogeneity in the symptoms, disease course,and outcomes (Compston and Coles 2008).Typically affecting patients between 20 and 40years of age, MS is a leading cause of disability inyoung adults in the United States and Europe(Tullman 2013).

MS is considered to be an autoimmune dis-ease mediated by autoreactive T helper (Th)1and Th17 cells. Initial contact with a yet-un-known antigen leads to production of proin-flammatory cytokines, interleukin (IL)-1, andinterferon (IFN)-γ by Th1 cells and IL-17 byTh17 cells. Production of cytokines leads tofurther Th cell up-regulation, production ofcertain metalloproteinases, and destruction ofthe blood–brain barrier (BBB), allowing Th cells

to migrate into the CNS. Recovery may be me-diated by distinctive Th2 cell populations secret-ing IL-10 and -4 anti-inflammatory cytokines(Dhib-Jalbut 2002; Sie et al. 2014). Although Tcells have long been considered integral to MSpathogenesis, B-cell follicles and oligoclonalbands (OCBs) are also present in the MS CNS,and it is becoming increasingly clear that B cellscontribute to MS through mechanisms morecomplex than previously appreciated (Crosset al. 2001).

The first formally defined MS phenotypes,relapsing remitting MS (RRMS), primary pro-gressive MS (PPMS), secondary progressive MS(SPMS), and progressive relapsing MS (PRMS),were proposed in 1996 by the U.S. NationalMultiple Sclerosis Society (NMSS) AdvisoryCommittee on Clinical Trials in Multiple Scle-rosis as a result of increased need for standard-ized terminology in the field. It was felt that lack

Editors: Howard L. Weiner and Vijay K. KuchrooAdditional Perspectives on Multiple Sclerosis available at www.perspectivesinmedicine.org

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of such terminology would be detrimental notonly to clinical practice and communicationamong clinicians but also to future advancesin clinical research. The unified terminologywould ensure the proper design of clinical trials,ensure the homogeneity of population recruit-ed, and thus provide the necessary groundworkfor successful outcomes. However, the Commit-tee also recognized the purely clinical nature ofthe phenotypes and acknowledged that this ter-minology might change over time (Lublin andReingold 1996).

The proposed nomenclature quickly becamean inherent part of clinical and research practiceandwas partly instrumental in the approval pro-cess of new MS therapeutics. However, withthe increased knowledge base of MS pathology,the limitations of purely clinical phenotypes,lacking imaging and biological correlates, be-came evident. In 2012, the Committee (spon-sored by NMSS and the European Committeefor Treatment and Research in MS) reexaminedthe original clinical phenotypes with a goal toprovide improved terminology while incorpo-rating imaging, fluid biomarkers, and otherassays. The Committee recommended retentionof the basics of the original 1996MS phenotypesbut provided enhanced characterization by in-troducing new descriptors of activity and pro-gression. The Committee also reported on twonew disease courses: radiologically isolated syn-drome (RIS) and clinically isolated syndrome(CIS) (Table 1) (Lublin et al. 2014).

We will review currently recognized andnew MS disease courses.

RADIOLOGICALLY ISOLATED SYNDROME

Although RIS is not considered a distinct MSphenotype (Lublin et al. 2014), increasing fre-quency of this incidental magnetic resonanceimaging (MRI) finding in patients has raisedits awareness in the MS community.

The term RIS, first introduced in 2009(Okuda et al. 2009), identifies patients withincidentally found MRI abnormalities highlysuggestive of demyelination in the absence ofclinical signs or symptoms. The proposed diag-nostic criteria used the original Barkhof criteria

(Barkhof et al. 1997) for dissemination in space-and lesion-specific morphologic features toenhance diagnostic certainty and eliminate pa-tients with nonspecific white matter changescaused by other causative etiologies, such as vas-cular disease or migraines. As those patients areat increased risk of developing clinically defini-tive MS (CDMS) in the future, identifying base-line factors with prognostic relevance for futurelong-term outcomes is of high importance.

Few studies explored the natural diseasecourse in RIS patients and attempted to identifyrisk factors for either clinical or radiologicaldisease progression.

In 2009, Okuda reported outcomes in 44 RISpatients with regard to conversion to CIS orradiological progression. The study showed a30% conversion rate to CIS or CDMS with amedian time of 5.4 years to the event. Radiolog-ical progression was found in 59% of patientsover a median time of 2.7 years. The presenceof gadolinium-enhancing lesions on the base-line MRI substantially increased the risk for ra-diological progression (hazard ratio [HR] = 3.4)(Okuda et al. 2009).

Another prospective study by French inves-tigators also from 2009 studied outcomes in 70RIS patients.

In agreement with the previous study, theinvestigators found a 37% CIS conversion rateamong the subjects over a mean follow-up peri-od of 5.2 years. The mean time to a second MRIwas 6 months and radiological progression wasfound in 91% of patients, with 37% of patientsdeveloping gad-enhancing lesions. With regardto other baseline predictive factors, this studyfound a significant impact of positive OCBsor an increased immunoglobulin G (IgG) indexbut only when associated with ≥9 T2-hyperin-tense lesions on a first MRI (Lebrun et al. 2009).

The largest study reporting on RIS diseasecourse to date was a retrospective, multinationalcohort study that in 2014 reported on 451 RISsubjects with the goal of estimating the 5-yearrisk of developing a first clinical event while alsoinvestigating the predictive validity of any asso-ciated demographic, clinical, and radiologicalrisk factors. Similar to the two previous studies,the investigators found a 34% risk of first acute

S. Klineova and F.D. Lublin

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Table 1. Changes in multiple sclerosis disease-course (or “type”) descriptions

1996 Disease-course definitions 2013 Disease-course definitionsa

N/A New course added: Clinically isolated syndrome (CIS)—referring to a firstepisode of inflammatory demyelination in the central nervous system thatcould become MS if additional activity occurs

Relapsing remitting multiplesclerosis (RRMS)—episodes ofacute worsening of neurologicfunctioning with total or partialrecovery and no apparentprogression of disease

RRMS—episodes of acute worsening of neurologic functioning (newsymptoms or the worsening of existing symptoms) with total or partialrecovery and no apparent progression of disease; RRMS can be furthercharacterized as:

Active—showing evidence ofnew relapses, newgadolinium enhancinglesions and/or new orenlarging T2 lesions on MRIover a specified time periodOR

Not active—showing noevidence of disease activity

AND Worsening—defined as increaseddisability confirmed over aspecified time period followinga relapseOR

Stable—defined no evidence ofincreasing disability over aspecified time period followinga relapse

Primary progressiveMS (PPMS)—steadily worsening neurologicfunction from the beginningwithout any distinct relapses orremissions

PPMS—steadily worsening neurologic function from the onset ofsymptoms without initial relapses or remissions; PPMS can be furthercharacterized as:

Active—showing evidence ofnew relapses, newgadolinium-enhancinglesions and/or new orenlarging T2 lesions on MRIover a specified time periodOR


AND With progression—evidence ofdisease worsening on anobjective measure of change,b

confirmed over a specifiedperiod of time, with or withoutrelapsesOR

Without progression—noevidence of disease worseningon an objective measure ofchangeb over a specified periodof time

Secondary progressive MS(SPMS)—progressive, with orwithout relapses

SPMS—following an initial relapsing remitting course, the disease becomesmore steadily progressive, with or without relapses; SPMS can be furthercharacterized as:

Active—showing evidence ofnew relapses, newgadolinium enhancinglesions and/or new orenlarging T2 lesions on MRIover a specified time periodOR


AND With progression—evidence ofdisease worsening on anobjective measure of change,b

confirmed over a specifiedperiod of time, with or withoutrelapsesOR

Without progression—noevidence of disease worseningon an objective measure ofchangeb over a specified periodof time

Continued

Clinical Course of MS

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or progressive clinical event observed within 5years. A unique observation in this study wasthat 9.6% of patients developed a progressivedisease course from onset. This study also de-fined spinal cord lesions as the strongest predic-tive factor for future clinical events (HR = 3.08).Additional relevant factors were younger ageand male gender. Risk also increased with thepresence of multiple risk factors. Interestingly,factors known for their importance in CIS, suchas gad-enhancing lesions, infratentorial lesions,and positive cerebrospinal fluid (CSF) profilewere not predictive of first clinical event devel-opment. Bearing in mind that this study wasnot investigating the impact of treatment onthe risk of first clinical event (16.2% of patientsin the cohort were treated with disease-modify-ing treatments [DMTs]), the investigators foundno benefit of DMT agents on extending the timeperiod to the first event (Okuda et al. 2014).

The importance of RIS and the need foraccurate characterization of its course and asso-ciated risks is supported not only by the fact thata meaningful number of patients do convert toclinical MS but also by the concern for misdiag-nosis and eventual exposure to treatment agents.Although still not yet recognized as a formal MScourse, research efforts to validate the above-reported findings and to establish the role ofDMT treatment in RIS are under way.

CLINICALLY ISOLATED SYNDROME

Although recognized for some time, the 2012MS disease course nomenclature codified CISas an established disease course.

The term CIS describes a first clinical eventhighly suggestive of demyelinating CNS disease

but not yet meeting dissemination in timefor diagnosis of CDMS. The presenting symp-toms are usually monofocal, evolve acutely orsubacutely over days to weeks, and involve opticnerve, spinal cord, brain stem, or cerebellum.Like other MS attacks, the episode is expectedto last at least 24 hours and occurs in the absenceof fever or infection (Miller et al. 2012).

The CIS harbors a possibility of CDMS inthe future. The relationship between CIS andMS was the subject of few observational studiesthat reported on a conversion rate to CDMSfollowing different CIS events: optic neuritis,brain stem syndromes, and transverse myelitis.Despite the variations in the conversion ratesobserved (CDMS conversion after optic neuritisup to 85%, transverse myelitis up to 61%, andbrain stem syndromes up to 60%), most likelyrelated to geographical differences in the courseof the disease and different follow-up periods, itis safe to conclude that CDMS risk rates aresimilar for all the CIS types (Optic NeuritisStudy Group 2008; Young et al. 2009; Tintoreet al. 2010).

Similar to RIS, certain demographic andimaging characteristics influence the risk ofclinically definite multiple sclerosis (CDMD)conversion. The presence and number of T2white matter lesions and abnormal CSF profile,defined as an elevated IgG index or the presenceof OCBs, are the two predictors most commonlyused in clinical practice.

The majority of CIS patients (50%–70%)will have asymptomatic T2 white matter abnor-malities on the baseline brain MRI consistentwith demyelinating lesions. The predictive roleof this finding with regard to CDMS conversionwas reported in multiple observational long-

Table 1. Continued

1996 Disease-course definitions 2013 Disease-course definitionsa

Progressive relapsingMS (PRMS)—steadily worsening neurologicfunction from the beginning withoccasional relapses

Course eliminated: PRMS—individuals who were previously diagnosedwith progressive relapsing MS would now be considered primaryprogressive: active (at the time of relapses or new MRI lesions) or notactive

Based on data from the National Multiple Sclerosis Society.MRI, Magnetic resonance imaging.aLublin et al. (2014).bFor example, the Expanded Disability Status Scale (EDSS).



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term studies and showed up to 80% conversionrate in up to 20 years follow-up period. The riskof CDMS conversion is also correlated with thenumber of lesions (Brex et al. 2002; Tintore et al.2010; Miller et al. 2012).

Although the presence of abnormal CSFprofile did not provide much added prognosticvalue to the presence of abnormal MRI in CISpatients, the predictive value further increasedin patients with normal brain MRI, raisingthe risk to CDMS conversion from 4% to 23%(Tintore et al. 2008).

RELAPSING REMITTING MS

The most common MS phenotype, found inabout 85% of MS patients, RRMS, is character-ized by alternating periods of neurological dys-function—relapses and periods of relative clini-cal stability free of new neurological symptoms—remissions (Fig. 1). The frequency of relapsescan vary from patient to patient but generallydoes not exceed 1.5 per year. Various neurolog-ical symptoms, such as weakness, altered sensa-tion, balance impairment, impairment of visualacuity, and color vision or double vision, can bepresent during the relapse, lasting at least 24hours in the absence of infection or metabolicderangement. Relapses result in residual deficits

in almost half of episodes, leading to stepwiseaccrual of impairment (Lublin et al. 2003).

Pathologically, areas of inflammation richin perivascular lymphocytic infiltrates with sub-sequent demyelination and axonal transectionare the substrate of a relapse episode. Recoveryof the symptoms during the relapse resolutionsuggests remyelination, which is most activeduring the early inflammatory phase of MS(Compston and Coles 2008).

The magnitude of inflammatory pathologyand frequency of relapses, most prominent inyoung adulthood, decreases with advanced dis-ease and age. One of the natural disease historystudies found a relapse rate of 0.54 associatedwith average disease duration of 16 years alongwith decreased duration of second remissionfrom 71.32 months to 58.07 months (Boikoet al. 2002).

Many potential relapse triggers have beeninvestigated over the years to identify potentialinterventions to prevent an acute attack. Infec-tions and stress, as well as pregnancy and theirassociation with relapse, are the most relevantfactors to everyday clinical practice.

Studies show an association between infec-tions and increased relapse rate, prolongedrelapse duration, and increased accumulationof disability; but no specific pathogen has yet

Time

Relapse

RRMS

Active without worseningWorsening (incomplete recovery from relapse)

Stable without activity

New MRI activity

Dis

abili

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Figure 1.Disease course of relapsing remitting multiple sclerosis (RRMS). (Reprinted, with permission, from theNational Multiple Sclerosis Society.)



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been identified. Upper respiratory infectionshave been most often reported as potential trig-gers, but urinary tract infections and gastroen-teritis are also associated with an increasedrelative risk for relapse (Vollmer 2007). Al-though many patients report stressful events asa trigger for MS relapse, the review of literatureby Mohr et al. (2004) did not find a strong caus-ative relationship and proposed a rather additiverole of stress to many other factors influencingrelapse onset.

Pregnancy and associated biochemicalchanges are known to affect the relapse rate inMS. A study by the Pregnancy in Multiple Scle-rosis Group showed a decreasing relapse rateduring pregnancy, from 0.7 in the year beforepregnancy to 0.5, and 0.6 and 0.2 duringthe subsequent trimesters. The relapse rate in-creased in the immediate postpartum periodof 3 months to 1.2 before returning to 0.6 bythe end of the postpartum year. This effect isbelieved to be caused by the natural immuno-tolerant effect of pregnancy, which is then lost atthe time of delivery (Confavreux et al. 1998).

Knowing that a significant number of theRRMS patients will eventually progress intoSPMS; can relapse characteristics serve as a sur-rogate marker to predict the time of onset anddegree of future progression? The research inthis field showed conflicting results. Althoughseveral studies showed no effect of relapses,either before the progression or superimposed,on the severity of the progression, others clearlyshowed the opposite.

Using a natural history cohort, a study byWeinshenker et al. (1989) showed that the num-ber of relapses within first 2 years of diagnosisdid influence the median time of onset of theprogressive disease. Another study, a systematicreview of predictors for long-term disabilityidentified the short interrelapse period afterthe first attack to be the strongest predictorfor the time to onset of disability (Langer-Gould et al. 2006). Work by Paz Soldan et al.(2015) also showed that pre- and postprogres-sive relapses independently accelerated the timeto severe disability in progressive MS.

In concordance with these results, the studyby French investigators showed slower onset of

progression in patients with RRMS when com-pared with PPMS, but once the threshold of aprogression was reached, both groups behavedin a similar fashion (Confavreux et al. 2000).

In 2006, a large Canadian cohort study fromLondon, Ontario, following more than 1000 pa-tients with RRMS, did not confirm the relapsefrequency as a substantial surrogate marker forthe future progression. The investigators foundno effect of the relapse rate on the slope of theprogressive disease. The study showed dissocia-tion between relapses and disease progression,evidenced by parallel progression of disability inboth PPMS and SPMS with or without relapses.Using the same Canadian cohort in a subse-quent study in 2009, the investigators foundthat frequent early attacks (first 2 years fromonset) lead to earlier onset of progressive disease(Kremenchutzky et al. 2006; Scalfari et al. 2013).

Differences in methodology and data inter-pretation are the possible reasons for such con-tradicting views on this topic; however, the im-portance of relapses on future disability shouldbe recognized as it directly influences treatmentstrategies (Lublin 2011).

SECONDARY PROGRESSIVE MS

The majority of untreated RRMS patients doeventually progress into SPMS, and researchdata suggest a median time to progressive phaseof about 19 years after the onset of RRMS (Ro-varis et al. 2006). The diagnosis is most oftenestablished retrospectively, years after the actualprogression started. On an individual patientlevel, it is difficult to determine when exactlyin the disease course does the transition start,and patients as well as clinicians can encounterseveral years of diagnostic uncertainty. Themostcommon reasons for this period of uncertainty,reported to last 2.9 ± 0.8 years on average in oneexamined population (Katz Sand et al. 2014), aresubtle and often fluctuating initial symptomsindicating early progression and reluctance toestablish a diagnosis of progressive disease andthus increasing patient’s anxiety regarding prog-nosis and lack of approved therapies.

A few predictors of the conversion to SPMShave been identified, namely, higher age at



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RRMS onset was associated with earlier progres-sion to SPMS, as well as male gender, albeit notconsistently in all studies. Spinal cord symptomsand incomplete relapse recovery have alsobeen shown to shorten the time to progression(Rovaris et al. 2006).

Phenotypically, the course of SPMS is notuniform and consists of periods of progressionwith possible superimposed relapse activity butalso periods of relatively stable disability (Fig. 2).To date, there are no available imaging or im-munological markers of progression, which isestimated based on clinical grounds over a peri-od of at least 6 to 12 months.

The pathology involved in SPMS is poorlyunderstood and most likely complex, involvingsome degree of persistent inflammation, albeitto a lesser extent than in RRMS, combined withneurodegeneration caused by mitochondrialdysfunction and resultant axonal damage.

The peripheral innate immune systemcomposed of the cells of myeloid origin, suchas dendritic cells, macrophages, and naturalkiller cells, is now recognized to play an impor-tant role in mediating and regulating pathologyin MS, notably in the progressive phase. A shiftfrom adaptive to innate immunity has beenproposed as a potential mechanism of progres-sion. Recent research has shown changes in thecytokines (IL-12 and -18) and costimulatory

molecules in the dendritic cells of patientstransitioning from RRMS to SPMS. Additionalprocesses leading to neuronal and oligoden-drocyte cell death may include nitric oxideproduction and respiratory burst as well assecretion of soluble proteins (matrix metallo-proteinases) with a direct effect on the BBB(Weiner 2008).

The inflammatory changes present in pro-gressive disease are thought to be compartmen-talized within the CNS behind a closed orrepaired BBB. This compartmentalized inflam-mation is the postulated driving force behindexpansion of existing lesions and diffusechanges in normally appearing white matter.In addition, focal areas of inflammation can bealso found within the meninges of progressivepatients in lymphoid follicle-like structures con-taining dense clusters of B cells and plasma cells,possibly causing the higher degree of corticalpathology observed in progressive disease (Lass-mann et al. 2007).

The reorganization of voltage-gated sodiumchannels along demyelinated axons leading toincreased energy requirements, failing ATP pro-duction, and accumulation of intracellular cal-cium resulting in mitochondrial dysfunctionand axonal damage is a proposed mechanismexplaining the role of mitochondria in neuro-degeneration (Su et al. 2009).

SPMS

Active (relapse or MRI activity) with progression

RRMS

Active (relapse or MRI activity) without progressionNot active with progression

Not active without progression (stable)

New MRI activity

Time

Dis

abili

ty

Figure 2. Disease course of secondary progressive multiple sclerosis (SPMS). RRMS, Relapsing remittingmultiple sclerosis; MRI, magnetic resonance imaging. (Reprinted, with permission, from the National MultipleSclerosis Society.)



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PRIMARY PROGRESSIVE MS

About 10%–20% of patients will develop this dis-ease phenotype, characterizedby the lackof initialRR phase and ongoing progression from the dis-ease onset (Compston andColes 2008; Ransohoffet al. 2015). On an individual patient level, pro-gression is not uniform throughout the courseand superimposed relapses as well as periods ofrelative disease stability are possible (Fig. 3).

Increasing clinical, imaging, and geneticdata suggest that PPMS is a part of the MSdisease spectrum and any pathological differ-ences from SPMS are relative rather than abso-lute. Natural history studies have shown thatdisability progresses in parallel in patientswith PPMS and SPMS with or without relapses(Kremenchutzky et al. 2006). The fact that∼10% of RIS patients develop a PP diseasecourse further supports the theory that the ab-sence of RR phase in PPMS patients is poten-tially caused by clinically silent CNS lesions(Okuda et al. 2014; Ransohoff et al. 2015).

Similar to SPMS, pathology in PPMS is com-plex and includes neurodegeneration occurringalong with mild-to-moderate inflammation.

MODIFIERS OF ACTIVITY ANDPROGRESSION IN MS

The addition of two new modifiers, activity andprogression, to the established MS phenotypes,

was proposed in the 2013 revision based onan increased understanding of the MS clinicalcourse and the increasingly important role ofMRI in clinical care and research. While the1996 MS phenotypes provide a more static dis-ease description, addition of the descriptors ofactivity and progression enhances characteriza-tion of the ongoing disease dynamic in a giventime period and enhances prognostication,treatment decisions, and outcomes in clinicalcare as well as research.

Disease activity is defined as aclinical relapseor new MRI activity—presence of gad-enhanc-ing lesions or new/enlarging T2 lesions. The de-scriptor of disease activity applies to relapsingand progressive MS patients. The Committeesuggested yearly assessment of disease activityusing the clinical examination in both RRMSand progressiveMSpatients. Annual assessmentofMRI activity in relapsing patients was deemedsatisfactory but no consensus on appropriateMRI frequency in progressive patients wasreached. Because of the correlation betweenbrain and spine MRI activity, annual spinalMRI surveillance scans to detect activity werenot recommended unless there were new spinalsymptoms present (Bot and Barkhof 2009).

Inclusion of the new descriptive terminolo-gy then results in various MS phenotypes, suchas RRMS-active, in RRMS patients with eitherclinical or MRI disease activity or PPMS–not

PPMS

Not active without progression (stable)

Active (relapse or new MRI activity) with progression

Not active with progression

Active without progression

New MRI activity

Time

Dis

abili

ty

Figure 3. Disease course of primary progressive multiple sclerosis (PPMS). MRI, Magnetic resonance imaging.(Reprinted, with permission, from the National Multiple Sclerosis Society.)



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active in PPMS patients with no acute attacks orMRI activity within a stated time period.

The descriptor of disease progression ap-plies to either SPMS or PPMS patients. Asprogression in MS is not a uniform feature andpatients can remain relatively stable over time,yearly assessment of progression is recommend-ed. Owing to the lack of imaging or immuno-logical biomarkers, the progression of thedisease is determined on a clinical basis only,combining objective findings and patient-pro-vided history. Again, combining features ofactivity and progression, various MS pheno-types can be observed, such as SPMS-activeand progressing in SPMS patient with clinicalor imaging activity and progression of the dis-ability (Table 1) (Lublin et al. 2014).

The addition of the MS phenotypical mod-ifiers of activity and progression is a first steptoward more patient-specific terminology andsubsequently toward more individualized care.

The original 1996 MS phenotypes werebased on purely clinical grounds and clinicalconsensus and it was hoped that in the future,biomarkers, either imaging or biological, wouldbe able to better support and define the pheno-types. Yet, to date, none of the many proposedcandidates have made it into clinical practice. Areview of biomarkers is beyond the scope of thisarticle, but we will briefly review some of themwith regard to the MS disease course.

MRI

The 2010 revision of McDonald diagnosticcriteria enhanced the usage of MRIs in the di-agnostic process and allowed for earlier RRMSdiagnosis and treatment. The importance ofan MRI in MS is indisputable but, to date,MRIs are not able to distinguish among MSdisease courses.

It is clear that the presence of white matterlesions on MRIs in the correct clinical circum-stances defines RIS and CIS disease phenotypesas well as transition fromCIS to RRMS. Enhanc-ing or new T2 lesions are now used as one ofthe markers of activity. However, in establishedMS, the conventional MRI metrics correlateonly moderately with disability measures, caus-

ing the radiological and clinical paradox (Filippiand Rocca 2011). This is caused by the relativelack of specificity that conventionalMRImetricshave for the heterogeneous pathological sub-strates of the disease. Novel imaging techniques,such as magnetization transfer ratio (MTR), dif-fusion inversion recovery (DIR), and diffusiontensor imaging (DTI) have been expected to fillthis knowledge gap.

Statistically significant differences in thedegree of MTR reduction in T1 hypointense le-sions have been reported among patients withRRMS and SPMS (Filippi and Agosta 2007).Additionally, MTR changes found in normallyappearing white matter and gray matter evolvedin distinguished pattern among major MS phe-notypes (Filippi and Agosta 2010). The subtleDTI changes, specifically, increased mean diffu-sivity, can be found in some patients early beforethe formation of acute inflammatory lesions.

The introduction of DIR sequences en-hanced the ability to detect cortical lesions.Cortical lesions are more frequently seen inSPMS patients than in RRMS or CIS patients,and association has been reported between theselesions and the progression of disability in spe-cific MS phenotypes (Filippi and Rocca 2011).

From the present and ongoing research, aswell as our clinical experience, it is safe to saythat only combining conventional and uncon-ventional MRI techniques with different spec-trums of specificity toward different processesmight enhance our understanding of this com-plex disease and its course. Although this mightbe a feasible approach in clinical research, it isquestionable whether the same is applicable toclinical care.

BIOLOGICAL BIOMARKERS

There are different requirements for biologicalbiomarkers with regard to identifying an MSsubtype (specific) or predicting an MS course(dynamically changing ahead, not after, thetransition), but the common expectations arestandardized analysis techniques, validation inlarge independent cohorts, and cost-effective-ness for clinical practice. The ideal biomarkershould not be redundant in information already



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provided by MRI imaging, but rather additive,and provide a different spectrum of information.

Many promising biomarkers, either serumor CSF, have been identified but very few werealso validated in at least two independent stud-ies, and none of those have made it into clinicalpractice as yet.

The main areas where disease biomarkerscould provide more information are identifica-tion of earlyMS and prediction of CIS toCDMDconversion, identification of MS subtypes andprognostication within and across the MS phe-notypes, and response to therapy.

The following biomarkers showed promisingresults andwere validated in at least one indepen-dent cohort for identification of early CIS toCDMS converters: CSF IgM OCBs, CSF C–X–C motif chemokine 13 (CXCL13), CSF chiti-nase-3-like protein 1 (CHI3L1), and CSF neuro-filament light chain (NfL). Identification of MSsubtypes, specifically identification of PPMSversus RRMS, was supported by the presenceof serum microRNAs miR-223 and miR-15b.Decreased levels of CSF N-acetylaspartate(NAA) were found in patients with SPMS incomparison with RRMS and CIS. With regardto prognostication and intraphenotypical char-acterization of individual patients, CSF-restrict-ed IgM OCBs were found in patients with highrelapse rate and early progression to SPMS, ele-vated CSF CHI3L1 levels were associated withearlier progression to high Expanded DisabilityStatus Scale (EDSS) scores in RRMS patients(Teunissen et al. 2015).

Development of new biomarkers is a longprocess and large, collaborative studies areessential for the validation of results beforeany biomarker makes it into clinical practice.As optimal use of resources is an importantfactor in any health-care setting, we shouldconsider the usage of information that anybiomarker is able to provide and prioritize themost pressing clinical needs—progressive MSand prediction of treatment response.

CONCLUDING REMARKS

Our increased understanding of MS clinicalcourse changed the view of the originally de-

fined MS phenotypes and resulted in new MSsubtypes with enhanced characterization of theindividual patient disease course. This is thefirst step into personalized care in MS. New de-velopments in the field of MRI and biomarkerswill further pave the way toward a better futurefor our patients.

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published online January 22, 2018Cold Spring Harb Perspect Med Sylvia Klineova and Fred D. Lublin Clinical Course of Multiple Sclerosis

Subject Collection Multiple Sclerosis

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Clinical Course of Multiple SclerosisSylvia Klineova and Fred D. Lublin

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