The natural history of relapses in multiple sclerosis

nces 256 (2007) S5–S13www.elsevier.com/locate/jns

Journal of the Neurological Scie

The natural history of relapses in multiple sclerosis

Timothy Vollmer⁎

Division of Neurology, Barrow Neurological Institute, 500 W. Thomas Road, Suite #710, Phoenix, Arizona 85013, USA

Available online 7 March 2007

Abstract

Relapses are a defining feature of multiple sclerosis (MS), serving as the basis for categorizing the different phases of the disease, andproviding a means of measuring treatment success, following disease activity, and defining prognostic features. While the dissociationbetween relapses and disease progression indicates the boundaries of relapse history in determining disease course over time, it alsohighlights the importance of relapses to overall disease evolution. A broad understanding of relapse definition and dynamics is important topromote accurate diagnosis, patient management, and treatment decisions. In an attempt to describe the underlying etiology and clinicalimpact of relapses in MS, this review will examine relapse findings from natural history studies, the utility of relapse as a predictor of diseasecourse, the factors that may contribute to relapse, and data on relapse resolution. The relationship of clinical relapses to MRI disease activityand to the onset of progressive disease will also be addressed.© 2007 Elsevier B.V. All rights reserved.

Keywords: Multiple sclerosis; MS; Natural history; Relapse; Epidemiology; Pathophysiology

1. Introduction

Multiple sclerosis (MS) is the prototype inflammatoryautoimmune disease of the central nervous system (CNS).MS affects approximately 400,000 Americans and 2.5million individuals worldwide, with an incidence ofapproximately 7 new cases per 100,000 people per year,and a lifetime risk of 1 in 400 [1]. Because relapses, alsocalled exacerbations, are a defining feature of MS, they act asthe basis for categorizing different forms of the disease andas a marker to define the disease's natural history and tomeasure the success of new therapies. Further, as arecognizable and prevalent component of MS, relapses areused clinically to follow disease activity and to defineprognostic features. Given the key role of relapse in the studyand management of MS, a broad understanding of relapsedynamics is important to promote accurate diagnosis, patientmanagement, and treatment decisions.

This review will attempt to describe the underlyingetiology and clinical impact of relapses in MS. As a complete

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picture emerges, it will become clear how essential relapse isto the understanding of MS.

1.1. Background

Three signs now known to be associated with MS–dysarthria, ataxia, and tremor–were described by physiciansas early as the turn of the 19th century. By 1824, CharlesOllivier d'Angers documented what may have been the firstdescription of relapse in a case now recognized to be MS [2].It was the French neurologist Jean-Martin Charcot who, in1868, assimilated these findings into a single syndrome hecalled “sclerose en plaques,” and characterized it as a distinctneurologic disease [3]. One hundred years after Charcot,Schumacher and colleagues offered a definition of MSrelapse for clinical research purposes as “a focal disturbanceof function, affecting a white matter tract, lasting for morethan 24 hours that does not have an alternative explanationand is preceded by N30 days of clinical stability” [4].

Relapse history has long been used as a tool to study thenatural history, etiology, and pathogenesis of MS, and toestablish the efficacy of treatment in both research andclinical settings. This has been a rational and productivemeans to follow disease course and to anticipate progression.

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Table 1Clinical course in 113 patients with early onset MS who initially had RRMS

Characteristics during relapsing–remitting period No. (%) ormean±SE

Mean duration of relapsing–remitting period, years 16.13±0.89Total number of relapses 5.53±0.32Annual relapse rate for the whole relapsing–remitting period 0.54±0.05Mean duration of the first remission, months 71.32±5.79Mean duration of the second remission, months 58.07±8.74Proportion of patientswithRRMSwith first remission b1 year 27/113 (23.9)Proportion of patients with RRMS with 2 or more relapses in

first 2 years33/113 (29.2)

Proportion of patients with RRMS with 2 or more relapses infirst 5 years

67/113 (59.3)

RRMS = relapsing–remitting multiple sclerosis.Adapted from Boiko A, Vorobeychik G, Paty D, Devonshire V, SadovnickD. Early onset multiple sclerosis: a longitudinal study. Neurology2002;59:1006–10.

Fig. 1. Relative frequency of relapse per year during 3.6 years after diagnosis(n=102). Adapted with permission from Patzold U, Pocklington PR. Courseof multiple sclerosis. First results of a prospective study carried out of 102MS patients from 1976–1980. Acta Neurol Scand 1982;65:248–66.

S6 T. Vollmer / Journal of the Neurological Sciences 256 (2007) S5–S13

We have found in recent years, however, that the workingdefinition of relapse as originally established by Schumacherand colleagues requires reconsideration today. We nowbelieve that, in general, a relapse in MS is a reflection of asubacute to acute focal inflammatory event in the CNS thathas damaged myelinated axons or neurons, which has lead tofailure of neurological signaling. In addition, we recognizethere are pseudo relapses, which reflect a change inneurological function in patients with MS due to physiolog-ical processes other than a new inflammatory process in theCNS (e.g., fever) that lead to increased conduction delay andblock in previously damaged white matter and that is re-versible when the physiologic stress is removed. The criteriafor relapse confirmation as enunciated by Schumacher et aldo not necessarily address these issues directly. Also, todaywe recognize that MS is a disease not only of white matterbut also of gray matter. Sanfilipo and colleagues reportedthat loss of gray matter may, in fact, have more relevance toclinical status in MS than does loss of white matter [5,6],explaining why early attempts to localize the lesionsresponsible for attacks often were incorrect. In onepathologic study, 84% of demyelinating plaques werenoted in the purely intracortical gray matter and 15.6%were observed to transverse both white and gray matter areas[7]. Moreover, the 30-day time frame of clinical stabilitybetween relapses defined by Schumacher [4] is arbitrary anddoes not necessarily correspond with the actual biology ofthe disease since patients often have more than one area ofactive inflammation in the CNS, each of which runs anindependent time course. Also, it is now known from naturalhistory studies performed using frequent MRI scanning thatclinical relapses represent only the tip of the iceberg of CNSinflammatory events [8].

Along the same lines, most clinical trials today stipulatethat a minimum of 48 h of symptom duration as well aschanges in functional measures, as assessed using tools likethe Expanded Disability Status Scale (EDSS), should beincluded in the criteria for relapse. However, this definitiondoes not always distinguish between clinical relapses andpseudo relapses. And, although the change in EDSS orKurtzke Functional Neurological Status (FSS) scores isintended to ensure that there are objective findings to supportthe diagnosis, in actual practice any change in the EDSS orFSS is used to confirm the relapse even if it does notanatomically localize to the area responsible for thesymptoms of the relapse. Therefore, from a clinicalperspective, the wide interpatient variability in the nature,timing, and duration of relapses that we acknowledge todaysuggests a need to revisit the question of what a relapse is,what it reflects in terms of disease activity, and what itforetells about clinical status over a span of years.

2. MS epidemiology and relapse findings from naturalhistory studies

Today, we know MS as a chronic disease of the CNS thathas been reported to affect twice as many women as it doesmen. The average age of onset is from 20–40 years of age, butb10% patients with MS are diagnosed before age 16. Asmany as 25% of patients with MS live without impairedmobility in their lifetime, but conversely, nearly 15% becomerapidly disabled. Despite the increasing neurologic disabilityoccurring over time, reduction in life expectancy is small andmost patients with MS live at least 25 years after diagnosisand die from a cause unrelated to the disease [1]. About 85%of MS cases originate with relapsing–remitting (RR) disease,which moves through periodic exacerbations with subse-quent full or partial recovery before entering the progressivephase, in which any recovery of function is rare. The diseaseis progressive from onset, however, in approximately 15% ofpatients [1]. Relapse events average about 1.1 per year earlyin the disease course but appear to decrease with advancing

Fig. 2. Inflammation and axonal loss in progression of MS. Over time, relapses become less frequent as axonal loss and cumulative disabilities mark thesecondary progressive stage of disease. Adapted with permission from Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221–31.

S7T. Vollmer / Journal of the Neurological Sciences 256 (2007) S5–S13

disease, increasing neurologic dysfunction, and age (Fig. 1)[9]. In fact, Boiko and colleagues followed the clinical courseof MS in 113 patients with onset before age 16 and noted arelapse rate of 0.54 associated with an average diseaseduration of 16 years (Table 1). The mean duration of firstremission was 71.32 months, decreasing to 58.07 months forthe second remission. An EDSS score of 3.0 was reached atan average of 16.03 years after diagnosis [10]. Although thesefindings indicate that some disease behaviors might be usefulin predicting the natural history of MS, and thus, form thebasis for disease subtype definitions (see Section 2.1. Relapsepatterns), these data fail to predict an individual patient'sexperience or prognosis.

2.1. Relapse patterns

The natural history of MS follows unpredictable patternsof evolution and widely variable timetables, with disabilityaccumulation adhering to no particular blueprint. The diseasemay lie dormant for months to years only to be interruptedwith a relapse. On the other hand, it might progress steadilyfrom onset, with or without overlying relapse symptoms.

The classification of clinical subtypes into 4 distinctcategories was outlined by Lublin and Reingold for theNational Multiple Sclerosis Society in 1996 in order to unifythe vocabulary and predict expected disease behavior as ameans to aid physicians in providing care [11]. Thecategories they identified included:

• RR disease with unpredictable attacks followed byperiods of prolonged (months to years) remission;

• Secondary–progressive (SP) MS, to indicate the stage ofcontinuous neurologic decline that follows an initialperiod of RR disease;

• Primary–progressive (PP) MS, characterized by a slowworsening from onset, with no evidence of remission; and

• Progressive–relapsing (PR) MS, to reflect those patientswith slow worsening disease from onset, but whoexperienced superimposed relapse events as well.

The practical challenge of this classification is that RRMSand SPMS are 2 stages of the same disease, not distinctdiseases. The boundary between these 2 stages of MS isarbitrary. Also, one third of the patients originally classifiedas PPMS will ultimately have a relapse, moving them to thePRMS category. However, there is little evidence this isdistinct from the other relapsing forms of the disease. All ofthese classifications are complicated by the fact much of thedisease activity (up to 90%) is subclinical, particularly in theearly stages of MS. Hopefully, current research willultimately provide a more biological basis for classifyingpatients with MS for the purposes of prognosis, treatmentselection, and clinical trials.

In RRMS, the relapse generally lasts for a week to a monthor more and is associated with MRI evidence of inflammation,demyelination, axonal transection, and remyelination [1]. Thischaracteristic pattern of activity, including relapse resolutionand recovery, is related to the temporally and spatiallysegregated effects of activated autoreactive T cells. Early inthe disease course, there is, in most patients, a full recovery ofneurologic activity after the acute episode and the duration ofremission can be prolonged. As time goes on, relapses becomemore frequent and although recovery generally occurs, adegree of neurologic damage begins to accumulate [11,12]. Asthe disease enters the SP stage, relapses are less frequent in asetting generally associated with substantial axonal loss andcumulative disabilities (Fig. 2).

2.2. Complicating factors in predicting relapse

While these classifications have helped a great deal in thestandardization of diagnosis and treatment decisions, thereremains too much variability in other parameters to predict anindividual patient's disease course. For instance, when MSbegins earlier in life, it is likely to progress more slowly, but inindividuals N50 years of age, progression often is rapid andcontinuous from onset. However, onset of MS in the youngwill, in general, result in onset of disability in early life.Although relapses and remissions are the primary expression


ofMS for 85% of patients in the early years of disease, 90% ofthese individuals will convert from RR disease to the SPphase by ≥25 years of disease duration [13]. Furthermore,approximately 40% of patients will experience relapseepisodes during secondary progression and a similarproportion of patients originally classified as PP will suffera relapse, but there are no identifiable features that predictwhen or in whom neurologic symptoms will recur [14]. Themeasurement of relapse rates is confounded by theoccurrence of pseudo relapses and the question of whetheran inflammatory event as identified by gadolinium-enhancedMRI is required or if a clinical event alone can be a truemeasure of relapse. Given the range of subtypes and vari-ability of markers and chronologies, identifying the clinicalcourse and prognosis of individual patients can be challeng-ing indeed. Because of evidence that MRI changes aregenerally associated with neurologic relapse, it has beentheorized that imaging may prove valuable in anticipating arelapse event. However, while the value of MRI in diag-nosing and following the natural history of MS is undisputed,its predictive value in forecasting a relapse event has provenunclear. Although some studies have suggested that enhanc-ing lesions on T1-weighted MRI scans can be seen to predictupcoming relapse, Koziol and colleagues found that neitherenhancing lesions nor black holes correlated closely withimpending relapse [15]. Nevertheless, in general, patientswith higher levels of MRI disease activity as measured bygadolinium-enhancing MRI lesions, have higher concurrentand subsequent relapse rates [16].

2.3. The immunomechanics of MS onset

MS is generally believed to be a T-cell–mediated auto-immune disease [17]. This means that in a geneticallysusceptible individual, pre-existing autoreactive T cells arepresent in a naïve state; on exposure to a provocative insult,such as viral infection, these cells become activated, incitinga T-cell–mediated attack on self proteins. In MS, these selfproteins (e.g., myelin basic protein) are believed to residemostly in the white matter of the CNS [18–21]. Whether thenaïve auto-reactive T cells become activated and mature inthe peripheral compartment or in the CNS remains unclear.But recent data from the animal model of MS (EAE)indicates that the epitope spreading that characterizes bothEAE and MS occurs only in the CNS [22].

The traditional view of immunogenic progression in MSinvolves several phases. The first phase is initiation, duringwhich normally suppressed autoreactive myelin T cellsescape the control of regulatory T cells, leading to theirproliferation, activation, and entry into the circulation [1].The next phase, transmigration, is marked by the upregula-tion and activation of adhesion molecules on the activatedautoimmune T cells, alterations in the endothelium of theblood–brain barrier, and migration of the T cells into theperivascular space surrounding CNS microvessels, particu-larly postcapillary venules. As a result, proinflammatory TH-

1 T cells release interferon gamma and other cytokines in theCNS that activate nearby endothelial and glial cells, which,in turn, leads to another transmigration, or proinflammatorycascade, that draws mononuclear cells from blood vesselsinto the CNS, causing intrathecal inflammation [23]. Thepresence of these inflammatory cells and substances such ascytokines and autoreactive antibodies causes demyelination,axonal damage, and other pathophysiologic mediators of thesymptoms of MS [24,25].

Although the exact mechanisms of viral induction of MSare not completely understood, the current literature largelyfocuses on the process of epitope mimicry [26]. Epitopemimicry depends on systemic infection with a virus withsequence homology in a viral protein similar to CNS selfproteins, which triggers autoreactive T cells, which, aftercrossing the blood–brain barrier, are activated in situ bymyelin proteins with similar homology, resulting in aninappropriate immunological attack on the CNS [27]. It isnow known many viral and bacterial proteins share homologywith human proteins, including myelin proteins, indicatingepitope mimicry is mostly likely a very common occurrence.Although the theory of epitope mimicry as applied to MS hasbeen supported by evidence from animal models of autoim-mune disease and human immunologic studies [28,29], thesystemic nature of the immunological regulatory failure(namely, prevention of epitope mimicry) as hypothesized inthis model is inconsistent with the CNS specificity of theinflammatory disease in MS. Most patients with MS do notmanifest non-CNS autoimmune diseases. If the autoreactiveT cells are activated in the periphery through epitope mimicrythen there must be a defect in a peripheral immune regulatoryprocess that normally prevents epitope mimicry, leading toautoimmune disease. If this were the case, why do affectedpatients generally not develop autoimmune diseases inadditional organ systems along with MS? A recent reportfrom a study of epitope spreading (whereby reactivity to aspecific protein sequence is extended to other epitopes) mayclarify this issue [22]. In this study, the investigators were ableto show, via administration of radio labeled T cells and mixedbonemarrow chimeras inmouse models ofMS, that activationof naïve T cells occurs in the CNS itself and not in theperiphery. It was found that T cells that are trafficked to theCNS during inflammation remain naïve until entry, wherelocal dendritic cells present endogenous antigens that activatethe T lymphocytes. Although this was an intriguing study thatattempted to clarify the CNS specificity of MS, questionsremain and more research is needed to establish the processesinvolved in the initiation of MS and onset of subsequentrelapse events.

3. Relapse as a predictor of disease course

It has been suggested that the history of the RR phase ofMS may be a window into patient prognosis and quality oflife. The relapses during the early phase of MS appear toreflect underlying inflammatory activity and with each

Fig. 3. Kaplan–Meier estimates of Kurtzke Disability Status Scaleprogression indicate overlaying patterns of progression in both relapsing–remitting and progressive-phase patients once DSS scores reach 4.0.Kaplan–Meier estimates of the time from the assignment of a score of 4.0 toa score of 6.0 among 1844 patients with multiple sclerosis, according to theinitial course. Adapted with permission from Confavreux C, Vukusic S,Moreau T, Adeleine P. Relapses and progression of disability in multiplesclerosis. N Engl J Med 2000;343:1430–8.

Table 2Infection-related relapses in MS occurring during weeks with (at-risk) orwithout (outside at-risk period) confirmed infection

Period Weeks follow-up Relapses Annual relapse rate

At-risk period 1169 46 2.05 a

Outside at-risk period 5297 99 0.97

Adapted from Buljevac D, Flach HZ, Hop WC, Hijdra D, Laman JD,Savelkoul HF, et al. Prospective study on the relationship between infectionsand multiple sclerosis exacerbations. Brain 2002;125:952–60.a Rate ratio 2.1 (95% CI 1.4–3.0; pb0.001).


relapse may impart some functional impairment [24,30].Disease progression, on the other hand, reflects theoccurrence of demyelination, axonal loss, neuronal dropout,and gliosis–the classic neurodegenerative markers of MS–and the permanent functional disabilities that this cellulardamage can wreak. Whereas irreversible disability occursmore rapidly in patients with PPMS versus RRMS, once athreshold of cumulative disability is reached (EDSS score ofabout 4.0), the time course of progression for both diseasesubtypes proceeds at roughly the same pace (Fig. 3) [14].

Because relapses may be suppressed or reduced bycurrent therapies, it is hoped that treating patients during theearly phase of MS may provide an opportunity to preventrelapses and CNS inflammatory disease and delay transitionto SPMS. This theory is supported by the finding thatincomplete relapse recovery predicts a shortened time toonset of disease progression [31]. Once disease progressionbegins, however, it advances independently of relapses andMS responds poorly, if at all, to available treatments [31].Thus, an important goal of MS therapy may be to interveneagainst relapses early in the course of the disease in anattempt to delay or prevent worsening and clinical onset ofthe progressive phase of disease.

4. Factors that may contribute to relapse

Efforts have been made to identify triggers that mightpredict relapses in order to make the most of any potentialpreventive benefits associated with treatment and to identifyopportunities to initiate interventions before a relapse begins.The factors that have been investigated range from infectiousevents, stress, and termination of pregnancy to cranial

irradiation and tumor necrosis factor (TNF) inhibitors. Somerelevant factors are reviewed below.

4.1. Infection

Because the immune system is key in the pathophysiol-ogy of MS, several reports suggest that inflammatorymediators associated with acute infection may precede theonset of a relapse about 20–30% of the time [32–34]. Mildand nonspecific upper respiratory infections or flu-likesyndromes have been most often reported as potentialtriggers, but bladder infections and gastroenteritis also areassociated with an increased relative risk for relapse. Panitchreported that relapses occurred at a rate of 2.92 per year in at-risk weeks (serological confirmation of upper respiratorypathogens) compared with 1.16 per year in weeks not at risk( pb0.001). No specific viral pathogen was identified [33].

A proposed mechanism for the worsening of MSsymptoms suggestive of a pseudo relapse during the actualinfection suggests that the inflammatory factors releasedduring acute viral infection or their biological effects (i.e.,fever) can exaggerate conduction block in MS, leading totemporary aggravation of neurologic impairment [35]. Theincrease in relapse rate associated with infection primarilyoccurs 1 week prior to symptoms of infection to 5 weeksafter the infectious process has terminated [33].

Buljevac and colleagues observed that infections caninduce prolonged relapses and cumulative disability as well[36]. In a longitudinal study involving 73 patients withRRMS, the investigators observed 167 infections and 145relapses over 6466 patient-weeks (Table 2). The infectionscomprised upper respiratory tract viral infections (77%),gastrointestinal symptoms (16%), or urinary tract infection(7%). There was an increased risk (2.1 relative risk) for arelapse associated with systemic infections, including a 2.7-fold increase in relapses that lasted N3 weeks and a 3.8-foldincrease in events lasting N3 months [36]. Because thedegree of functional recovery drops with the increasingduration of neurologic impairment, the authors suggestedthat extended relapses associated with primary infectionsmay contribute substantially to neurologic deterioration inpatients with MS.

Further investigation is needed to confirm this relation-ship between infection and MS relapse, to identify specific

Fig. 4. Relapse rates for 3-month periods during 227 pregnancies amongwomen with MS. The relapse rate drops during each trimester of pregnancythen spikes after birth before returning to baseline. Relapse rates per womanper year for each 3-month period before, during, and after pregnancy in 227pregnancies resulting in a live birth among women with multiple sclerosis.The values shown are means and 95% confidence intervals. Adapted withpermission from Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T, and the Pregnancy in Multiple Sclerosis Group. Rateof pregnancy-related relapse in multiple sclerosis. N Engl J Med1998;339:285–91.


organisms (if any) that might produce this response, and todetermine the disease processes underlying the relationship.However, one can speculate that, based on the fact that awide variety of infections are associated with an increasedrelapse rate, the mechanism underlying this observation isthrough non-antigen specific activation of the immunesystem during infection, which leads to increased migrationof immune cells into the brain and other organs, allowingentry of already present autoreactive T cells into the CNS.

4.2. Proinflammatory cytokines

Certain cytokines involved in the inflammatory responseare produced by and activate pathogenic autoimmune cells inMS. Both interferon-gamma and TNF-alpha are proinflam-matory cytokines that have been shown to correlate withonset of acute MS attacks. Caggiula and colleagues observedsignificant increases in levels of both of these cytokinesduring relapses compared with baseline (baseline versusrelapse levels of TNF-alpha were 10–110 pg/mL versus 100–1500 pg/mL, respectively; and of IFN-gamma, 10–65 pg/mLversus 30–405 pg/mL, respectively; both pb0.05) [37]. Inthe post-relapse period, the levels returned toward baseline.They also observed that, early in the disease course, theproduction of certain neuroprotective cytokines, such asbrain-derived neurotrophic factor (BDNF), nerve growthfactor (NGF), and glial cell line-derived neurotrophic factor(GDNF), was induced by the interferon-gamma and TNF-alpha elevations that may promote the recovery process. Thisprotective mechanism was observed to abate with increasingage and longer disease duration, leading to incompleterecovery and disability accumulation. Thus, treatment aimedat controlling the cytokine response to acute infection inpatients withMSmay help to reduce relapses or delay diseaseprogression.

4.3. High-dose cranial radiation

Demyelination resulting from radiation therapy has beenreported in people without MS [38,39]. Several individualcase reports also indicate that brain irradiation to patientswith demyelinating CNS disease may induce a relapse and/orworsen disease progression [40–42]. In these case reports,patients with MS exposed to cranial irradiation for presumedcancer experienced exacerbation of MS symptoms, progres-sive functional deterioration, and even death in the post-irradiation period. In Peterson's series, patients treated withstandard tumoricidal radiation doses developed progressiveneurologic symptoms and 2 died within months fromprogressive demyelination [41]. In Murphy's case, newneurologic symptoms developed in a 30-year-old woman6 weeks after radiotherapy for a parotid malignancy [42].Although these anecdotal case reports do not include enoughpatients to draw formal conclusions, they suggest arelationship between cranial radiation and MS relapse thatwarrants further investigation.

4.4. Termination of pregnancy

Pregnancy and postpartum biochemical changes areknown to affect the frequency of relapses in MS. Confavreuxand colleagues found that the relapse rate fell from 0.7 in theyear before pregnancy to 0.5 in the first trimester, 0.6 in thesecond trimester, and 0.2 in the third trimester of pregnancy( p=0.03, 0.17, and b0.001, respectively) [43]. In theimmediate postpartum period (first 3 months after birth),however, the relapse rate increased substantially (1.2),exceeding the rate observed in the year prior to pregnancy,but returned to 0.6 by the end of the postpartum year (Fig. 4).Interestingly, in another study there was no evidence ofdisease activity on MRI examination during the thirdtrimester of pregnancy in a cohort of patients with RRMS[44].

Furthermore, despite the varying relapse rates over thestudy period, the overall rate of disability progression did notchange and remained within the range expected forminimally disabling disease. These results are consistentwith those of other studies investigating the impact of pre-gnancy and the postpartum period on MS status [45–48]. Ofnote, analysis of pregnancy and disability in patients withMSin the NARCOMS Patient Registry indicates that womenwith multiple pregnancies actually exhibit less disability thanwomen without pregnancy matched for disease duration anddemographics (unpublished data).

The relapse-diminishing effect of pregnancy is believedto be related to secretions of the fetal–placental unit to inhibitrejection of the pregnancy [49,50]. Investigating thisresponse could help clarify the influence of childbearingon MS disease processes and perhaps identify new strategiesfor intervention in treating MS.


4.5. CNS trauma

Cervical cord hyperextension–hyperflexion injuries havebeen shown to induce relapse and worsen clinical symptomsin MS [51]. Chaudhuri and Behan described 39 cases inwhich MS was initiated or aggravated by acute focal traumato the spinal cord. The onset of MS symptoms occurred asearly as 12 hours post-trauma, but generally appeared within2–3 weeks. Disease progression was typically accelerated inthese patients. The authors suggested a possible relationshipwith elevated nitric oxide levels induced by trauma oralteration of the blood–brain barrier after injury, bothpotential mechanisms contributing to the destructiveness ofdemyelinating diseases.

4.6. Stress

The proposition that stress is a trigger for MS relapse hasbeen controversial, although most patients would assert thatstressful events often precede their exacerbations [52]. In asystematic and quantitative meta-analysis of 14 empiricalstudies of the role of stress in MS symptom onset, Mohr et alfound a consistent association between stressful life eventsand MS exacerbations [53]. Although their findings were notsuggested to indicate a causal relationship and the effect sizewas deemed modest, the results indicate that stressmanagement skills or appropriate neuropharmacology maybe a valuable adjunct to pharmacologic treatment for MS andmay help to reduce the onset of MS relapse.

4.7. Altered peptide ligands

Altered peptide ligands (APLs) interfere with the normalcytokine response to T-cell activation and have been used withsuccess in animal models of MS [54,55]. In human trials,however, APLs have been found in some cases to induce acontrary response and to activate autoreactive T cells [56].When 7 patients were given high dosages of APL to myelinbasic protein peptide (aa 83–99), 3 patients experiencedrelapses, and in 2 of those patients the relapse could beimmunologically linked to APL treatment as evidenced bymyelin basic protein-reactive T cells. Patients who receivedlower dosages, however, had reduced flare-ups and evidence ofa protective Th2 immune response [56,57]. Both trials hadto be terminated prematurely due to poor outcomes or un-expected toxicity. Thus, exposure to APLs remains of ques-tionable therapeutic value and potentially deleterious clinicaloutcome.

5. Relapse resolution

The average time between exposure to a potentialinstigating factor and the onset of relapse symptoms rangesfrom 2–6 weeks. In fact, evidence of CNS tissue changes ongadolinium-enhanced MRI has been reported months priorto the onset of a clinical relapse [58].

This finding is consistent with the hypothesis that arelapse's precipitating event begins with the breakdown ofthe blood–brain barrier, allowing transmigration of enceph-alitogenic T cells into the brain. During the resultingprodromal period, subclinical CNS inflammation may beexpanding and evolving, ultimately reaching a point wherethe CNS dysfunction becomes apparent as an MS relapse.Random migration of autoaggressive T cells into the CNSpossibly precipitated by a systemic or CNS infectionactivates an inflammatory cascade leading to tissue injury[1]. Alternatively, local tissue injury, which leads toactivation of microglia and astrocytes, may also contributeto inflammation in the CNS. In fact, investigators inAustralia suggested this model in an elegant review ofpathological findings from 12 patients with RRMS who diedshortly after relapse onset. In 7 of the 12 cases, the in-vestigators noted oligodendrocyte apoptosis and microglialactivation in the absence of both lymphocytes and myelinphagocytes during new lesion formation. These findingssuggest a novel pathway in which local tissue injury mayinduce secondary activation of phagocytic macrophages[59]. Over the ensuing 2–6 weeks, the neurodestructiveprocesses intensify, leading to sufficient CNS dysfunction tocause recognition of a relapse by the patient and physician.Having said this, it must be kept in mind that more than 90%of gadolinium-enhancing lesions are not associated withidentifiable signs or symptoms [8]. Although this is usuallyexplained based on location of the lesions, other factors suchas neurological reserve function, cortical remodeling, and thenature of the immune response itself may play a role indetermining if clinical symptoms are produced.

Early in the course of MS, the quick resolution of arelapse is believed to be related to the resolution of naturalimmunologic processes. Local microglia are incited toproduce anti-inflammatory cytokines like TGF-beta toimpede the inflammatory process, and there is a reductionin soluble immune mediators. Some investigators have foundevidence of programmed apoptosis in the myelin-targetedautoaggressive T-cell population during spontaneous recov-ery from relapse [60], suggesting a self-modulating mech-anism. In addition, CD25+ regulatory T, or Treg, cells alsoappear to play a role in recovery. This image shows that inthe EAE animal model of MS, depletion of CD25+ T cellsvia administration of anti-CD25 monoclonal antibody inanimals with active disease induced by myelin-oligodendro-cyte glycoprotein (MOG), relapse recovery is lost comparedwith EAE animals positive for CD25. Other factors with aputative role in relapse recovery are CD8+ T cytotoxic Tcells and Th2 myelin-specific T cells [61]. More recently,cortical remodeling has been proposed as a mechanism offunction recovery after MS relapse [62].

5.1. Deterioration of neurologic recovery

Remyelination is a natural part of the relapse recoveryprocess early in the course of MS. Following the appearance


of phagocytes released to absorb the products of myelindegradation, cytokines and growth factors are released bymicroglia and astrocytes in the brain to promote myelinregeneration and repair the acute damage associated with thepassage of toxic substances into the CNS. Oligodendrocyteprecursor cells appear and proliferation and differentiation ofthese early cells into myelin-forming cells helps to repopulateand repair the active lesion [63]. Waxman and colleagueshave also suggested that deployment of sodium channels toareas of demyelinated brain restores conduction of the actionpotential and contributes to disease quiescence in patientswith MS [64]. Finally, evidence of functional reorganizationin the cerebral cortex during relapse recovery implies thatcortical adaptation may minimize the irreversible effects oftissue damage in early stages of MS [62].

With time, however, the repetitive inflammatory attackleads to development of reactive astrocytes and gliosis of thelesion, producing a physical barrier to further remyelination.Microglia or macrophage repair dominates the immuneresponse, with little evidence of lymphocyte involvement[63]. This disease “evolution” from an inflammatory processto a neurodegenerative one is associated with increasingpermanent axonal injury and disease progression. Anotherexplanation for deteriorating relapse recovery over timesuggests that upregulation of p53 in oligodendrocytes due toprevious injury makes the oligodendrocytes susceptible toimmediate damage during subsequent insult. Other cumula-tive damage, such as changes in the nature of the immuneresponse, e.g., recruitment of ganglioside antibodies orevolution of cytotoxicity, or loss of plasticity and reducedfunctional neuronal pool to support cortical rewiring overtime, are other proposed reasons for diminished recovery.Although the exact explanation remains unknown, it is clearthat the reduced capacity for repair leads to onset andaccumulation of neurologic defects and functional deficitsand marks the transition to the progressive phase of MS andthe beginning of irreversible cumulative disability [1].

6. Conclusion

Although our understanding of the natural history of MSand the course of its symptoms has realized huge advancessince Charcot first defined the disease, important informationcontinues to be gleaned from research using relapse as a keymarker for disease progression. Studies like those reportedfrom the Lyon cohort and the London, Ontario, Canada group[31,65] have helped define hallmark features of the disease,including pathophysiology, clinical features, and prognosticfactors based on the history and chronology of relapses. Thedissociation observed between relapses and disease progres-sion, as evidenced from parallel progression of neurologicdisability in both PP and SP with or without relapses,indicates the boundaries of relapse history in determiningdisease course over time, but highlights the importance ofrelapses to overall disease evolution in patients with relapsingforms of MS.

Acknowledgements

This supplement was supported by an educational grantfrom Teva Neuroscience. BioScience Communicationscontributed to the editorial refinement of this article and tothe production of this supplement. Authors may haveaccepted honoraria for their supplement contributions.

References

[1] Compston A, Coles A. Multiple sclerosis. Lancet 2002;359:1221–31.[2] Murray TJ. Multiple sclerosis: the history of a disease. New York:

Demos; 2005.[3] Charcot JM. Histologie de sclerose en plaques. Gazette Hopitaux

41:405–6,9.[4] Schumacher GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF,

McDowell F, et al. Problems of experimental trials of therapy inmultiple sclerosis: report by the panel on the evaluation ofexperimental trials of therapy in multiple sclerosis. Ann N Y AcadSci 1968;122:552–68.

[5] SanfilipoMP, Benedict RH, Sharma J, Weinstock-Guttman B, Bakshi R.The relationship between whole brain volume and disability in multiplesclerosis: a comparison of normalized gray vs. white matter withmisclassification correction. Neuroimage 2005;26:1068–77.

[6] Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Bakshi R. Grayand white matter brain atrophy and neuropsychological impairment inmultiple sclerosis. Neurology 2006;66:685–92.

[7] Bo L, Vedeler CA, Nyland HI, Trapp BD, Mork SJ. Subpialdemyelination in the cerebral cortex of multiple sclerosis patients.J Neuropathol Exp Neurol 2003;62:723–32.

[8] Stone LA, Frank JA, Albert PS, Bash C, Smith ME, Maloni H, et al.The effect of interferon-beta on blood–brain barrier disruptionsdemonstrated by contrast-enhanced magnetic resonance imaging inrelapsing–remitting multiple sclerosis. Ann Neurol 1995;37:611–9.

[9] Patzold U, Pocklington PR. Course of multiple sclerosis. First resultsof a prospective study carried out of 102 MS patients from 1976–1980.Acta Neurol Scand 1982;65:248–66.

[10] BoikoA,VorobeychikG, PatyD,DevonshireV, SadovnickD. Early onsetmultiple sclerosis: a longitudinal study. Neurology 2002;59:1006–10.

[11] Lublin FD, Reingold SC. Defining the clinical course of multiplesclerosis: results of an international survey. National Multiple SclerosisSociety (USA) Advisory Committee on Clinical Trials of New Agentsin Multiple Sclerosis. Neurology 1996;46:907–11.

[12] Thompson AJ, Kermode AG, MacManus DG, Kendall BE, KingsleyDP, Moseley IF, et al. Patterns of disease activity in multiple sclerosis:clinical and magnetic resonance imaging study. BMJ 1990;300:631–4.

[13] Confavreux C, Vukusic S. Natural history of multiple sclerosis: aunifying concept. Brain 2006;129:606–16.

[14] ConfavreuxC,Vukusic S,MoreauT,Adeleine P.Relapses and progressionof disability in multiple sclerosis. N Engl J Med 2000;343:1430–8.

[15] Koziol JA, Wagner S, Sobel DF, Slivka LS, Romine JS, Sipe JC.Predictive value of lesions for relapses in relapsing–remitting multiplesclerosis. Am J Neuroradiol 2001;22:284–91.

[16] Held U, Heigenhauser L, Shang C, Kappos L, Polman C, for the SylviaLawry Centre for MS Research. Predictors of relapse rate in MSclinical trials. Neurology 2005;65:1769–73.

[17] Martin R, McFarland HF, McFarlin DE. Annu Rev Immunol1992;10:153–87.

[18] Sorensen TL, Ransohoff RM. Etiology and pathogenesis of multiplesclerosis. Semin Neurol 1998;18:287–94.

[19] Martino G, Hartung H-P. Immunopathogenesis of multiple sclerosis:the role of T cells. Curr Opin Neurol 1999;12:309–21.

[20] Hemmer B, Archelos JJ, Hartung H-P. New concepts in theimmunopathogenesis of multiple sclerosis. Nature Rev Neurosci2002;3:291–301.


[21] Sellebjerg F. Methylprednisolone treatment, immune activation, andintrathecal inflammation in multiple sclerosis. Dan Med Bull2004;51:167–83.

[22] McMahon EJ, Bailey SL, Castenada CV, Waldner H, Miller SD.Epitope spreading initiates in the CNS in two mouse models ofmultiple sclerosis. Nat Med 2005;11:335–9.

[23] Ransohoff RM. Mechanisms of inflammation in MS tissue: adhesionmolecules and chemokines. J Neuroimmunol 1999;98:57–68.

[24] McDonald I. Pathophysiology of multiple sclerosis. In: Compston A,Ebers G, Lassmann H, McDonald I, Matthews B, Wekerle H, editors.McAlpine's multiple sclerosis. London: Churchill Livingstone; 1998.p. 359–78.

[25] Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiplesclerosis: relationship to neurologic disability. Curr Opin Neurol1999;12:295–302.

[26] Olson JK, Croxford JL, Calenoff MA, Dal Canto MC, Miller SD.A virus-induced molecular mimicry model of multiple sclerosis. J ClinInvest 2001;108:311–8.

[27] Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clonesspecific for myelin basic protein. Cell 1995;80:695–705.

[28] Oldstone MB, Nerenberg M, Southern P, Price J, Lewicki H. Virusinfection triggers insulin-dependent diabetes mellitus in a transgenicmodel: role of anti-self (virus) immune response. Cell 1991;65:305–17.

[29] Hemmer B, Fleckenstein BT, Vergelli M, Jung G, McFarland H,Martin R, et al. Identification of high potency microbial and selfligands for a human autoreactive class II-restricted T cell clone. J ExpMed 1997;185:1651–9.

[30] Lublin FD, Baier M, Cutter G. Effect of relapses on development ofresidual deficit in multiple sclerosis. Neurology 2003;61:1528–32.

[31] Kremenchutzky M, Rice GPA, Baskerville J, Wingerchuk DM, EbersGC. The natural history of multiple sclerosis: a geographically basedstudy 9: observations on the progressive phase of the disease. Brain2006;129:584–94.

[32] Anderson O, Lygner PE, Bergstrom T, Andersson M, Vanhle A. Viralinfections trigger multiple sclerosis relapses: a prospective seroepide-miological study. J Neurol 1993;240:417–22.

[33] Panitch HS. Influence of infection on exacerbations of multiplesclerosis. Ann Neurol 1994;36:S25–8 [suppl.].

[34] Edwards S, Zvartau M, Clarke H, Irving W, Blumhardt LD. Clinicalrelapses and disease activity on magnetic resonance imaging associatedwith viral upper respiratory tract infections in multiple sclerosis.J Neurol Neurosurg Psychiatry 1998;64:736–41.

[35] Smith KJ, McDonald WI. The pathophysiology of multiple sclerosis:the mechanisms underlying the production of symptoms and thenatural history of the disease. Philos Trans R Soc Lond B Biol Sci1999;354:1649–73.

[36] Buljevac D, Flach HZ, Hop WC, Hijdra D, Laman JD, Savelkoul HF,et al. Prospective study on the relationship between infections andmultiple sclerosis exacerbations. Brain 2002;125:952–60.

[37] Caggiula M, Batocchi AP, Frisullo G, Angelucci F, Patanella AK,Sancricca C, et al. Neurotrophic factors and clinical recovery in relapsing–remitting multiple sclerosis. Scand J Immunol 2005;62:176–82.

[38] Lampert P, Tom M, Rider W. Disseminated demyelination of the brainfollowing Co 60 (gamma) radiation. Arch Pathol 1959;68:322–30.

[39] Lampert P, Davis R. Delayed effects of radiation on the human centralnervous system. Neurology 1964;14:912–7.

[40] McMeekin RR, Hardman JM, Kempe MC. Multiple sclerosis after X-radiation. Arch Otolaryngol 1969;90:617–21.

[41] Peterson K, Rosenblum MK, Powers JM, Alvord E, Walker RW,Posner JB. Effect of brain irradiation on demyelinating lesions.Neurology 1993;43:2105–12.

[42] Murphy CB, Hashimoto SA, Graeb D, Thiessen BA. Clinicalexacerbation of multiple sclerosis following radiotherapy. Arch Neurol2003;60:273–5.

[43] Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P,Moreau T, and the Pregnancy in Multiple Sclerosis Group. Rate of

pregnancy-related relapse in multiple sclerosis. N Engl J Med1998;339:285–91.

[44] van Walderveen MAA, Tas MW, Barkhof F, et al. Magnetic resonanceevaluation of disease activity during pregnancy in multiple sclerosis.Neurology 1994;44:327–9.

[45] Poser S, Poser W. Multiple sclerosis and gestation. Neurology1983;33:1422–7.

[46] Bernardi S, Grasso MG, Bertollini R, Orzi F, Fieschi C. The influenceof pregnancy on relapses in multiple sclerosis: a cohort study. ActaNeurol Scand 1991;84:403–6.

[47] Roullet E, Verdier-Taillefer MH, Amarenco P, Gharbi G, Alerovitch A,Marteau R. Pregnancy and multiple sclerosis: a longitudinal study of 125remittent patients. J Neurol Neurosurg Psychiatry 1993;56:1062–5.

[48] Worthington J, Jones R, Crawford M, Forti A. Pregnancy and multiplesclerosis—a 3-year prospective study. J Neurol 1994;241:228–33.

[49] Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectionalcytokine interactions in the maternal–fetal relationship: is successfulpregnancy a TH2 phenomenon? Immunol Today 1993;14:353–6.

[50] SarasteM, Ryynanen J, AlanenA,Multanen J, FarkkilaM,Kaaja R, et al.Cerebrospinal fluid findings in multiple sclerosis patients before, duringand after pregnancy. J Neurol Neurosurg Psychiatry 2006;77:1195–6.

[51] Chaudhuri A, Behan PO. Acute cervical hyperextension–hyperflexioninjury may precipitate and/or exacerbate symptomatic multiplesclerosis. Eur J Neurol 2003;10:109–10.

[52] Rabins PV, Brooks BR, O'Donnell P, Pearlson GD, Moberg P, JubeltB, et al. Structural brain correlates of emotional disorder in multiplesclerosis. Brain 1986;109:585–97.

[53] Mohr DC, Hart SL, Julian L, Cox D, Pelletier D. Association betweenstressful life events and exacerbation in multiple sclerosis: a meta-analysis. BMJ 2004;328:731.

[54] Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK. Analtered peptide ligand mediates immune deviation and preventsautoimmune encephalomyelitis. Immunity 1995;3:397–405.

[55] Brocke S, Gijbels K, Allegretta M, Ferber I, Piercy C, Blankenstein T,et al. Treatment of experimental encephalomyelitis with a peptideanalogue of myelin basic protein. Nature 1996;379:343–6.

[56] Bielekova B, Goodwin B, Richert N, Cortese I, Kondo T, Afshar G, et al.Encephalitogenic potential of the myelin basic protein peptide (aminoacids 83–90) in multiple sclerosis: results of a phase II clinical trial withan altered peptide ligand. Nat Med 2000;6:1167–75.

[57] Kappos L, Comi G, Panitch H, Oger J, Antel J, Conlon P, et al.Induction of a non-encephalitogenic type 2 T helper-cell autoimmuneresponse in multiple sclerosis after administration of an altered peptideligand in a placebo-controlled randomized phase II trial. The alteredpeptide ligand in relapsing MS study group. Nat Med 2000;6:1176–82.

[58] Goodkin DE, RooneyWD, Sloan R, Bacchetti P, Gee L, Vermathen M,et al. A serial study of newMS lesions and the white matter from whichthey arise. Neurology 1998;51:1689–97.

[59] Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis:pathology of the newly forming lesion. Ann Neurol 2004;55:458–68.

[60] SchmiedM,BreitschopfH,GoldR, ZischlerH,RotheG,WekerleH, et al.Apoptosis of T lymphocytes in experimental autoimmune encephalomy-elitis. Evidence for programmed cell death as a mechanism to controlinflammation in the brain. Am J Pathol 1993;143:446–52.

[61] Ziemssen T, Ziemssen F. The role of the humoral immune system inmultiple sclerosis (MS) and its animal model experimental autoim-mune encephalomyelitis (EAE). Autoimmun Rev 2005;4:460–7.

[62] Pantano P, Mainero C, Caramia F. Functional brain reorganization inmultiple sclerosis: evidence from fMRI studies. J Neuroimaging2006;16:104–14.

[63] Antel J. Oligodendrocyte/myelin injury and repair as a function of thecentral nervous system environment. Clin Neurol Neurosurg2006;108:245–9.

[64] Waxman S. Sodium channel blockers and axonal protection inneuroinflammatory disease. Brain 2005;128:5–6.

[65] Ebers GC. Prognostic factors for multiple sclerosis: the importance ofnatural history studies. J Neurol 2005;252(suppl 3) [III/15–20].

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The natural history of relapses in multiple sclerosis