Relapses do not matter in relation to long-term disability: No (they do)

Abstract

MULTIPLE SCLEROSIS MSJ JOURNALIt seems rather perverse to have to defend the most defining element of multiple sclerosis (MS), the relapse. And yet here we are…The relapse is best defined as patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the central nervous system (CNS), current or historical, with duration of at least 24 hours, in the absence of fever or infection. 1 The clinical, radiologic (as a measure of in vivo pathology) and pathologic evidence for a role of relapses in the long-term evolution of MS is considerable. The onset of a relapse is relatively easy to discern (although determining the end is more problematic). The neurologic deficits are obvious and the residual dysfunction is observable and measurable. Despite this, the role of relapses in production of long-term disability has been questioned in several natural history cohorts.Relapses produce immediate and obvious neurologic dysfunction, frequently with MRI correlation. The early course of MS is most often dominated by exacerbations and remissions. The role of relapses in the accrual of disability has been most directly addressed in studies that have utilized well-characterized cohorts, frequently followed over a period of years. Studies of these groups have shown quantifiable residual neurologic dysfunction in 40-50% of subjects experiencing relapses. [2][3][4] The degree of residual dysfunction from relapses may well be underestimated in these studies as they measured residual with changes in Expanded Disability Status Scale (EDSS), likely not the most sensitive measure of persistent deficit. These results nicely complement the earlier natural history studies that correlate early relapse frequency and residual with rapidity of reaching disability status scale (DSS) 6. 5,6 The differences in the types of populations that have been utilized to study this problem highlight some of the methodological issues at play. Natural history cohorts and clinical trial studies differ markedly in their study populations, length of follow up, standardization of assessments (e.g. use of DSS or EDSS), frequency of assessments, rigor of data collection, consistency of examiners, data collection methods and other factors. 7 Is the DSS or EDSS too insensitive to change in any functional system other than ambulation after one reaches a level of 4? If an exacerbation affected upper extremity or brain stem function, might the EDSS in the 4-7 range remain unchanged? These factors alone may explain the discrepancies. This issue can best be resolved through analysis of prospectively studied, wellcontrolled populations for longer duration than the usual MS clinical trial.All pivotal clinical trials in relapsing-remitting MS have demonstrated the development of irreversible disability over time in a proportion of subjects. This is most likely produced by stepwise worsening from relapses, as development of secondary progressive MS has been uncommon in these studies of early MS patients.Several more recent na...

Onset of secondary progressive phase and long-term evolution of multiple sclerosis

“…Nevertheless, the type of initial attack has been shown to have limited prognostic value,2 3 17 as confirmed in this study, despite speculation that severe symptoms during inflammatory attacks might impact adversely on prognosis 41 42. However, unlike neuromyelitis optica,43 relapses in MS only rarely cause permanent severe disability, as result of incomplete recovery.…”

Are we studying MS relapses in the right way?

“…In terms of gauging the importance of relapse frequency, although a high early attack rate is indeed associated with an earlier progression to high levels of EDSS, attack frequency beyond the first few years from onset seems to be non-predictive (Scalfari et al, 2010;Kurtzke et al, 1977). Inspite of these facts concerning our limited knowledge and negative findings, attacks causing stepwise decline leading to the initial development of moderate disability obviously occur in many patients during the ''first phase'' of MS (Lublin, 2011;Edan, 2012). Examining the impact of particularly severe attacks, may be a good way to understand the contribution of relapses to long term disability in at least some patients.…”

Multiple sclerosis relapse phenotype is an important, neglected, determinant of disease outcome – YES

“…Perhaps these studies will help conclude the awkward debate among MS specialists, 'do relapses matter?'. 16 At least a modest effect, and quite possibly something more, is suggested by the accumulation of these studies of specifically phenotyped relapses. Ultimately, treating physicians will apply these findings in conjunction with magnetic resonance imaging (MRI) data and other predictive information, which at this time remains limited.…”