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`Research paper
`
`1 Faculty of Medicine Neurology,
`University of British Columbia,
`Vancouver, Canada; 2 Faculty of
`Medicine, School of Public and
`Population Health, University of
`British Columbia, Vancouver,
`Canada; 3 Faculty of Medicine
`MS/MRI Research Group,
`University of British Columbia,
`Vancouver, Canada
`
`Correspondence to:
`Helen Tremlett, PhD,
`Department of Medicine
`(Neurology), rm S178, 2211
`Wesbrook Mall, University of
`British Columbia, Vancouver, BC
`V6T 2B5, Canada; tremlett@
`interchange.ubc.ca
`
`*The UBC MS Clinic
`Neurologists (in alphabetical
`order): D Adams, D Craig,
`L Daly, S Hashimoto,
`O Hiebiceck, J Hooge, B Jones,
`L Kastrukoff, S Meckling,
`J Oger, D Parton, D Paty,
`P Rieckmann, P Smyth,
`W Shtybel, T Traboulsee.
`
`Received 28 January 2008
`Revised 5 May 2008
`Accepted 12 May 2008
`Published Online First
`5 June 2008
`
`Relapses in multiple sclerosis are age- and time-
`dependent
`H Tremlett,1,2 Y Zhao,3 J Joseph,2 V Devonshire,1 the UBCMS Clinic Neurologists*
`
`ABSTRACT
`Objectives: To examine the relative relapse-rate patterns
`over time in a relapsing multiple sclerosis (MS) cohort and
`to investigate potential predictors of relapse rates and
`periods of low-relapse activity.
`Methods: This retrospective cohort study followed 2477
`relapsing-remitting (RR) MS patients from onset to 1 July
`2003. Annualised relapse rates were examined according
`to sex, age at onset, the patient’s current age and disease
`duration. The relationship between relapse rates and
`baseline characteristics (sex, onset age and onset
`symptoms) were examined using Poisson regression.
`Time to the first 5 years relapse-free was examined using
`Kaplan–Meier survival analysis.
`Results: The mean follow-up time (from onset of MS
`symptoms) was 20.6 years, during which time 11,722 post-
`onset relapses were recorded. The relapse rate decreased
`by 17% every 5 years (between years 5 to 30 post-onset),
`but this decline increased in magnitude with increasing
`onset age. Women and those with onset sensory symptoms
`exhibited a higher relapse rate (p(0.001). More than
`three-quarters of patients (1692/2189) experienced a 5-
`year relapse-free period during the RR phase.
`Conclusion: Relapse rates were age- and time-
`dependent. Our observations have clinical implications: 1)
`any drug able to modify relapse rates has the greatest
`potential for a population impact in patients ,40 years
`old and within the first few demi-decades of disease; 2)
`continuation of drug beyond these times may be of limited
`value; 3) long-term follow-up studies must consider that
`relapse rates probably decline at different rates over time
`according to the patient’s onset age; 4) a relapse-
`quiescent period in MS is not uncommon.
`
`Multiple sclerosis (MS) is a chronic inflammatory
`and degenerative disease of the central nervous
`system (CNS). Relapses (or ‘‘attacks’’) affect 85%
`of patients and are a defining feature of MS,1
`differentiating the MS phenotypes:
`relapsing-
`remitting (RR), secondary-progressive (SP) and
`primary-progressive (PP) MS.2 Relapses are asso-
`ciated with acute focal inflammation and demye-
`lination.3 From the patient’s perspective, relapses
`are disruptive and are a source of anxiety.4
`Currently, the primary effect of the most widely
`used immunomodulatory drugs (IMDs) for MS has
`been to reduce the relapse rate; the much-hoped-for
`beneficial effect on disability progression has not
`been conclusively shown.5 6 Consequently, when
`treating MS, an understanding of the natural history
`of the targeted disease process—ie, relapses—is
`fundamental. This population-defining information
`is required to facilitate the: prognosis of disease
`activity (expected relapse rate); evaluation of drug
`effectiveness in clinical practice; selection of the
`
`most appropriate patients to treat in clinical practice
`(ie, which patients will derive the most benefit from
`IMD treatment). However, to date, many natural
`history studies in MS have centered around the
`(important) outcome of disability progression, with
`relapses typically being a risk factor rather than an
`outcome.7 Often, time to a fixed disability milestone
`or to onset of SP MS is measured;7 however, neither
`of these outcomes may ultimately be altered by use
`of an IMD.
`Those requiring relapse data might derive this
`information from the placebo arms of clinical
`trials.8 9 The relapse information derived from
`these well-controlled prospective studies can be of
`considerable value—for instance, in the design or
`interpretation of other similar studies. However,
`these cohorts are rarely representative of the RR
`MS population that are treated in clinical practice.
`In addition, relapse data are typically only collated
`for patients with (recent) disease activity who are
`followed for relatively short periods of time, which
`is of limited use in a slowly evolving disease such as
`MS, which spans decades.
`Natural history studies can provide relapse
`information of a more encompassing nature, being
`representative of the MS population over longer
`periods of time. However, the nature and duration
`of these studies means that regular examinations
`are impractical,
`such that
`these studies will
`probably underestimate the true relapse rates.10 11
`Valuable information has been derived from
`previous natural history studies explicitly describing
`relapses as an outcome (rather than just a risk factor).
`However, these studies are now dated, typically
`being published more than two decades ago.10 12–14
`Divergence in other measures of disease activity
`(disability progression) between older and more
`recent studies is now evident,15 16 further highlighting
`the need for updated relapse information.
`We set out to provide a contemporary descrip-
`tion of relapses in our British Columbian MS
`population. Given the well-known limitation of
`retrospective studies of MS relapses,10 11 we pri-
`marily examined the relative pattern of relapse
`rates over time (rather than absolute values) and
`also investigated the onset of extended relapse-free
`periods.
`
`METHODS
`This study refers to a cohort of patients previously
`described.15 17–20 Briefly, patients with laboratory-
`supported or clinically definite MS (Poser criteria21)
`with an initial RR course were selected from the
`British Columbia (BC)-wide MS database (estab-
`lished in 1980), which linked the four MS clinics in
`BC, capturing 80% of the MS population in this
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`Canadian province.22 23 Patients were followed prospectively
`from their initial MS clinic visit. Detailed historical information,
`including the onset date and subsequent relapses, were recorded
`on the first visit by an MS specialist neurologist. This
`information was elicited from both the patient and the
`accompanying physician(s) referral letters. Thereafter, relapse
`and other clinical information was recorded by the same MS
`specialist neurologist, typically on a yearly basis (this frequency
`of follow-up for a neurological specialty follow-up is typical in
`BC). The same five core neurologists examined more than 95%
`of patients over the course of the study. Immunomodulatory
`drug use (beta-interferon or glatiramer acetate; natalizumab
`was not licensed during the study) either through clinical
`practice or clinical trials was captured by the database and
`examined. The study end date was 1 July 2003. The inclusion
`criteria are shown in figure 1. To maximise the possibility of a
`substantial and meaningful follow-up time, patients with first-
`onset symptoms prior to July 1988 were selected and, to enable
`establishment of the disease course, a first clinic visit prior to
`July 1998 was required. No minimum active follow-up time was
`required; therefore, those who died or moved away could still be
`eligible. Ten patients were excluded because of the absence of
`clinical data (no disability scores).
`All relapses were confirmed by an MS specialist neurologist,
`and were defined by new or worsening symptoms lasting more
`than 24 hours in the absence of fever or infection. Episodes
`occurring within 30 days of each other were considered to be
`part of the same relapse. Relapse rate patterns were described
`over time, from both the onset of MS and according to the
`current age of the patient as well as age at onset and by sex. Sex
`differences might be biased by the frequency of visits/follow-up
`for men and women, affecting the frequency of reported
`relapses.10 11 We therefore examined the potential for frequency
`
`Figure 1 Selection of patients from the
`British Columbian MS clinics’ database.
`
`Research paper
`
`bias by comparing the visit rate (number of visits/follow-up)
`between men and women using the Mann–Whitney U-test.
`The first (onset) attack was also defined as a ‘‘relapse’’ but was
`excluded from the analyses unless otherwise specified (inclusion
`of this first attack could artificially inflate the magnitude of the
`decline in relapse rates overtime).
`
`Statistical analyses
`Longitudinal analysis
`A longitudinal analysis of the relapse count in each 5-year
`incremental interval from onset (.0–5 years (the onset relapse
`was excluded); .5–10; .10–15; .15–20; .20–25; .25–30;
`.30) was carried out using a (quasi) Poisson regression model
`with a free scale parameter (to account for over-dispersion).24
`The generalised estimating equation (GEE)25 method with an
`independent ‘‘working correlation matrix’’ was used to fit the
`model. The logarithm of exposure time was included as an
`offset to account for the differences in follow-up time for each
`patient. This model was used to examine the relationship
`between the relapse rate after onset of MS and baseline
`characteristics (sex, age at onset (.20 years, .20–30, .30–40
`and .40) and onset symptoms (motor, sensory, optic neuro-
`pathy and cerebellar, ataxia or brainstem)), as well as disease
`duration. Interaction between age at onset and disease duration
`was allowed in a further analysis as the relapse rate appeared to
`vary over time among the different age at onset groups. Results
`were expressed as a percentage change in relapse rate with 95%
`confidence intervals (adjusted for the other factors included in
`the model).
`The main longitudinal analysis included all patients (regard-
`less of whether SP MS had been reached or not). This, in part,
`mimics clinical practice whereby IMD treatment that was
`initiated in the RR MS phase may well continue regardless of
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`whether SP MS is subsequently reached. However, this analysis
`was repeated only considering relapses occurring in the RR
`phase.
`
`Relapse-free periods
`A relapse-free period of 5 years occurring during the RR phase
`was considered to be an outcome of clinical interest. Time to
`the first 5 years relapse free was estimated from Kaplan–Meier
`curves as the time from onset to the first relapse-free year,
`which heralded the start of five consecutive relapse-free years.
`Those patients who did not reach the outcome of interest were
`censored at the time of their last recorded relapse.
`Although IMD use was low in the population,20 the main
`longitudinal analysis was repeated, excluding data collected
`subsequent to the first use of an IMD.
`Some patients exhibited a longer lag time between onset of
`MS and first clinic visit than others. Although those referred to
`clinic earlier probably exhibit a more active disease, recall bias
`might also be the lowest in this group. The main longitudinal
`analysis was therefore repeated in those who came to clinic
`within the first few years from onset.
`SPSS version 15 was used for all statistical analyses. Ethical
`approval was obtained from the University of British Columbia.
`
`RESULTS
`Aspects of this population have been described previously.15 17–20
`Of the 2837 patients eligible for this study (see fig 1), 2485
`(87.6%) patients exhibited a relapsing course from onset, the
`remainder being primary-progressive.19 Eight patients were
`excluded from this current analysis as their relapse history
`was unclear (typically, the patient had no referral notes when
`being transferred from a clinic outside of BC). The character-
`istics of the 2477 considered in the current analysis are shown in
`table 1. The mean follow-up time from onset of MS was 20.6
`years. There were 51,120 person-years of follow-up, during
`which time 11,722 post-onset relapses were recorded.
`
`Relapse rate from onset and by age
`The annualised relapse rates for the entire cohort steadily
`decreased over time from disease onset (see fig 2A), averaging a
`17% reduction every 5 years (time period considered: .5–30
`years from onset). However, the relapse rate did not decrease
`over time for all patients, with those aged ,20 years exhibiting
`a smaller increase in relapses, peaking at 20–,30 years of age
`(see fig 2B and 3). When expressed according to the patients’
`age, there was an observed increase in relapse rates, peaking in
`the third decade of life (see fig 2B).
`
`Table 1 Characteristics of the relapsing at onset population
`
`N patients
`Gender
`
`Women (%)
`Men (%)
`Age at onset, years (mean, SD)
`Onset symptoms
`
`Motor
`Sensory
`Optic neuropathy
`Cerebellar, ataxia or brainstem
`Number patients reaching SP MS (%)
`Median time to SP MS (95%CI)*
`
`2477
`
`1804 (72.8%)
`673 (27.2%)
`29.2 (9.02)
`
`327 (13.2%)
`1102 (44.5%)
`503 (20.3%)
`390 (15.7%)
`1439 (58.1%)
`19.0 years (95%CI: 18.2–19.8)
`
`*from Kaplan–Meier curves.
`SP MS, secondary-progressive multiple sclerosis.
`
`Predictors of relapse rate—longitudinal analysis
`The estimated percentage change in relapse rates are shown in
`figures 4, 5A and 5B. Women had a 14.3% (95%CI: 5.8% to
`23.3%) higher relapse rate than men over the course of the study
`(p = 0.001, adjusted for onset symptoms, age at onset and
`disease duration; see fig 4). This gender difference is also
`depicted in figures 2A and 2B. The actual clinic visit rate
`(number of visits/follow-up) was not different between men
`and women (p = 0.450, Mann–Whitney U-test, data not
`shown), indicating that the observed gender differences were
`unlikely to be due to frequency bias.
`The presence of sensory symptoms at onset were associated
`with a 19.1% (95%CI: 9.1% to 30.1%) higher relapse rate
`(compared to an absence of sensory symptoms at onset,
`p,0.0005, GEE; see fig 4). No other onset symptom exhibited
`a substantial effect (p.0.05; see fig 4).
`The relapse rate tended to decline as the onset age increased
`(see fig 4), with patients 40+ years at onset having a reduced
`relapse rate during follow-up compared to those who were
`younger at onset (,20 years, p,0.0005, GEE; see fig 4).
`The relapse rate also varied with increasing disease duration
`(p,0.0005; see fig 5A). For every 5-year increase in disease
`duration, there was a significant decrease in the relapse rate
`(compared to the first 5 years’ disease duration; see fig 5A). The
`largest decrease occurred in those with .5–10 years disease
`duration where a 22.7% (95%CI: 17.6% to 27.6%) relapse rate
`reduction occurred (onset relapse was excluded). However, this
`pattern was influenced by the age at onset of MS (see fig 5B).
`Each onset age group started with a different relapse rate and
`
`Figure 2 Relapse rate for men and women from onset and by current
`age (A) from onset (n = 2477), (B) by patient’s current age (n = 2477).
`Key: all relapsing at onset patients are considered (RR and SPMS). The
`onset relapse was excluded.
`Annualised relapse rate = (relapse count/number days contributed by
`each patient) 6 365.25.
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`Figure 3 Relapse rate according to the
`patients’ age and by age at onset.
`Key: all relapsing at onset patients are
`considered (RR and SPMS). The onset
`relapse was excluded.
`Annualised relapse rate = (relapse count/
`number days contributed by each
`patient) 6 365.25. This was calculated
`separately for each time period.
`
`declined with a different rate over time, as follows: 30.5%
`(95%CI: 24.5% to 35.9%) decrease for every 5 years’ disease
`duration in those oldest at onset (40+ years); a 22.9% (95%CI:
`19.4% to 26.2%) decline in those aged 30–,40 years at onset; a
`16.9% (95%CI: 14.3% to 19.4%) decline in those aged 20–,30
`years and a 6.9% (95%CI: 2.1% to 11.5%) decline in those
`subjects aged ,20 years (estimations were derived from the
`longitudinal analysis adjusted for gender and onset symptoms,
`with disease duration included as a continuous predictor as the
`decline in relapses followed an approximate linear trend (on the
`
`log scale); only data gathered prior to 30 years from onset were
`considered).
`
`Relapse-free periods (during the RR phase only)
`In those patients with more than 5 years of follow-up in the RR
`phase (n = 2189; 30 were excluded because they reached SP MS
`at an unknown date20), 1692 (77.3%) experienced a 5-year
`relapse-free period. The median time to the start of the first 5
`years’ relapse-free period was 4.0 years (95%CI: 3.6 to 4.4).
`
`Figure 4 Multivariate longitudinal
`analysis: Baseline factors affecting the
`relapse rate over all follow-up.
`Key: all relapsing at onset patients are
`considered (RR and SPMS). The onset
`relapse was excluded.
`Reference variable: gender (men); age
`at onset (,20 years); onset symptom
`(absence of respective onset symptom).
`Percentage change in relapse rates were
`derived from coefficient estimates
`generated using the GEE method based
`on a (quasi) Poisson regression, adjusted
`for: gender, onset symptoms, age at
`onset and disease duration. Interpretation
`of Figure: variables predictive of a higher
`relapse rate: female gender (p,0.005)
`and sensory symptoms at onset
`(p,0.0005).
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`Figure 5 Multivariate longitudinal
`analyses: Influence of disease duration
`and onset age on the relapse rate over all
`follow-up. (A) Influence of disease
`duration on the relapse rate over all
`follow-up. (B) Influence of onset age and
`disease duration on the relapse rate over
`all follow-up.
`Key: all relapsing at onset patients are
`considered (RR and SPMS). The onset
`relapse was excluded.
`* = p,0.005; ** = p,0.05 (compared
`to the reference category). Percentage
`change in relapse rates were derived from
`coefficient estimates generated using the
`GEE method based on a (quasi) Poisson
`regression, adjusted for: gender, onset
`symptoms, age at onset and disease
`duration. Figure 5b included age at onset
`and disease duration as an interaction
`term.
`
`Events occurring before and after the first 5 years relapse free
`The relapse rate prior to the first 5 years’ relapse-free period
`varied considerably, averaging 1.04 relapses per year (SD: 0.561,
`range: 0.27–6.0). Relapses did occur after a relapse-free period,
`albeit at a seemingly lower rate (see fig 6; again, only relapses in
`the RR phase are shown).
`We examined whether the first 5-year relapse-free period
`(experienced during the RR phase) merely heralded the onset of
`SP MS. This did not appear to be the case, as those patients who
`experienced a 5-year relapse-free period took longer to reach SP
`MS, taking an estimated median 23.0 years (95%CI: 22.2 to
`23.9) compared to 10.9 years (95%CI: 10.0 to 11.9) in those
`without such a relapse-free period (p,0.0005 (log-rank test)).
`
`Use of IMDs
`Four hundred and sixteen of 2477 (16.8%) patients started an
`IMD at sometime during the study; 78.2% (326/417) were
`women, being a mean 45.1 years (SD = 7.92) at the start of
`therapy, which was initiated a mean of 17.8 years post-onset of
`MS (range: 2–49 years). The fraction of time spent on an IMD
`was relatively small—the mean follow-up time decreased
`slightly from 20.6 years (SD = 9.79) for the whole study to
`
`19.9 years (SD = 9.83) when ‘‘IMD contaminated’’ data was
`removed. Consequently, findings differed little when the main
`longitudinal analysis was repeated after removing any follow-up
`that occurred subsequent to starting an IMD (data not shown).
`The direction of findings also did not differ when the main
`longitudinal analysis was repeated, excluding relapses occurring
`in the SP MS phase.
`
`Seen within 5 years from onset
`The mean time to the first clinic visit from onset was 12.1 years
`(median = 10.4 years). In all, one-quarter of patients (626/2477)
`were seen within 5 years from onset. The main longitudinal
`analysis was repeated in this group. Although relapse rates were
`initially higher in this subgroup—averaging 0.9 per year for the
`first 5 years of disease duration, as expected—these rates were
`not sustained and declined steeply, ranging from a 57.5%
`(95%CI: 44.3% to 67.6%) decrease for every 5 years’ disease
`duration in those aged 40+ years at onset to 40.8% (23.6% to
`54.1%) in subjects aged ,20 years at onset. As in the whole
`cohort, those oldest at onset (40+ years) exhibited a reduced
`relapse rate during follow-up than those youngest at onset
`(p = 0.012), and women had an 18.4% (95%CI: 2.6% to 36.7%)
`
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`peak (see fig 3 and 5B). Second, continuation of a relapse-
`modifying drug much beyond these periods may result in the
`risk of adverse effects from drug treatment, outweighing any
`possible benefits. Third, caution is required when interpreting
`long-term follow-up studies or those without a placebo arm—
`not only must ‘‘regression to the mean’’28 be taken into account,
`but also the magnitude of a natural reduction of relapses with
`increasing age and disease duration, coupled with periods of
`time with little or no clinical disease activity.
`There has been a lack of consensus with respect to the effect
`of gender on relapse rates; some studies found relapse rates to be
`similar for men and women,10 11 others found rates higher for
`women.13 Our
`findings
`support
`the latter, with women
`exhibiting a higher relapse rate than men. The sex difference
`appeared to be unrelated to the onset of SP MS or to a possible
`visit frequency bias. We were, however, unable to examine any
`possible reporting or physician recording biases that might occur
`based on the gender of the patient. MRI studies of SPMS also
`found women to exhibit a more inflammatory disease course
`than men.29 Why sensory symptoms at onset should be
`associated with a higher relapse rate is unclear and warrants
`further investigation. Our study was not designed to examine
`the existence of temporal changes. Neither were we able to
`examine MRI data—this information was not collated in our
`database, which was created before MRI and other imaging
`techniques were introduced.
`Exposure to any IMD carries an inherent risk of an unwanted
`adverse event. Unnecessary exposure to IMDs might be avoided
`if a ‘‘low-risk relapse period’’ could be identified and predicted.
`These low-risk periods existed in a high proportion of patients,
`with more than three-quarters experiencing a demi-decade
`relapse free (in those with more than 5 years of follow-up in the
`RR phase). Interestingly, the onset of a 5-year relapse-free
`period (during the RR phase) did not merely herald the
`imminent onset of SP MS. First, the median time to the first
`5 years relapse free was much shorter than the median time to
`SP MS, which was previously shown to be 18.9 years in the
`entire RR MS cohort.20 Second, patients actually took longer to
`reach SPMS if they had experienced a 5-year relapse-free period.
`Future research efforts to elucidate an accurate method of
`predicting the onset of extended relapse-free periods, in which
`initiation or continuation of a therapeutic agent aimed at
`reducing relapses is unlikely to be beneficial, could prove useful.
`
`Acknowledgements: Special thanks is extended to: the MS Clinic nurses—R Grigg,
`J Geddes, A Springer, A Moore, L Plasche and staff; the University of British
`Columbia’s Clinical Trials Group for providing IMD information and to the individuals
`with MS who participated.
`
`Funding: This study was funded by a grant from the National MS Society (NMSS). HT
`is funded by: a ‘Don Paty Career Development Award’ from the MS Society of Canada,
`the Christopher Foundation and is a Michael Smith Foundation for Health Research
`Scholar. The BC-wide MS database was funded by an unrestricted grant from Don
`Paty and the MS/MRI research group.
`
`Competing interests: The authors report no conflicts of interest or competing
`interests.
`
`2.
`
`REFERENCES
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`4.
`
`Figure 6 Relapse rate in patients with relapsing-remitting multiple
`sclerosis in the years subsequent to the first 5 years’ relapse-free period.
`Key: only relapses recorded during the RR phase were considered.
`
`higher relapse rate than men (p = 0.021, adjusted for onset
`symptoms, age at onset and disease duration). Although there
`was a trend for the presence of sensory symptoms to be
`associated with a higher relapse rate (by 10.6% (95%CI: 26.0–
`30.0), this did not reach significance in this smaller subgroup
`(p = 0.223).
`
`DISCUSSION
`We report relapse patterns over time in a sizable and largely
`IMD-free MS population. The ubiquitous use of IMDs reduces
`the likelihood of future ethically designed population-based
`natural history studies. Our findings must be taken in context
`of the retrospective study design, with higher absolute relapse
`rates being expected in a prospective study.10 11 However, in
`recognition of this, we focused findings on the relative relapse
`frequencies
`rather
`than absolute rates and,
`in addition,
`replicated findings in patients examined relatively soon after
`onset. Our study has additional practical relevance, being more
`representative of the evaluation frequency and patient char-
`acteristics seen in clinical practice, with relapse histories taken,
`on average, every 1.1 years
`from the first clinic visit.
`Additionally, the consistency of neurological care in our study
`(more than 95% of patients were examined by the same five
`core neurologists over the course of the whole study) minimises
`problems associated with inter-rater variability.
`From the population perspective, the impact of any ther-
`apeutic agent targeting the inflammatory processes in MS, and
`hence ability to modify recurrence of relapses, has the greatest
`potential during periods of high relapse activity. Relapse rates
`were found to be age-related, peaking for those in their third to
`fourth decades of life. Similar age-related patterns have been
`found with gadolinium-enhanced lesions,26 a biomarker for
`inflammatory white matter lesions.27 Relapse rates were also
`time-dependent, declining from onset for the whole population,
`averaging a 17% reduction for every 5 years post-onset; an
`exception being in those ,20 years at onset in which a small
`initial increase in relapses was observed. When both onset age
`and disease duration were considered, the decline in relapse
`rates was greater for those who were older at onset than for
`those who were younger. These observations have several
`clinical
`implications. First, any drug that is able to modify
`relapse rates has the greatest potential for a population impact
`in those aged ,40 years and within the first demi-decades of
`disease when the risk of a future relapse is at or approaching its
`
`J Neurol Neurosurg Psychiatry 2008;79:1368–1375. doi:10.1136/jnnp.2008.145805
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`Neurological picture
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`Diffusion tractography of axonal
`degeneration following shear injury
`
`A 22-year-old construction worker presented after falling from a
`scaffold onto the vertex of his head. After suffering a