Thursday, December 06, 2007

ECTRIMS 2007 Data: Effective Diagnosis and Management of Patients With MS

Data Presented at ECTRIMS 2007 to Assist in Effective Diagnosis and Management of Patients With MS CME

Howard L. Zwibel, MD John F. Kross, DDS Disclosures


Effective diagnosis and management of patients with multiple sclerosis (MS) were 2 topics discussed during the ECTRIMS 2007: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic. Highlights of the new findings are reviewed, and implications for clinical practice are described.

Predicting Clinical Course

"Benign" MS Designation Is Temporary and Lacks Predictive Power

Existence of a less aggressive form of MS is well recognized. However, use of the term "benign MS" (BMS) is problematic. An extensive literature review found that current definitions of BMS are highly variable, -- both quantitatively and qualitatively; -- allow for considerable disability; do not consider insensible symptoms; and are lacking in predictive power.[1]

Moreover, long-term follow-up studies indicated that an initially benign course of MS does not necessarily remain benign over time.[2,3] A 20-year longitudinal cohort study found that the proportion of patients with BMS (Expanded Disability Status Scale [EDSS] ≤ 3.0 for ≥ 10 years post onset; N = 186) decreased by approximately half from 1995 (37.6%) to 2005 (23.7%).[2]

A 21-year longitudinal analysis confirmed that BMS is a temporary condition. Of 47 original benign cases identified in 1985 and followed up in 2006, seven remained benign; 18 died; and 22 had secondary progressive MS (SPMS) (mean EDSS 7.4).[3] Thus, the majority of benign patients progressed. Nevertheless, the median survival of patients with BMS in 1985 was significantly better than for those with non-BMS (52.1 vs 41.6 years, P = .008, hazard ratio [HR] 0.47). Although designating patients as having BMS has a poor predictive value, this cohort survives significantly longer than those without benign disease.

Predictors of a Benign Clinical Course

Logistic regression modeling of data from a 15-year longitudinal study of immunomodulatory treatment-naive patients (N = 46) with relapsing-remitting MS (RRMS) and SPMS indicated that a younger age at onset and lower frequency of relapses were independent predictors of a benign course.[4] There were highly significant differences in age of onset (23.32 vs 33.71, P = .003) and frequency of relapses at the end of 15 years (3 vs 7.5, P < .0001) between patients with BMS (undefined) and those with EDSS > 2.[4]

Although no single clinical or paraclinical parameter can predict a benign course, the Bayesian Risk Estimate for MS (BREMS) score and newer MRI techniques offer some prognostic insights.[5]

MRI and Other Imaging Modalities

Diagnostic Criteria and Tools

The 2001 and 2005 McDonald criteria for MS in patients presenting with clinically isolated syndrome (CIS) requires clinical or MRI demonstration of demyelinating lesions disseminated in space and time. Several studies investigated alternative diagnostic methodology and the diagnostic performance of MRI.

Evaluation of newly proposed diagnostic criteria, in which dissemination in space requires more than 1 T2 MRI lesion in ≥ 2 of 4 locations (juxtacortical, periventricular, infratentorial, and spinal cord) and dissemination in time requires a new T2 lesion on follow-up scan, indicated that the new criteria are simpler than the McDonald criteria without compromising specificity and accuracy.[6]

Findings from another study suggested that a single brain MRI (assessing number and topography of T2 lesions and the number of gadolinium [Gd]-enhancing lesions) may be sufficient to identify a subset of CIS patients at high risk for clinically definite MS (CDMS).[7]

The presence of both brain and spinal cord lesions on MRI has added diagnostic value. A prospective cohort study of CIS patients (N = 178) recruited into a serial MRI study with 10-year follow-up found that the presence of both brain and cord lesions significantly increased the HR for CDMS (HR 9.9) after adjusting for age, sex, and presenting CIS.[8]

Although upgrades of scanner hardware and software may improve image quality, reduce acquisition time, and increase the reliability of imaging, one investigation cautioned that upgrade-related changes affect MRI-derived measures of brain and ventricular volumes, and must be corrected in order to obtain reliable measures of volume changes.[9]

Insight Into MS Pathogenesis

Triple-dose Gd-enhanced MRI was used by Bolokadze and colleagues[10] in consecutive CIS patients (N = 55) with an abnormal baseline MRI scan to show that visible inflammation is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: Atrophy appeared months following acute inflammation.

A voxel-based morphometric study in pediatric MS indicated that regional rather than global atrophy of deep gray matter structures is likely to occur in this primarily white matter disease.[11] Gray matter loss in the thalami was significantly correlated with T2 LL (P < .05), which suggests that transynaptic degeneration is associated with these findings.

Atrophy Progression Is Variable and Difficult to Predict

A study that tested nonlinearities in brain parenchymal fraction change over time and relations to disease activity (attacks) and progression found substantial individual differences in early atrophy rate.[12] Atrophy rates appeared to slow significantly compared with 1-year estimates, and more so for patients with more attacks. Such strong slowing in atrophy progression can lead to significant overestimation when extrapolating from 1-year data.

Detecting Early Organic Changes

In order to enhance clinical efficacy and effectively manage MS, clinicians need to effectively measure and monitor changes in disease status. Findings from a serial proton magnetic resonance spectroscopic study in the first 3 years after a CIS indicated that a significant glial response occurs in normal-appearing white matter soon after a CIS and predominates over axonal damage.[13] A significant decline in total N-acetylaspartate -- a marker of axons -- was not seen until year 3 (P = .003). The decline in total N-acetylaspartate correlated with EDSS (r = -0.402; P = .001) and relapses (r = -0.330; P = .006) at 3 years. The concentration of myo-inositol -- a glial marker -- continued to rise over the 3-year period (P = .027) and correlated with EDSS at 1 year (r = 0.29; P = .020). The negative correlations seen between myo-inositol and total N-acetylaspartate suggest that this glial response reflects the extent of tissue damage caused by the initiating insult.

Increased permeability of the blood-brain barrier is an early phenomenon in plaque development in MS and might precede monocyte infiltration into the central nervous system. Microvascular permeability measurements by first-pass T2-weighted MRI indicated that blood-brain barrier permeability in MS is increased not only in Gd-enhancing lesions but also in nonenhancing lesions and in normal-appearing white matter.[14]

Disease-Modifying Therapy

Slowing Disease Progression and Conversion

A Cochrane review of published randomized controlled trials on early interferon-beta (IFN-beta) treatment of CIS patients including the CHAMPS, ETOMS, and BENEFIT trials demonstrated that IFN-beta is effective in preventing conversion from CIS to CDMS over the first year of follow-up.[15] Some efficacy was also demonstrated over 2 years of follow-up.

In the open-label phase of the BENEFIT trial, the development of neutralizing antibodies to interferon beta-1b (IFN beta-1b), regardless of titer, does not affect the efficacy of IFN beta-1b in delaying conversion to CDMS over 3 years in patients with a first event suggestive of MS.[16] In BENEFIT, patients were randomized to IFN beta-1b (n = 292) or placebo (n = 176) subcutaneously every other day for 2 years (or until CDMS-diagnosed) followed by an open-label phase of IFN beta-1b treatment for up to 5 years.

"Real-world" estimates – derived from Canadian provincial clinic and health service data – indicated that disease-modifying-therapy (DMT), as a class, is effective in delaying EDSS progression in relapsing-onset definite multiple sclerosis (R-onset MS), although more so in RRMS than SPMS.[17] However, effectiveness of the first DMT tended to decline with disability progression and years since onset.

A retrospective cohort analysis of RRMS outpatients receiving either glatiramer acetate (GA) or IFN-beta (N = 491) detected a 20.7% probability of becoming SPMS in the 4-year interval after treatment.[18]

Effect on MRI Disease Activity

IFN beta-1b therapy is known to reduce the formation of contrast-enhancing lesions on MRI, which represent initial inflammatory events in MS. However, a study of IFN beta-1b failed to show a significant change in average contrast-enhancing lesion size during the 6-month treatment period and 3-month natural history phase (P = .393) in patients with RRMS.[19] These results suggest that contrast-enhancing lesions persisting despite therapy do not reduce in severity, pointing to the limits of therapeutic effect once blood-brain barrier breakdown has occurred.

Impact on Brain Atrophy Changes

Short-term examination of brain atrophy is subject to several confounding factors, including resolution of edema that may falsely register as a change in brain volume. Thus, long-term brain volume measurements may be more appropriate to assess the ability of DMT to influence this pathologic process.

Several long-term studies provided insight into the impact of DMT on brain atrophy. Investigation of brain atrophy changes -- assessed by T2-weighted dual-echo MRI images -- in a large SPMS cohort (N = 718) from the EUSPMS trial detected significant atrophy over 3 years in both the placebo and IFN beta-1b arms (P < .0001 in both arms).[20] However, from year 1 to year 3, there was significantly less atrophy in IFN beta-1b-treated patients (median -1.35% vs -2.00%, P = .032). The greater loss of brain volume with IFN beta-1b in the first year probably reflected resolution of pre-existing inflammation accompanied by a reduction in new inflammatory lesions.

A 5-year comparison of GA, high-dose IFN-beta subcutaneously, and low-dose IFN-beta intramuscularly in early RRMS patients showed a significantly lower mean annualized rate of brain atrophy (ARBA) in all of the 3 treatment groups compared with the untreated group (P < .001).[21] Between treatment groups, the GA-treated patients demonstrated significantly less ARBA than either the high-dose or low-dose IFN-beta patients (P < .001). Within the IFN-beta group, low-dose IFN-beta showed significantly less ARBA than high-dose IFN-beta. This long-term assessment showed that all DMTs are effective in reducing the risk for brain atrophy in early RRMS compared with no treatment. GA therapy followed by low-dose IFN-beta appears to be more effective than high-dose IFN-beta in reducing brain atrophy in RRMS.

Predicting Clinical Outcome

Predicting the clinical outcome of acute MS relapse is important in light of the disability risk. Logistic regression analysis of data from RRMS patients (N = 376) with severe acute MS relapses indicated that immunomodulatory treatment and lower EDSS score change during relapse best predicted better clinical outcomes.[22] In addition, a study of the long-term response to IFN-beta in 200 RRMS patients found that it is possible to predict at 2 years the clinical outcome at 5 years, with a combination of 2 out of 3 clinical and MRI criteria (relapse rate, EDSS progression, and presence of Gd-enhancing lesions).[23]

Reducing Progression of Disability

MS can follow different patterns of evolution and variable rates of disability accumulation. A prospectively planned analysis of BENEFIT trial data indicated that early initiation of IFN beta-1b treatment prevents accumulation of sustained disability in patients with a first event suggestive of MS.[24] Over the 3-year follow-up period, early treatment reduced the risk for confirmed progression of disability by 40% vs delayed treatment (HR 0.60, P = .022). The risk for CDMS remained 41% lower (HR 0.59, P = .0011). This finding supports the value of IFN beta-1b treatment in the very early phase of MS.

A community-based study indicated that the benefit of early IFN-beta treatment on long-term disability was greatest in high-risk RRMS patients (EDSS > 3 and > 1 bout).[25] Treatment started within 2 years from disease onset showed significant reductions of risk of nearly 90% for the high-risk and 47% medium-risk cohorts (EDSS 2-3).

Quality-of-Life Issues

MS has diverse effects on patients and their families, including its impact on physical, social, and psychological functioning. Collectively, this disruption in functioning represents the impact that MS has on health-related quality of life.

A cross-sectional study of 111 consecutive MS patients showed significant correlations between cognitive functioning and MS quality-of-life dimensions.[26] The worse the cognitive functioning scores, the lower the health-related quality of life.

Diagnosis disclosure had a positive impact on the quality of life of patients with CIS or MS, probably due to the decrease in uncertainty and consequent feeling of greater control over one's own physical condition.[27] Delaying progression to EDSS 6 is also important because it preserves a higher quality of life for MS patients.[28]

Fatigue and Depression

Depression and fatigue are among the leading contributors to deterioration to health-related quality of life in the early stages of MS. Although fatigue of MS patients has been described, knowledge of longitudinal variations in fatigue and of factors contributing to fatigue in MS is limited. A community study of 502 patients with definite MS found that that 37% had persistent fatigue, with depression, heat-sensitive fatigue, and physical impairment all independently associated with both sporadic and persistent fatigue.[29] Similarly, another longitudinal study found that signs of depression, weak or moderate sense of coherence, living with a partner, and not working were independent predictors of fatigue.[30]

The underlying etiology of fatigue is unclear, but a relation to active central nervous system inflammation is possible. Consistent with this hypothesis, several studies indicated that commonly used DMTs can ameliorate fatigue. Results from the FOCUS study, for example, indicated that GA may have a sustained positive effect on fatigue and quality of life in RRMS patients.[31] All Fatigue Impact Scale (FIS) domains were lower and quality of life was higher at month 12 than baseline. A community-based study in first-time-treated RRMS patients similarly found that 12-month GA treatment was associated with a significant decrease in fatigue symptoms (P ≤ .001) and an overall stable or slight decrease in disability (P ≤ .05).[32]

"Mild" benefits on fatigue and depression were also seen in a small open-label, longitudinal study of natalizumab, a monoclonal antibody directed against VLA4.[33] Fatigue Severity Scale (FSS) and total Modified Fatigue Impact Scale (MFIS) scores were significantly reduced (P = .03 and P = .04, respectively), as well as the Beck's Depression Inventory (BDI) score (P = .04).

The benefit of nonpharmacologic treatment on fatigue was demonstrated in a pilot fatigue management program blending cognitive-behavioral and energy effectiveness approaches. This approach produced significant improvements in levels of perceived self-efficacy for managing fatigue (P = .001) at 4-week follow-up in MS patients.[34]

However, patients with newly diagnosed MS employ less coping strategies important for adaptation to stress situations than healthy controls, possibly because depressive symptoms enhance avoidance strategies in which patients "hold back" and avoid dealing with stressful situations.[35]

Of note, a risk factor analysis indicated that the rate or value of depression occurs independently of the course of MS, duration of disease, or long-term treatment.[36] The major risk factor for depression was the severity of disability in MS. Similarly, a clinic-based study showed that fatigue and depression at baseline did not predict the development of secondary progression or progression of disability.[37] Most patients who were fatigued or depressed at baseline remained so at 10 years (74% and 67%), and the majority of patients not experiencing these symptoms remained free of them (59% and 61%).


Because sleep is known to have a substantial impact on perceived quality of life, it is important to determine the prevalence of, and factors associated with, sleep problems in MS. A survey of a large cross-sectional sample (N = 933) of community dwellers with MS indicated that sleep problems are a significant concern for most individuals with MS.[38] As assessed by the Medical Outcomes Study (MOS) Sleep Scale, 51.2% were categorized as having moderate or severe sleep problems. Depression accounted for 36% of the variance, whereas pain and fatigue accounted for only 3.6% and 0.4%, respectively.

Psychiatric Symptoms

The presence of psychiatric symptoms in MS has long been recognized. According to a clinic-based study, about 3% of MS patients could experience a psychiatric onset of MS (defined as major depressive episode, manic episode, psychotic disturbances, or panic disturbance).[39]

Cognitive Impairment

MS can also rarely present as a pure cognitive deficit, with a rapidly evolving brain injury and a poor functional outcome.[40] Several strategies showed some benefit in preserving cognitive function.

A retrospective study of the progression of cognitive impairment in MS (RRMS and SPMS) showed little change at a median follow-up of 3 years, possibly reflecting the effects of DMTs.[41] Phonologic fluency seemed to progress, but attentional ability improved in some cognitively preserved patients. Separately, cognitive rehabilitation targeting specific impairments in MS was shown to be effective to varying degrees in improving cognitive functioning.[42]

The Betaferon 16-year, long-term, follow-up study provided insight into cognition in the later stages of MS, indicating marked impairment levels, relative to published norms, in a broad panel of cognitive assessment tests.[43]

Cognitive dysfunction has been described in early MS, but few studies have addressed CIS. A study using a panel of bedside cognitive tests in matched patients with CIS (n = 23), definite early MS (n = 21), and ≥ 5-year definite MS (n = 22) indicated that patients' subjective perception of cognitive impairment was more common in CIS (35%) than definite early MS (10%), but most common in late MS (86%).[44] CIS and definite early MS performed similarly (and better than late MS) in visuoconstructive abilities and verbal memory.[44] Measuring cognitive status can assist in distinguishing between early and late MS.

Patient Adherence and Compliance With Therapy

A multivariate analysis of data from the Global Adherence Project (GAP) demonstrated that factors, including disease duration, type and frequency of DMT, education level, social support, ease of injection, and therapy satisfaction, influence treatment adherence.[45] Female gender (odds ratio [OR] 1.25), ease of injection (OR 1.47), and satisfaction with treatment (OR 1.54) were independently associated with an increased probability of treatment adherence. A separate study in RRMS patients treated with a DMT ≥ 3 months found that compliance was improved by the patients' own perception of their disease and treatment.[46] Compliance was significantly higher among patients who considered themselves well-informed about their disease and treatment (P < .05).

Results from the follow-up phase of the BENEFIT trials indicated satisfactory adherence to IFN beta-1b therapy.[47] Of the patients completing the double-blind phase, 80.8% opted for treatment with IFN beta-1b and 73.3% were still on treatment with IFN beta-1b at 3 years. The high proportion of patients opting for IFN beta-1b in the follow-up study and the high adherence rate after 3 years suggested that patients accepted this treatment.

Although efficacy data (from controlled trials) of the 4 DMTs -- IFN beta-1a (intramuscular or subcutaneous), IFN beta-1b, and GA exists -- evidence of effectiveness is needed. Results from a managed care claim-based analysis demonstrated that IFN beta-1a (intramuscular injection) may be more effective in a real-world setting than the other 3 DMTs.[48] Both at 1 and 2 years after treatment, a significantly higher number of IFN beta-1a (intramuscular injection) patients stayed on therapy and were less likely to discontinue treatment than comparators. At 1 year, for example, 62% of IFN beta-1a patients (P < .001) remained on therapy (ie, persistent) compared with IFN beta-1b (11%), IFN beta-1a (subcutaneous) (52%), and GA (54%). Furthermore, IFN beta-1a patients were also more likely to be compliant and take their medication as directed compared with IFN beta-1b.

Supported by an independent educational grant from Teva Neuroscience.


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