Disability Progression In Multiple Sclerosis Research Articles

Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis.

Vascular comorbidity adversely influences health outcomes in several chronic conditions. Vascular comorbidities are common in multiple sclerosis (MS), but their impact on disease severity is unknown. Vascular comorbidities may contribute to the poorly understood heterogeneity in MS disease severity. Treatment of vascular comorbidities may represent an avenue for treating MS. A total of 8,983 patients with MS enrolled in the North American Research Committee on Multiple Sclerosis Registry participated in this cohort study. Time from symptom onset or diagnosis until ambulatory disability was compared for patients with or without vascular comorbidities to determine their impact on MS severity. Multivariable proportional hazards models were adjusted for sex, race, age at symptom onset, year of symptom onset, socioeconomic status, and region of residence. Participants reporting one or more vascular comorbidities at diagnosis had an increased risk of ambulatory disability, and risk increased with the number of vascular conditions reported (hazard ratio [HR]/condition for early gait disability 1.51; 95% confidence interval [CI] 1.41-1.61). Vascular comorbidity at any time during the disease course also increased the risk of ambulatory disability (adjusted HR for unilateral walking assistance 1.54; 95% CI 1.44-1.65). The median time between diagnosis and need for ambulatory assistance was 18.8 years in patients without and 12.8 years in patients with vascular comorbidities. Vascular comorbidity, whether present at symptom onset, diagnosis, or later in the disease course, is associated with a substantially increased risk of disability progression in multiple sclerosis. The impact of treating vascular comorbidities on disease progression deserves investigation.

Relapses in multiple sclerosis

In this issue of Neurology ®, Tremlett et al.1 examine whether relapses influence disability progression in multiple sclerosis (MS), and specifically how the influence of relapses on disability progression differs by disease duration. This is important because of the implications of costly disease-modifying therapies and their potential long-term benefits; they clearly reduce relapse frequency but exhibit less impressive benefits on disability in clinical trials of 2 to 3 years’ duration.2 Prior studies of placebo groups from clinical trials suggest that relapses affect the accumulation of disability over short observation periods,3 while other studies using similar populations argued that relapses do not influence disability consistently.4 Investigators examining the Lyon MS cohort suggested that relapses during the first 5 years after disease onset influence the speed of disability accumulation initially, but once a certain level of (irreversible) disability is reached, disability progression is independent of other factors.5 Tremlett et al. used a large population-based clinical database including 2,477 patients with more than 11,000 relapses to examine the effect of relapses throughout the disease course using 2 measures, the time to needing a cane (Expanded Disability Status Scale [EDSS] score = 6) and the time to developing secondary progressive MS (SPMS).1 They included the cumulative number of relapses in their regression model as a time-dependent covariate, a previously unused approach. Having relapses within …

Interferon-β1b Treatment in Neuromyelitis Optica

Background: The effects of interferon-β_1b (IFN-β_1b) administration in multiple sclerosis (MS) patients have been confirmed, however, those in neuromyelitis optica (NMO) patients have not been shown. In this study, we assessed the effects of IFN-β_1b treatment on disease exacerbation and disability progression in MS or NMO patients. Methods: We reviewed a series of 104 consecutive patients with relapsing-remitting MS (RRMS) (69) or NMO (35) treated with IFN-β_1b in the MS clinical center of a national hospital in Japan. Results: The relapse number in the RRMS patients significantly decreased within 1 year after IFN-β_1b treatment (p < 0.00001); however, that in the NMO patients did not show a significant decrease (p = 0.5601). The decrease in annualized relapse rates in each RRMS patient after treatment was significant (p < 0.01), but that in each NMO patient was not (p > 0.05). The change in Kurtzke’s Expanded Disability Status Scale score 1 year after treatment was higher in the NMO patients than in the RRMS patients (p = 0.0225). Conclusion: In NMO patients, IFN-β_1b treatment was not effective in reducing the relapse number and the disability progression.

Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease

The pathological substrate of progressive disability in multiple sclerosis is hypothesized to be axonal loss. Differences in the demographic, pathological and radiological features of patients with primary progressive compared with secondary progressive multiple sclerosis raise the question as to whether they actually represent separate clinical entities. So far, large pathological studies comparing axonal damage between primary progressive and secondary progressive multiple sclerosis have not been reported. In this clinico-pathological study we examined the cervical spinal cord in patients with primary and secondary progressive multiple sclerosis. Human cervical spinal cord was derived at autopsy from 54 patients (17 primary progressive, 30 secondary progressive and 7 controls). Tissue was stained immunohistochemically and examined to determine: (i) the number of surviving corticospinal tract axons; (ii) the extent of grey and white matter demyelination; (iii) the degree of inflammation inside and outside of lesions; and (iv) the relationship between demyelination and axonal loss. Associated clinical data was used to calculate expanded disability status scale for each patient preceding death. Motor disability in the primary progressive and secondary progressive groups was similar preceding death. Secondary progressive multiple sclerosis patients showed considerably more extensive demyelination of both the white and grey matter of the cervical spinal cord. The total number of corticospinal axons was equally low in primary progressive and secondary progressive multiple sclerosis groups versus controls. The reduction of axonal density in demyelinated regions compared to normal appearing white matter was significantly more extensive in primary progressive versus secondary progressive patients (33% reduction versus 16% reduction, P < 0.001). These findings suggest axonal loss is the pathological substrate of progressive disability in both primary progressive and secondary progressive multiple sclerosis with a common plaque-centred mechanism. More extensive axonal loss within areas of demyelination in primary progressive multiple sclerosis could explain high levels of axonal loss observed in these patients despite low levels of demyelination.

Patients’ Stratification and Correlation of Brain Magnetic Resonance Imaging Parameters with Disability Progression in Multiple Sclerosis

Aims: The objective was to correlate the change in the lesion load (LL) and brain atrophy in patients with multiple sclerosis (MS) with progression of clinical disability, represented by the Expanded Disability Status Scale (EDSS), and to test if stratification of patients according to magnetic resonance imaging (MRI) criteria can increase the predictive ability of MRI for MS clinical development. Methods: 181 patients with clinically definite relapsing-remitting MS underwent MRI for a period of up to 5 years. Grouping of patients according to the LL value at the study entry revealed a substantial increase in the Spearman rank correlation coefficient R. Results: For the low LL cohort of patients, we found a statistically significant correlation (R up to –0.71 with p < 0.01) of a later increase in the EDSS score (years 4 and 5) with increased brain atrophy in the first 2 years. For the high LL group, we found a statistically significant correlation (R up to 0.72 with p < 0.01) of a later increase in the EDSS score (years 4 and 5) with an increase in the LL value in the first year. Conclusions: We conclude that stratification of patients according to the MRI criterion (LL) can increase the predictive ability of MRI.

Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS

Background Gray matter (GM) pathology is an important component of the multiple sclerosis (MS) disease process. Accelerated gray matter atrophy has been observed in MS patients, but its relationship to neurological disability is not defined. This study was done to determine the relationship between whole brain, GM, and white matter (WM) atrophy and MS disability progression. Methods Patients with MS and Clinically Isolated Syndromes (CIS), and age- and gender-matched healthy controls were entered into an observational protocol. Baseline brain parenchymal fraction (BPF), GM fraction, and WM fraction, and change over 4 years were correlated with sustained disability progression over the entire study duration. Disability progression was measured using the Multiple Sclerosis Functional Composite (MSFC) and the Expanded Disability Status Scale (EDSS). Results Seventy MS and CIS patients and 17 HCs were studied for an average of 6.6 years (range, 3.6–7.8 years). At the final visit, 7 patients were classified as CIS, 36 as relapsing–remitting MS (RRMS), and 27 as secondary progressive MS (SPMS). Baseline whole brain, GM, and WM atrophy predicted EDSS > 6.0 at the last study visit. Twenty-one (33%) patients worsened using the EDSS to define disability progression; 29 (46%) worsened using MSFC to define disability progression. Patients with MSFC progression had significantly higher GM atrophy rates compared with patients who were stable on MSFC. White matter atrophy was similar in patients with and without disability progression. Atrophy rates were not different in patients with or without disability progression defined using EDSS. Conclusions Whole brain, GM, and WM atrophy predicted MS disability progression observed over the next 6.6 years. Gray matter atrophy rates over 4 years correlated with disability progression measured with the MSFC, but not EDSS. This indicates that MSFC defined disability progression is more closely linked to brain atrophy than EDSS defined disability progression, and provides important new insight into the poor correlation between MRI and clinical disability in MS. The findings confirm the clinical relevance of gray matter atrophy in MS.

Magnetic resonance imaging measures of brain and spinal cord atrophy correlate with clinical impairment in secondary progressive multiple sclerosis

Background Neuroaxonal loss is a pathological substrate of disability in progressive multiple sclerosis (MS) and can be estimated in vivo by measuring tissue atrophy on magnetic resonance imaging (MRI). While there is some evidence that brain atrophy correlates better with disability than T2 lesion load in secondary progressive MS, the clinical relevance of atrophy within specific regions of the central nervous system requires further evaluation. Methods Clinical and MRI examinations were performed in 117 subjects with secondary progressive MS. MRI analysis included measures of normalized brain volume (NBV), normalized grey matter (NGMV) and white matter volume (NWMV), central cerebral volume (CCV), spinal cord cross-sectional area (SCCA), and brain T2 and T1 lesion volume. Clinical assessments included the expanded disability status scale (EDSS) and MS functional composite (MSFC). Results All MRI measures correlated significantly with the MSFC score, with the strongest correlation being for the NBV (r = 0.47; P < 0.001). NBV and SCCA were the only significant independent predictors of the MSFC score in a stepwise regression model containing all the MRI measures, and SCCA was the only MRI measure to show a significant association with the EDSS. While NGMV had stronger correlations with the clinical variables than NWMV, NBV was more correlated with clinical impairment than either measure. Conclusions This data suggests that measures of atrophy, particularly of the whole brain and spinal cord, are relevant and useful disease markers in secondary progressive MS.

An investigation of the retinal nerve fibre layer in progressive multiple sclerosis using optical coherence tomography

Axonal loss is thought to be the predominant cause of disability in progressive multiple sclerosis (MS). The retinal nerve fibre layer (RNFL) is composed largely of unmyelinated axons of retinal ganglion cells, and is accessible to study with optical coherence tomography (OCT), giving a measure of axonal loss. OCT measures of the RNFL thickness (RNFLT) and macular volume were studied in 23 patients with primary progressive multiple sclerosis (primary progressive MS) (13 male; 10 female; mean age 52 years; median EDSS 6.0; mean disease duration 11 years), and 27 patients with secondary progressive multiple sclerosis (secondary progressive MS) (8 male; 19 female; mean age 50 years; median EDSS 6; mean disease duration 22 years). Of the patients with secondary progressive MS, 14 had clinical history of optic neuritis (ON) in a single eye; the remaining patients had not had ON. Twenty healthy controls (11 male; 9 female; mean age 46 years) had RNFLT and macular volume studied. Of the patients' eyes not previously affected by ON, both the mean RNFL thickness and macular volume were reduced when compared with control values. The mean RNFL thickness and macular volume were significantly reduced in secondary progressive MS, but not in primary progressive MS when compared with control RNFL thickness and macular volume. RNFL loss was most evident in the temporal quadrant, where significant reduction was seen in primary progressive MS versus controls and in secondary versus primary progressive MS. There were significant correlations of decreased RNFLT and macular volume with measures of visual acuity, low contrast visual acuity and visual field mean deviation in the MS patients. There are significant global reductions in RNFLT and macular volume in the eyes of secondary progressive MS patients not previously affected by ON, but not in primary progressive MS patients, compared with controls. This may indicate a difference in the extent of the pathological processes that cause axonal loss in the retina, and by inference the optic nerve, in secondary progressive MS and primary progressive MS.

Plasma lipid peroxidation and progression of disability in multiple sclerosis

Oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS), but its relation to disease progression is uncertain. To evaluate the relationship of plasma lipid peroxidation with progression of disability in MS, we measured blood plasma fluorescent lipid peroxidation products (PFLPP) levels in 23 patients with RRMS with a benign course, 32 with secondary progressive MS, 24 with primary progressive MS and 30 healthy controls. None of the patients had a relapse within the previous 3 months. Progression of disability was evaluated during a follow-up period of 5 years by the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). We found plasma PFLPP levels elevated in patients with MS compared with controls (P < 0.0001), but there was no difference between patients with a benign and progressive disease course. There was no correlation between PFLPP levels and worsening of disability on the EDSS and speed of progression on the MSSS. Our data suggest that there is no relation between the degree of oxidative stress in plasma and progression of disability in MS.

Disability Evolution in Multiple Sclerosis: How to Deal with Missing Transition Times in the Markov Model?

Markov modeling of disability progression in multiple sclerosis requires knowledge of all times of transitions from a given level of disability to the next level, but such data are often missing. We address methodological challenges due to partly missing transition times. To estimate the effects of prognostic factors on the risk of transitions between three consecutive disability levels, two methods were used to deal with missing data. Listwise deletion limited the analysis to subjects with complete data. Multiple imputation of missing data revealed that data were missing at random (MAR mechanism) and imputed the missing transition times from the Weibull model. The results were then compared with the full data set with the actual times established through chart review. Multiple imputation estimates were systematically closer to those from the full data set than the listwise deletion estimates.

Measuring disability progression in multiple sclerosis

■ Abstract The management of patients with relapsing-remitting multiple sclerosis is difficult for the treating physician due to the extremely variable clinical course of the disease, with widely differing rates of progression of disability observed between patients. The determinants of this variability are unknown. Life table analysis provides a method to classify patients on the basis of initial disability scores into percentiles that define their probability of disease progression over a 10-year period. Using this method, a series of standardised disease progression curves have been generated by analysis of disability data in over one thousand subjects with multiple sclerosis, obtained from Sheba Medical Center, Tel-Hashomer, Israel, database. These curves show acceptable validity for predicting disease progression in individual patients. The comparison of individual patient data against these standardised disability progression curves provides a useful method to assess the risk of progression in individual patients and enables practising neurologists to use a valuable tool for making treatment decisions.

Mediators of apoptosis Fas and FasL predict disability progression in multiple sclerosis over a period of 10 years

TNF-α, IL-12p35, IL-12p40, IL-4, IL-10, TGF-β1, CCR3, CXCR3, CCR5, Fas and FasL mRNA levels in PBMC of 25 multiple sclerosis (MS) patients were quantified at baseline by real-time PCR according to a post-hoc study design. The baseline values of the different markers were analysed with respect to their correlation with the increase in disability over a period of 10 years. High levels of Fas mRNA were associated with a favourable disease course in relapsing-remitting (RR) MS (R2 = 0.74, P = 0.0001, n = 13), as measured by the Expanded Disability Status Scale (EDSS); high levels of FasL mRNA were associated with relatively mild disease progression (R2 = 0.86, P = 0.0001, n = 12) in secondary progressive (SP) MS. These findings suggest that Fas-mediated apoptosis plays a major role in the mechanism underlying long-term disease progression in MS.

Disability progression in multiple sclerosis is slower than previously reported

To investigate disease progression and risk factors in a large geographically based population with multiple sclerosis (MS), using two different inception points--clinical onset and date of birth. The authors reviewed a database of subjects with definite MS and symptom onset prior to July 1988. The main outcome was sustained progression to Expanded Disability Status Scale (EDSS) 6 (requires a cane), using the date of birth and date of MS onset as inception points in separate analyses. Risk factors examined were sex, relapsing vs primary progressive course, onset age, and onset symptoms. The study included 2,837 patients, followed prospectively for 22,723 patient years. The median time to EDSS 6 was 27.9 years, 15 years after onset; only 21% reached EDSS 6, and by age 50, 28% required a cane. Men progressed 38% more quickly than women from onset (p < 0.0005), yet both required canes at similar ages: 58.8 years for men and 60.1 for women (p = 0.082). A younger onset age predicted a slower progression, but those older at onset were consistently older when reaching EDSS 6. A primary progressive course predicted a more rapid progression from both onset (p < 0.0005) and birth (hazard ratio = 2.7 [95% CI: 2.2 to 3.3]). No onset symptom consistently predicted progression. Disability progression in multiple sclerosis (MS) accrued more slowly than found in earlier longitudinal studies. The authors also challenged two fundamental concepts in MS, demonstrating that neither male sex nor older onset age was associated with worse disease outcome.

Psychosis as a possible side-effect of treatment with glatiramer acetate

Multiple sclerosis (MS) is a common neurological disorder in younger adults. After an initial phase, which is characterized by complete or partial remission of neurological deficits (relapsing/remitting form), the illness enters a progressive phase with accumulation of neurological disability. Glatiramer acetate (GA, copolymer 1) is a new drug, which has recently been approved for the treatment of relapsing MS. GA is a synthetic mixture of relatively short polypeptides with a molecular weight between 4.7 and 10 kDa consisting of a random sequence of the four amino acids l-alanine, l-lysine, l-glutamic acid, and l-tyrosine. The substance is supposed to inhibit myelin-reactive T cells, to promote the induction of anti-inflammatory Th2 and CD8+ T cells, thus suppressing autoimmune responses in the CNS. Additional neuroprotective and repair mechanisms may be the result of local accumulation of GA-reactive T cells. In randomized, double-blind, placebo-controlled clinical trials the compound has been shown to reduce the relapse rate and to slow progression of disability in MS (Bornstein et al., 1991; Johnson et al., 2000). Side-effects of the drug were assessed, and GA was claimed as a well-tolerated drug (Johnson et al., 2001). Mild local injection site reactions occur in 90% of patients, while 15% of patients experience an immediate post-injection reaction with flushing, chest tightness, shortness of breath, palpitation and anxiety.

Relating neocortical pathology to disability progression in multiple sclerosis using MRI

Cortical grey matter (cGM) develops a substantial burden of pathology in multiple sclerosis (MS). Previous cross-sectional studies have suggested a relationship between measures of cortical atrophy and disability. Our objective was to develop a method for automatically measuring the apparent cGM thickness as well as the integrity of the interface between cGM and subcortical white matter (GM/WM) both globally and regionally on T(1)-weighted MRI, and use this method in a longitudinal investigation of how these measures differed between patients with stable MS and patients with progressing disability. Measurements were made over the whole brain and for anatomically specified cortical regions, both cross-sectionally at baseline and longitudinally on two MRI scans performed on average 1 year apart. We found a higher average rate of apparent loss of cGM thickness across the whole brain in the group that progressed over the interscan interval compared to the group that remained stable (progressing = -3.13 +/- 2.88%/year, stable = 0.06 +/- 2.31%/year, P = 0.002). This difference was detected with regional measures in parietal and precentral cortex. In contrast, change in the GM/WM interface integrity did not show detectable regional differences, although the group of MS patients whose disability progressed showed a significant decrease in GM/WM interface integrity compared to the stable group (P = 0.003). Regional measures of apparent loss of cGM thickness enhance sensitivity to cortical pathological changes. A measure of integrity offers a new index of disease-associated cortical changes at the GM/WM interface. The results suggest that progression of disability in MS is associated with the progression of MRI-detectable cortical pathology.

Prevention of autoimmune attack and disease progression in multiple sclerosis: current therapies and future prospects.

Multiple sclerosis (MS) is an important cause of progressive neurological disability, typically commencing in early adulthood. There is a need for safe and effective therapy to prevent the progressive central nervous system (CNS) damage and resultant disability that characterize the disease course. Increasing evidence supports a chronic autoimmune basis for CNS damage in MS. In the present study, we review current concepts of autoimmune pathogenesis in MS, assess current therapies aimed at countering autoimmune attack and discuss potential therapeutic strategies. Among currently available therapies, beta-interferon and glatiramer acetate have a modest effect on reducing relapses and slowing the accumulation of disability in relapsing-remitting MS. Beta-interferon is of doubtful efficacy in secondary progressive MS and appears to aggravate primary progressive MS, possibly by increasing antibody-mediated CNS damage through inhibition of B-cell apoptosis. Mitoxantrone may reduce relapses and slow disability progression in relapsing-remitting and secondary progressive MS, but its use is limited by the risk of cardiomyopathy. There are currently no effective treatments for primary progressive MS. Many therapies that are effective in the animal model, experimental autoimmune encephalomyelitis (EAE), are either ineffective in MS or--in the case of gamma-interferon, lenercept and altered peptide ligands--actually make MS worse. This discrepancy may be explained by the occurrence in MS of defects in immunoregulatory mechanisms, the integrity of which is essential for the efficacy of these treatments in EAE. It is likely that the development of safe, effective therapy for MS will depend on a better understanding of immunoregulatory defects in MS.

Age-related disability in multiple sclerosis.

There is evidence that the clinical course of multiple sclerosis is age related. The present study evaluated the relationship between age and rate of disability progression in a large hospital-based cohort of definite cases of multiple sclerosis (n= 1,463). Patients were followed every 6 to 12 months for a total period of observation of 11,387.8 person-years. Expanded Disability Status Scale scores increased significantly with increasing current age and longer duration of disease (p=0.007). Median times to reach Expanded Disability Status Scale scores of 4.0 and 6.0, assessed using an extended Kaplan-Meier method with age as a categorical time-varying covariate, were significantly longer among patients aged 20 to 35 years compared with patients aged 36 to 50 and 51 to 65 years (p < 0.0001). Significant associations were observed between mean Expanded Disability Status Scale scores and age at disease onset, current age, and the interaction of age at disease onset and current age (p < 0.001). Current age had a greater effect (59% of variability in the model) on disease severity than did age at disease onset. Furthermore, a multiplicative effect on Expanded Disability Status Scale score was observed for age at disease onset and current age combined, indicating a faster rate of disease progression in older patients. In conclusion, the results of the current study demonstrate the impact of age on rate of disability progression in multiple sclerosis and suggest that an age-adjusted progression index may be a more relevant criterion for defining differences between multiple sclerosis groups.

Systemic disease and neuro-ophthalmology: annual update 2000 (Part I).

Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system (1–86), with substantial long-term neurologic consequences (1,4,9,25,34, 52,54,55,57,60,63,65). After 10 years with MS, 50% of patients are unable to perform household and occupational responsibilities; after 15 to 20 years, 50% are unable to walk without assistance; after 25 years, 50% are unable to ambulate. The average annual cost of MS in the United States is greater than 6.8 billion dollars (1). There are three main subtypes of the disease: relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP). This update reviews the current status of MS therapy (1–86). We have chosen to focus on the new and emerging immunomodulatory therapies for disease relapses and the treatments to prevent disease progression. We do not review the treatments for common MS-related sensory and motor symptoms, fatigue, or depression (35).

Cost-effectiveness of interferon beta-1b in slowing multiple sclerosis disability progression. First estimates.

To estimate the cost-effectiveness (CE) of interferon beta-1b (IFN beta-1b) in slowing disability progression in persons with relapsing-remitting multiple sclerosis (RRMS). Treatment program costs and health outcomes are modeled for cohorts of 1,000 females and 1,000 males followed 40 years from onset. Fifteen scenarios model MS natural history progression, treatment efficacy, direct treatment costs, and MS healthcare costs. A single randomized placebo-controlled trial of IFN beta-1b found reduced disease activity by MRI, reduced frequency and severity of exacerbations, and a tendency toward slower disability progression. Disability years avoided are modeled as the primary health outcome analyzed. A ministry of health (MOH) perspective is adopted, using Nova Scotia population-based data. Annual IFN beta-1b direct treatment costs (Can $16,685) are high relative to both MOH healthcare costs per person with MS (Can $2,000) and estimated MOH costs avoided. Given "reference case" assumptions for women with RRMS, treatment reduces lifetime disability years by 10%. Cost per disability year avoided before discounting is Can $189,230 (US $124,892), and Can $274,842 (US $181,395) after discounting at 5%. Estimates for alternative scenarios vary greatly, leaving main findings unchanged. Using the Expanded Disability Status Scale, cost per disability year avoided due to interferon beta-1b treatment in RRMS is quite high. Comparable CE estimates, using MS-specific or generic health-related quality-of-life outcome measures, are even higher. Further research is required to better measure treatment effects, modification of MS natural history, and net societal costs of IFN beta-1b in RRMS.