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1.  Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors 
OBJECTIVE—To establish the characteristics of patients following a benign course of multiple sclerosis and evaluate the importance of potential prognostic factors. Also, an assessment of the value of the Kurtzke EDSS as a prognostic indicator has been undertaken in patients previously determined to have benign multiple sclerosis, after 10 years of follow up.
METHODS—A prevalence study in the Coleraine, Ballymena, Ballymoney, and Moyle districts of Northern Ireland used the Kurtzke expanded disability scale score (EDSS) in 259 patients with multiple sclerosis. Of these, 181 had had multiple sclerosis for⩾10 years, 36 having benign disease (EDSS⩽3.0) ⩾10 years after onset. Clinical and demographic details of the various patient groups, including the minimal record of disability, were compared. The 1987 study in Northern Ireland identified 33 patients with benign multiple sclerosis. Twenty eight were available for follow up in 1996 along with 42contemporary non-benign patients.
RESULTS—Patients with benign multiple sclerosis were predominantly women (ratio 4.1:1 v 2.1:1) and younger at onset (25.8 v 31.2 years). Commonest symptoms at onset were sensory and optic neuritis (33.3% each). Patients with late onset (older than 40 years) were less likely to have a benign course, more likely to have a progressive course from onset, significantly more likely to have motor disturbance at presentation, and had a lesser female predominance. Optic neuritis was significantly more common in those with a younger age at onset. In the follow up study, patients with benign multiple sclerosis continued to have a more favourable course than non-benign counterparts but progression of disability and to the secondary progressive phase remained significant. 
CONCLUSIONS—The association of female sex, early onset, and presentation with optic neuritis and sensory symptoms with a favourable course is confirmed. However, although the EDSS does provide a useful indicator of prognosis, the label "benign multiple sclerosis" is often temporary as apparently benign disease often becomes disabling.

PMCID: PMC1736487  PMID: 10406979
2.  Visual Pathway Axonal Loss in Benign Multiple Sclerosis: A Longitudinal Study 
Benign MS, traditionally defined as EDSS ≤3 and ≥15 years’ disease duration, is thought to follow a milder course. We determined the extent of visual pathway axonal loss by optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness in a benign MS cohort, and examined the relation to vision and quality of life (QOL).
In this longitudinal study of vision in MS at three academic centers, a subset of patients with EDSS, visual function, OCT, and QOL assessments was analyzed. Low- and high-contrast letter acuity were performed to assess visual function. RNFL thickness was determined using OCT-3. QOL scales included the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and SF-36.
Among 68 patients (135 eyes) studied longitudinally, 13 (26 eyes) had benign MS using criteria of EDSS ≤3 and ≥15 years disease duration. Benign MS eyes had as much RNFL thinning (-3.6 μm, P=0.0008 vs. baseline, paired t-test) as typical MS eyes (-3.3 μm, P<0.0001). Both groups had significant low-contrast acuity loss. Prior history of optic neuritis (ON) was more frequent in benign MS (69% vs. 33% of eyes). History of ON distinguished benign vs. typical MS (P=0.002) and correlated with RNFL thickness at baseline (P=0.002) and disease duration (P=0.03), but not EDSS (P=0.32, logistic regression). NEI-VFQ-25 scores were also worse for benign MS, accounting for age (75±21 vs. 88±11, P=0.005).
Patients with benign MS have RNFL axonal loss that is as marked as that of typical MS, and have reduced vision and QOL. While overall neurologic impairment is mild, visual dysfunction, not well-captured by the EDSS, accounts for a substantial degree of disability in benign MS.
PMCID: PMC3427935  PMID: 22269944
multiple sclerosis (MS); visual function; optical coherence tomography (OCT); quality of life
3.  Validating Predictors of Disease Progression in a Large Cohort of Primary-Progressive Multiple Sclerosis Based on a Systematic Literature Review 
PLoS ONE  2014;9(3):e92761.
New agents with neuroprotective or neuroregenerative potential might be explored in primary-progressive Multiple Sclerosis (PPMS) - the MS disease course with leading neurodegenerative pathology. Identification of patients with a high short-term risk for progression may minimize study duration and sample size. Cohort studies reported several variables as predictors of EDSS disability progression but findings were partially contradictory.
To analyse the impact of published predictors on EDSS disease progression in a large cohort of PPMS patients.
A systematic literature research was performed to identify predictors for disease progression in PPMS. Individual case data from the Sylvia Lawry Centre (SLC) and the Hamburg MS patient database (HAPIMS) was pooled for a retrospective validation of these predictors on the annualized EDSS change.
The systematic literature analysis revealed heterogeneous data from 3 prospective and 5 retrospective natural history cohort studies. Age at onset, gender, type of first symptoms and early EDSS changes were available for validation. Our pooled cohort of 597 PPMS patients (54% female) had a mean follow-up of 4.4 years and mean change of EDSS of 0.35 per year based on 2503 EDSS assessments. There was no significant association between the investigated variables and the EDSS-change.
None of the analysed variables were predictive for the disease progression measured by the annualized EDSS change. Whether PPMS is still unpredictable or our results may be due to limitations of cohort assessments or selection of predictors cannot be answered. Large systematic prospective studies with new endpoints are needed.
PMCID: PMC3961431  PMID: 24651401
4.  Relapsing–Remitting Multiple Sclerosis: Patterns of Response to Disease-Modifying Therapies and Associated Factors: A National Survey 
Neurology and Therapy  2014;3(2):89-99.
Current treatments for relapsing–remitting multiple sclerosis (RRMS) are only partially effective. The objective of this study was to characterize treatment response in RRMS patients in Portugal to 12-month therapy with first-line disease-modifying therapies.
In this retrospective study, neurologists at participating centers completed survey questionnaires using records of patients with RRMS who had received first-line treatment with one of five European Medicine Agency-approved agents in the 12 months prior to inclusion in the survey. Sub-optimal responders included patients treated for at least 1 year, and who had ≥1 relapse(s) or an increase of 1.5 points on the Expanded Disability Status Scale (EDSS; if baseline EDSS was 0) or an increase of ≥0.5 points (baseline EDSS ≥1). Optimal responders included patients treated for at least 1 year without relapse and who had an increase of <1.5 points on EDSS (if baseline EDSS was 0) or no increase in EDSS (baseline EDSS ≥1).
Data for 1,131 patients from 15 centers were analyzed. Twenty-six percent (95% confidence interval 23–28%) of patients had sub-optimal treatment response. Duration of therapy (P < 0.001), age at the start of therapy (P = 0.03), and baseline EDSS score (P < 0.001), were significantly different among treatments. Sub-optimal treatment response appeared to be related only to a more severe EDSS score at baseline and did not differ among therapies.
Neurologists should closely monitor patients to optimize treatment strategies and better control disease, improving prognosis.
Electronic supplementary material
The online version of this article (doi:10.1007/s40120-014-0019-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4386429  PMID: 26000225
β-Interferons; Disease-modifying therapies; Glatiramer acetate; Neurology; Relapsing–remitting multiple sclerosis
5.  Mitoxantrone in worsening secondary progressive multiple sclerosis: A prospective, open-label study 
An antineoplastic agent, mitoxantrone (MX) is used to treat neurologic disability and/or reduce the frequency of clinical relapses in patients with secondary progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (MS). Based on a MEDLINE search for literature concerning the use of IV MX in patients with secondary progressive MS (SPMS), there is a paucity of data to identify the clinical characteristics of responders.
The aim of this study was to monitor the effects of IV MX in patients with SPMS and varied clinical characteristics whose condition continued to worsen despite receiving IV methylprednisolone treatment.
This prospective, open-label study was conducted at the Multiple Sclerosis Clinic, Center for Neurologic Disorders, Milwaukee, Wisconsin. Male and female patients aged ≥18 years with SPMS whose neurologic condition, as assessed using routine neurologic examination, worsened despite at least one 5-day course of IV methylprednisolone treatment (1 g/d) were enrolled. Patients received premedication with an antiemetic and IV MX 12 mg/m2 every 12 weeks for up to 2 years, with a total cumulative dose not to exceed 96 mg/m2. All patients were followed up for 1 year after treatment cessation. Efficacy was assessed at baseline, end of treatment, and 1-year follow-up using the Extended Disability Status Scale (EDSS) (which measures the functional disability level) (0 = normal findings on neurologic examination to 10 = death from MS complications). Tolerability was assessed before, during, and immediately after each infusion and at 2 weeks after each infusion, using direct questioning of, and spontaneous reporting by, the patients; physical examination; and laboratory assessments. Cardiac multigated acquisition scanning was performed at baseline and every 24 weeks during the treatment period.
Forty-eight patients were enrolled (28 women, 20 men; mean [SD] age, 47.6 [8.6] years; mean [SD] disease duration, 12.5 [6.0] years; mean [SD] baseline EDSS score, 6.9 [1.2]). Twenty-three patients completed the entire course of treatment; the remaining 25 were withdrawn after 1 year of treatment due to lack of efficacy (22 patients), asymptomatic cardiac ejection fraction <40% (2), and severe septicemia and worsening of MS requiring extended respiratory support and hospitalization (1). Patients who completed only 1 year of treatment were younger compared with those who completed 2 years (mean age, 45.2 vs 50.1 years; P < 0.05). No significant change in mean EDSS score was found at the end of treatment or at 1-year posttreatment follow-up. In patients whose disability improved by 2–0.5 on the EDSS (11 patients at 1 year; 5 patients at 2 years), the degree of improvement noted at 1-year follow-up in patients with a baseline EDSS score 3.0 to 5.5 versus 6.0 to 7.5 and 8.0 to 9.0 was significant (both, P < 0.05). Severe adverse effects occurred in 14.6% of patients and included marked leukopenia (peripheral white blood cell count, <100 cells/μL) with urosepsis, requiring hospitalization in 7 patients, 1 of whom developed severe septicemia and worsening of MS, requiring >4 weeks of respiratory support. Cardiac ejection fraction decreased to <40% in 2 patients after 1 year of treatment (total dose, 48 mg/m2). These 2 patients were asymptomatic, but the investigators decided to discontinue treatment. Cardiac function returned to normal range (but not to near-baseline levels) within 12 weeks after treatment cessation. Although all patients were premedicated with antiemetics, 10 (20.8%) reported mild nausea (treated with repeat administration of antiemetics), and 2 of 16 (12.5%) premenopausal patients reported slightly increased bleeding during menstruation after l year of IV MX therapy, requiring no medical therapy or adjustment in the treatment protocol.
Based on the results of this study in this small group of patients with worsening SPMS, IV MX treatment for up to 2 years was not associated with a significant change in EDSS score at the conclusion of treatment or 1 year after treatment cessation.
PMCID: PMC3965966  PMID: 24678083
mitoxantrone; multiple sclerosis; responders; nonresponders
6.  Gray Matter Atrophy Correlates With MS Disability Progression Measured with MSFC But Not EDSS 
Journal of the neurological sciences  2008;282(1-2):106-111.
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.
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).
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.
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.
PMCID: PMC2726444  PMID: 19100997
7.  Cerebrospinal fluid detection of interleukin-1β in phase of remission predicts disease progression in multiple sclerosis 
Absence of clinical and radiological activity in relapsing–remitting multiple sclerosis (RRMS) is perceived as disease remission. We explored the role of persisting inflammation during remission in disease evolution.
Cerebrospinal fluid (CSF) levels of interleukin 1β (IL-1β), a major proinflammatory cytokine, were measured in 170 RRMS patients at the time of clinical and radiological remission. These patients were then followed up for at least 4 years, and clinical, magnetic resonance imaging (MRI) and optical coherence tomography (OCT) measures of disease progression were recorded.
Median follow-up of RRMS patients was 5 years. Detection of CSF IL-1β levels at the time of remission did not predict earlier relapse or new MRI lesion formation. Detection of IL-1β in the CSF was instead associated with higher progression index (PI) and Multiple Sclerosis Severity Scale (MSSS) scores at follow-up, and the number of patients with sustained Expanded Disability Status Scale (EDSS) or Multiple Sclerosis Functional Composite worsening at follow-up was higher in individuals with detectable levels of IL-1β. Patients with undetectable IL-1β in the CSF had significantly lower PI and MSSS scores and a higher probability of having a benign MS phenotype. Furthermore, patients with undetectable CSF levels of IL-1β had less retinal nerve fiber layer thickness and macular volume alterations visualized by OCT compared to patients with detectable IL-1β.
Our results suggest that persistence of a proinflammatory environment in RRMS patients during clinical and radiological remission influences midterm disease progression. Detection of IL-1β in the CSF at the time of remission appears to be a potential negative prognostic factor in RRMS patients.
PMCID: PMC3975953  PMID: 24548694
Cerebrospinal fluid; Cytokines; Inflammation; Disability; Neurodegeneration; Remission
8.  Clinical baseline factors predict response to natalizumab: their usefulness in patient selection 
BMC Neurology  2014;14:103.
Optimal patient selection would improve the risk-benefit ratio of natalizumab treatment for relapsing-remitting multiple sclerosis (RR MS). Clinical features of subjects responding to natalizumab have not been univocally recognized.
Longitudinal data on RR MS patients treated with natalizumab in Liguria, Italy are reported. Predictors of relapse occurrence and disability improvement were analyzed with a logistic regression method in subjects treated for one year (N = 62). A new score, called “Better EDSS Trend (BET)”, was devised to describe the impact of the treatment on disability. Changes in annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) after one and two years and proportion of disease-free patients were evaluated.
Previous EDSS worsening plus ARR ≥ 2 increased the risk of relapse during the treatment [Odds Ratio (OR) 4.12, P = 0.04], but this was not associated with an increase in disability at one year. EDSS 3.0-3.5 or high disease activity were associated with neurological improvement in the first year of treatment (respectively OR 5.78, P = 0.05 and OR 4.80, P = 0.05). Positive BET score, i.e. improvement in the disability trend, was observed in 40.3% of patients, and correlated with high ARR in the year before treatment (OR 1.69, P = 0.03).
Subjects with EDSS 3.0-3.5 and those with very active disease in the year before treatment are most likely to improve in neurological function under natalizumab. A relapse in the first year of treatment is associated to high pre-treatment disease activity; however, since the occurrence of a relapse did not have a negative impact on clinical improvement at one year, we suggest that it should not lead to treatment discontinuation. We propose BET as an additional endpoint of treatment response in MS.
PMCID: PMC4045962  PMID: 24885703
Multiple sclerosis; Natalizumab; Neuropharmacology; Clinical neurology
9.  The HV3 Score: A New Simple Tool to Suspect Cognitive Impairment in Multiple Sclerosis in Clinical Practice 
Neurology and Therapy  2014;3(2):113-122.
Cognitive impairment in multiple sclerosis (MS) is common even in the early stages of the disease. Our objective was to improve early detection of cognitive impairment in MS.
Seventy-five patients with relapsing remitting (RR) MS and 20 controls were enrolled. Two RRMS groups were defined according to their results at the Paced Auditory Serial Addition Test (PASAT). Patients with a z score below two standard deviations were considered impaired. We quantified T2 and T1 lesion volumes, and cerebral white and grey matter volumes on a conventional brain magnetic resonance imaging (MRI) scan. Global brain atrophy was evaluated using the third ventricle (V3) width (in mm). An average brain model was built based on controls and compared with the patient’s MRI to quantify regional volumetric changes.
Sixteen (21.3%) patients with RRMS had low PASAT performance. They had a higher Expanded Disability Status Scale (EDSS) score (P = 0.019). T2 and T1 lesion volumes, and grey and white matter volumes were the same in both groups. An enlargement of the V3 width was observed in the low performer group (P = 0.044) and V3 width was correlated with the PASAT score (r = −0.271; P = 0.021). A composite score, named HV3, was obtained by adding the EDSS and V3 width (in mm) and correlated with the PASAT (r = −0.325; P = 0.006). A cutoff HV3 score of over 5.5 identified patients with low PASAT performance, with a positive predictive value of 92.5% and an accuracy of 70.1%. Focal atrophy was detected in the supplementary motor area, the cingulate gyrus, the right thalamus, and the inferior parietal lobules of patients with lower PASAT performance.
Specific brain morphological changes, including an enlargement of the V3 width, are associated with low PASAT performance in patients with RRMS. The HV3 score is an additional and complementary tool, accessible in clinical practice, to suspect easily cognitive impairment in patients with RRMS and to better identify patients requiring a complete cognitive assessment.
Electronic supplementary material
The online version of this article (doi:10.1007/s40120-014-0021-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4386426  PMID: 26000227
Brain atrophy; Brain MRI; Cognitive impairment; Multiple sclerosis; V3 width
10.  Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study 
Evoked potentials are used in the functional assessment of sensory and motor pathways. Their usefulness in monitoring the evolution of multiple sclerosis has not been fully clarified.
The aim of this longitudinal study was to examine the usefulness of multimodal evoked potential in predicting paraclinical outcomes of disease severity and as a prognostic marker in multiple sclerosis.
Eighty four patients with clinically definite multiple sclerosis underwent Expanded Disability Status Scale (EDSS) and functional system scoring at study entry and after a mean (standard deviation) follow‐up of 30.5 (11.7) months. Sensory and motor evoked potentials were obtained in all patients at study entry and at follow‐up in 64 of them, and quantified according to a conventional score.
Cross‐sectionally, the severity of each evoked potential score significantly correlated with the corresponding functional system (0.32
These results suggest that evoked potential is a good marker of the severity of nervous damage in multiple sclerosis and may have a predictive value regarding the evolution of disability.
PMCID: PMC2077734  PMID: 16735397
OBJECTIVES—Recent phase III clinical trials of immunomodulatory therapies in relapsing-remitting multiple sclerosis have shown significant benefits of active treatment on relapse related end points, but effects on disability outcomes have been inconsistent. These apparent discrepancies could be due to differences in the clinical end points employed, the behaviour of placebo cohorts, or both.
METHODS—Disability data from the placebo cohorts of two large phase III studies, the United States glatiramer acetate trial (Copolymer 1 Multiple Sclerosis Study Group) and the multinational interferon β-1a trial (PRISMS Study Group) were combined and masked (n=313). Two groups of disability outcome measures were assessed. Firstly, measures of disability change (2 year EDSS difference and area under the EDSS/time curve, AUC) were calculated. Secondly, conventional disease progression end points ("confirmed progression" and "worsening to EDSS 6.0") were evaluated by using Kaplan-Meier analysis and compared with a categorical classification based on EDSS trends.
RESULTS—The average increase in disability for the entire cohort as assessed by mean 2 year EDSS change (<0.5 EDSS point) or mean AUC (+0.57 EDSS-years) was small. For the "confirmed progression" end points, increasing the stringency of the definition lowered their incidence (from 32% with 1.0 point at 3 months, to 9% with 2.0 points at 6 months), but did not improve the positive predictive accuracy for "sustained progression" maintained to the end of the study. The error rate for this outcome was about 50%. Worsening to EDSS 6.0 was a more reliable end point, but had even lower sensitivity (incidence <10%). EDSS trend analysis showed markedly heterogeneous disease courses, which were then categorised into "stable" (26%), "relapsing-remitting" (59%), and "progressive" (15%) courses. Patients with the last course had deteriorated considerably by the end of 2 years (mean worsening of 2.0 EDSS points).
CONCLUSION—In relapsing-remitting multiple sclerosis treatment trials, the conventional measure of mean EDSS change has low sensitivity, whereas the widely applied confirmed progression end points have high error rates regardless of their definition stringency. Alternative methods with better data utilisation include AUC summary measures and categorical disease trend analysis. The heterogeneity of disability outcomes in short trials, combined with unreliable clinical end points, diminishes the credibility of therapeutic claims aimed at reducing irreversible neurological deficits. The behaviour of patients treated with placebo should be carefully analysed before conclusions are drawn on the efficacy of putative treatments.

PMCID: PMC1736854  PMID: 10727480
Therapeutic options in progressive forms of multiple sclerosis (MS) are still limited. Dimethyl fumarate (DMF) has immunomodulatory properties but may also exert antioxidative cytoprotective effects. Hence, it may be a therapeutic option for progressive MS. The aim of this observational study was to evaluate safety, adherence and efficacy of fumarates in patients with primary progressive MS (PPMS) or secondary progressive MS.
Patients with progressive MS whose condition had failed to respond to standard therapies and had worsened received the fumarate mixture Fumaderm, licensed for psoriasis therapy in Germany, or DMF by pharmaceutical preparation (Bochum ethics approval no. 4797-13). At regular follow-up visits, tolerability and disease course were assessed.
Twenty-six patients [age 54 ± 7.8 years; female = 13 (50%); PPMS = 12 (46.2%); Expanded Disability Status Scale (EDSS) = 6.0 ± 0.4 (range 3.5–8.0); disease duration = 14.1 ± 8.7 years] were initiated on treatment with Fumaderm (n = 18) or pharmacy-prepared DMF (n=8). During a mean follow-up period of 13.2 ± 7.5 months (range 6–30) only five patients (19.2%) reported minor complaints. In 15 patients (57.7%) EDSS remained stable. In five cases (19.2%) there was even a decrease in EDSS while in six patients (23.1%) there was an increase in EDSS of more than 0.5 points, reflecting deterioration. Laboratory values were controlled for lymphopenia, renal and hepatic values, without any safety problems. We observed no significant differences between the two pharmaceutical forms.
Our pilot data indicate that fumarate therapy appears to be safe and well tolerated by patients with progressive MS. In more than 75% of cases no further disease progression was evident. However, controlled studies are warranted to evaluate the detailed therapeutic potential of fumarates and their long-term effects in progressive MS.
PMCID: PMC4206620  PMID: 25342977
antioxidative; cytoprotective; fumarate; neurodegeneration; progressive multiple sclerosis
The aims of this study were to determine the reliability, responsiveness and minimally important change score of the Multiple Sclerosis Impact Scale (MSIS)‐29 physical using the Expanded Disability Status Scale (EDSS) as an anchor measure.
214 patients with multiple sclerosis (MS) (EDSS 0–8.5) had concurrent MSIS‐29 and EDSS assessments at baseline and at up to 4 years of follow‐up.
116 patients had unchanged EDSS scores. Stability of the MSIS‐29 physical (mean change 0.1 points) was better in the 85 patients with EDSS 0–5.0 than in the 31 patients with EDSS 5.5–8.5 in whom the MSIS‐29 physical score fell by 8 points, a response shift phenomenon. A floor effect for the MSIS‐29 was observed in 5% of stable patients at both time points. 98 patients experienced EDSS change with moderately strong statistically significant correlations between change scores in the EDSS and the MSIS‐29 physical (r = 0.523, p<0.0001). Effect sizes for MSIS‐29 physical change were moderate to large. Using receiver operating characteristic curves, the MSIS‐29 change score which produced a combination of optimal sensitivity and specificity was chosen for both EDSS ranges. For EDSS range 5.5–8, a change score of 8 had a sensitivity of 87% and specificity of 67%. For EDSS 0–5.0, a change score of 7 had a sensitivity of 78% and a specificity of 51%.
The MSIS‐29 physical performs well over time, and is suitable for use in trials; a minimal change score of 8 points in the MSIS‐29 is clinically significant.
PMCID: PMC2117755  PMID: 17332049
PLoS ONE  2012;7(10):e46871.
Benign multiple sclerosis (BMS) occurs in about 15% of patients with relapsing-remitting multiple sclerosis (RRMS) that over time do not develop significant neurological disability. The molecular events associated with BMS are not clearly understood. This study sought to underlie the biological mechanisms associated with BMS. Blood samples obtained from a cohort of 31 patients with BMS and 36 patients with RRMS were applied for gene expression microarray analysis using HG-U133A-2 array (Affymetrix). Data were analyzed by Partek and pathway reconstruction was performed by Ingenuity for the most informative genes (MIGs). We identified a differing gene expression signature of 406 MIGs between BMS patients, mean±SE age 44.5±1.5 years, 24 females, 7 males, EDSS 1.9±0.2, disease duration 17.0±1.3 years, and RRMS patients, age 40.3±1.8 years, 24 females, 12 males, EDSS 3.5±0.2, disease duration 10.9±1.4 years. The signature was enriched by genes related RNA polymerase I (POL-1) transcription, general inflammatory response and activation of cell death. The most significant under-expressed pathway operating in BMS was the POL-1 pathway (p = 4.0*10−5) known while suppressed to activate P53 dependent apoptosis and to suppress NFκB induced inflammation. In accordance, of the 30 P53 target genes presented within the BMS signature, 19 had expression direction consistent with P53 activation. The transcripts within the pathway include POL-1 transcription factor 3 (RRN3, p = 4.8*10−5), POL-1 polypeptide D (POLR1D, p = 2.2*10−4), leucine-rich PPR-motif containing protein (LRPPRC p = 2.3*10−5), followed by suppression of the downstream family of ribosomal genes like RPL3, 6,13,22 and RPS6. In accordance POL-1 transcript and release factor PTRF that terminates POL-1 transcription, was over-expressed (p = 4.4*10−3). Verification of POL-1 pathway key genes was confirmed by qRT-PCR, and RRN3 silencing resulted in significant increase in the apoptosis level of PBMC sub-populations in RRMS patients. Our findings demonstrate that suppression of POL-1 pathway induce the low disease activity of BMS.
PMCID: PMC3470584  PMID: 23077530
BMC Neurology  2011;11:67.
The aim of this study was to assess the diagnostic accuracy (sensitivity and specificity) of clinical, imaging and motor evoked potentials (MEP) for predicting the short-term prognosis of multiple sclerosis (MS).
We obtained clinical data, MRI and MEP from a prospective cohort of 51 patients and 20 matched controls followed for two years. Clinical end-points recorded were: 1) expanded disability status scale (EDSS), 2) disability progression, and 3) new relapses. We constructed computational classifiers (Bayesian, random decision-trees, simple logistic-linear regression-and neural networks) and calculated their accuracy by means of a 10-fold cross-validation method. We also validated our findings with a second cohort of 96 MS patients from a second center.
We found that disability at baseline, grey matter volume and MEP were the variables that better correlated with clinical end-points, although their diagnostic accuracy was low. However, classifiers combining the most informative variables, namely baseline disability (EDSS), MRI lesion load and central motor conduction time (CMCT), were much more accurate in predicting future disability. Using the most informative variables (especially EDSS and CMCT) we developed a neural network (NNet) that attained a good performance for predicting the EDSS change. The predictive ability of the neural network was validated in an independent cohort obtaining similar accuracy (80%) for predicting the change in the EDSS two years later.
The usefulness of clinical variables for predicting the course of MS on an individual basis is limited, despite being associated with the disease course. By training a NNet with the most informative variables we achieved a good accuracy for predicting short-term disability.
PMCID: PMC3118106  PMID: 21649880
PLoS ONE  2013;8(4):e60647.
Dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis has frequently been reported in multiple sclerosis (MS). So far, HPA axis function in MS has predominantly been studied under pharmacological stimulation which is associated with a series of methodological caveats. Knowledge of circadian cortisol patterns and cortisol awakening response (CAR) is still limited.
A total of 77 MS patients (55 relapsing-remitting MS (RRMS)/22 secondary-progressive MS (SPMS)) as well as 34 healthy control (HC) subjects were enrolled. Diurnal cortisol release was assessed by repeated salivary cortisol sampling. Neurological disability was rated by the Kurtzke’s Expanded Disability Status Scale (EDSS). Depressive symptoms and perceived stress were assessed by self-report measures.
RRMS but not SPMS patients differed in circadian cortisol release from HC subjects. Differences in cortisol release were restricted to CAR. Treated and treatment naïve RRMS patients did not differ in CAR. In a RRMS follow-up cohort (nine months follow-up), RRMS patients with EDSS progression (≥0.5) expressed a significantly greater CAR compared to HC subjects. RRMS patients with a stable EDSS did not differ from HC subjects. Neither depressive symptoms nor perceived stress ratings were associated with CAR in RRMS patients. In a step-wise regression analysis, EDSS at baseline and CAR were predictive of EDSS at follow-up (R2 = 67%) for RRMS patients.
Circadian cortisol release, in particular CAR, shows a course specific pattern with most pronounced release in RRMS. There is also some evidence for greater CAR in RRMS patients with EDSS progression. As a consequence, CAR might be of predictive value in terms of neurological disability in RRMS patients. The possible role of neuroendocrine-immune interactions in MS pathogenesis is further discussed.
PMCID: PMC3628870  PMID: 23613736
BMC Neurology  2011;11:26.
In daily clinical setting, some patients affected by relapsing-remitting Multiple Sclerosis (RRMS) are switched from the low-dose to the high-dose Interferon beta (IFNB) in order to achieve a better control of the disease.
In this observational, post-marketing study we reported the 2-year clinical outcomes of patients switched to the high-dose IFNB; we also evaluated whether different criteria adopted to switch patients had an influence on the clinical outcomes.
Patients affected by RRMS and switched from the low-dose to the high-dose IFNB due to the occurrence of relapses, or contrast-enhancing lesions (CELs) as detected by yearly scheduled MRI scans, were followed for two years. Expanded Disability Status Scale (EDSS) scores, as well as clinical relapses, were evaluated during the follow-up period.
We identified 121 patients switched to the high-dose IFNB. One hundred patients increased the IFNB dose because of the occurrence of one or more relapses, and 21 because of the presence of one or more CELs, even in absence of clinical relapses. At the end of the 2-year follow-up, 72 (59.5%) patients had a relapse, and 51 (42.1%) reached a sustained progression on EDSS score. Overall, 85 (70.3%) patients showed some clinical disease activity (i.e. relapses or disability progression) after the switch.
Relapse risk after increasing the IFNB dose was greater in patients who switched because of relapses than those switched only for MRI activity (HR: 5.55, p = 0.001). A high EDSS score (HR: 1.77, p < 0.001) and the combination of clinical and MRI activity at switch raised the risk of sustained disability progression after increasing the IFNB dose (HR: 2.14, p = 0.01).
In the majority of MS patients, switching from the low-dose to the high-dose IFNB did not reduce the risk of further relapses or increased disability in the 2-year follow period.
Although we observed that patients who switched only on the basis on MRI activity (even in absence of clinical attacks) had a lower risk of further relapses, larger studies are warranted before to recommend a switch algorithm based on MRI findings.
PMCID: PMC3058026  PMID: 21352517
Journal of the neurological sciences  2011;305(1-2):103-111.
Sensory and motor dysfunction in multiple sclerosis (MS) is often assessed with rating scales which rely heavily on clinical judgment. Quantitative devices may be more precise than rating scales.
To quantify lower extremity sensorimotor measures in individuals with MS, evaluate the extent to which they can detect functional systems impairments, and determine their relationship to global disability measures.
We tested 145 MS subjects and 58 controls. Vibration thresholds were quantified using a Vibratron-II device. Strength was quantified by a hand-held dynamometer. We also recorded Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW). T-tests and Wilcoxon-rank sum were used to compare group data. Spearman correlations were used to assess relationships between each measure. We also used a step-wise linear regression model to determine how much the quantitative measures explain the variance in the respective functional systems scores (FSS).
EDSS scores ranged from 0-7.5, mean disease duration was 10.4±9.6 years, and 66% were female. In RRMS, but not progressive MS, poorer vibration sensation correlated with a worse EDSS score, whereas progressive groups’ ankle/hip strength changed significantly with EDSS progression. Interestingly, not only did sensorimotor measures significantly correlate with global disability measures (EDSS), but they had improved sensitivity, as they detected impairments in up to 32% of MS subjects with normal sensory FSS.
Sensory and motor deficits can be quantified using clinically accessible tools and distinguish differences among MS subtypes. We show that quantitative sensorimotor measures are more sensitive than FSS from the EDSS. These tools have the potential to be used as clinical outcome measures in practice and for future MS clinical trials of neurorehabilitative and neuroreparative interventions.
PMCID: PMC3090542  PMID: 21458828
multiple sclerosis; demyelinating disease; outcome measures; neurological disability; rehabilitation
The clinical course of multiple sclerosis (MS) evolves over many years. Its prognosis is highly variable among affected individuals, i.e. while some suffer from early severe disabilities, others remain ambulatory and functional for many years. We used Multiple Sclerosis Severity Score (MSSS) and the new classification for MS severity Herbert et al. introduced in 2006 according to MSSS, to investigate some clinical and demographic factors as potential indicators of disease severity in in MS.
During a six-month period, patients with definite MS according to the revised McDonald's criteria who referred to three neurology and MS clinics in Tehran (Iran) were included in the study. All patients were interviewed and examined by a neurology resident who had been trained for employing the Expanded Disability Status Scale (EDSS). For each patient, MSSS was determined by using EDSS and disease duration.
Overall, 338 (266 female and 72 male) patients were enrolled. Among demographic features, gender, younger age at onset, positive family history, and parental consanguinity were not associated with disease severity. Education was weakly associated with disease severity. Among clinical factors, presenting symptoms such as poly-symptomatic attacks, walking difficulty, and upper and lower extremity dysfunction were associated with more disability while presentation with optic neuritis had better prognosis. Complete recovery after the first attack, longer interval between the first and second attacks, lower number of symptoms at presentation, shorter duration of attacks, and relapsing-remitting course were associated with less disability and better prognosis. These results were noticed in ordinal logistic regression. However when multiple logistic regression was performed, the strongest determinant of disease severity was disease course with odds ratio (OR) = 49.12 for secondary progressive course and OR = 53.25 for primary progressive (± relapse) course. Walking difficulty as the presenting symptom had a borderline association with disease severity (OR = 2.31; P = 0.055). Increased number of onset symptoms was associated (but not significantly) with more severe disease.
Early prediction of disease severity by demographic and clinical features is currently impossible. We need to determine stronger predictors, possibly a combination of demographic, clinical, biomarkers, and imaging findings.
PMCID: PMC3829272  PMID: 24250889
Multiple Sclerosis; Severity; Demographic; Multiple Sclerosis Severity Score (MSSS)
Supplemental Digital Content is Available in the Text.
Low-contrast visual acuity (LCVA), a sensitive measure of visual function in multiple sclerosis (MS), demonstrated treatment effects as a secondary outcome measure in the Phase 3 trial of natalizumab, AFFIRM. In these posttrial analyses, we studied the relation of visual function to quality of life (QOL), magnetic resonance imaging (MRI) measures, and Expanded Disability Status Scale (EDSS) scores.
At baseline and at 52 and 104 weeks in AFFIRM, patients underwent binocular testing of LCVA (1.25% and 2.5% contrast) and high-contrast visual acuity (HCVA). Vision-specific QOL was assessed by the Impact of Visual Impairment Scale (IVIS), whereas the SF-36 Health Survey and Visual Analog Scale were administered as generic QOL measures and the EDSS as a measure of neurologic impairment.
Among QOL measures, IVIS scores showed the most significant correlations with visual dysfunction at all time points in the trial (r= −0.25 to −0.45, P < 0.0001 for LCVA and HCVA). Higher MRI T1- and T2-lesion volumes were also associated with worse vision scores at all time points (P < 0.0001). Clinically meaningful worsening (progression) of LCVA was noted in substantial proportions of patients in AFFIRM and was prevalent even among those without EDSS progression over 2 years (21.9% with LCVA progression at 2.5% contrast; 26.2% at 1.25% contrast). HCVA worsened in only 3.7% of patients without EDSS progression.
Loss of visual function, particularly as measured by LCVA, was common in AFFIRM, occurring in >20% of patients. Both LCVA and HCVA scores reflect vision-specific aspects of QOL, but LCVA provides information about disability progression not entirely captured by the EDSS. Vision represents a key dimension of outcome assessment for MS and adds valuable information on disability and QOL that can be useful to clinicians.
PMCID: PMC4337583  PMID: 25370598
The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 ±5.2, 4.81 ±3.69, and 13.6 ± 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12±0.82 at baseline to 0.25 ± 0.34 per year; 57% had stable/improved EDSS scores (change ± 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 ± 0.82 to 0.43 ± 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.
PMCID: PMC2850588  PMID: 20106943
disability; Expanded Disability Status Scale; glatiramer acetate; long-term; relapsing-remitting multiple sclerosis; secondary progressive multiple sclerosis
To investigate the association between brain volume loss during the first year of interferon treatment and clinical outcome at 4 years.
Patients with multiple sclerosis initiating interferon β were clinically evaluated every 6 months for the presence of relapses and assessment of global disability using the Expanded Disability Status Scale (EDSS). MRI scans were performed at baseline and after 12 months, and the percentage of brain volume change (PBVC), brain parenchymal volume change (BPVc%), gray matter volume change (GMVc%), and white matter volume change (WMVc%) were estimated. Patients were divided based on the cutoff values for predicting confirmed EDSS worsening obtained by receiver operating characteristic analysis for all atrophy measurements. Survival curves and Cox proportional hazards regression to predict disability worsening at last observation were applied, adjusting for demographic, clinical, and radiologic variables.
Larger PBVC and WMVc% decreases were observed in patients with disability worsening at 4 years of follow-up, whereas no differences were found in BPVc% or GMVc%. Cutoff points were obtained for PBVC (−0.86%; sensitivity 65.5%, specificity 71.4%) and WMVc% (−2.49%; sensitivity 85.3%, specificity 43.8%). Patients with decreases of PBVC and WMVc% below cutoff values were more prone to develop disability worsening (unadjusted hazard ratio [HR] 3.875, p = 0.005; HR 4.246, p = 0.004, respectively). PBVC (HR 4.751, p = 0.008) and the interaction of new T2 lesions with WMVc% (HR 1.086, p = 0.005) were found to be independent predictors of disability worsening in the multivariate analysis.
At the patient level, whole-brain and white matter volume changes in the first year of interferon β therapy are predictive of subsequent clinical evolution under treatment.
PMCID: PMC4496631  PMID: 26185778
BMC Public Health  2013;13:224.
Among individuals diagnosed with the chronic neurologic disease, multiple sclerosis (MS), a majority suffers from fatigue, which strongly influences their every-day-life. The aim of this study was to investigate work capacity and health-related quality of life (HRQoL) in a group of MS patients and also to investigate if work capacity and HRQoL could be predicted by background factors, fatigue, heat sensitivity, cognitive dysfunction, emotional distress or degree of disability.
A descriptive, cross-sectional, designed survey was undertaken A questionnaire was sent to 323 individuals diagnosed with MS, aged between 20 and 65 years, with physical disability on the expanded disability status score (EDSS) in the interval 0 ≥ EDSS ≤ 6.5, living in Östergötland county in eastern Sweden. Questions on background factors, occupation and work, together with the health-related quality of life short form instrument (SF-36), the fatigue severity scale (FSS), the perceived deficit questionnaire (PDQ) and the hospital anxiety depression scale (HAD) were posed. Associations between variables were analyzed using Pearson’s and Spearman’s correlations. Differences between groups were tested using the Chi-square test, the Mann Whitney U-test, and the Student’s t-test. Predictive factors were analyzed using multiple linear and multiple logistic regression analysis.
Of those who completed the questionnaire (n = 257, 79.6%), 59.8% were working. Work capacity was found significantly more among men (p < 0.005), those with a higher level of education (p < 0.001), those reporting less fatigue (p < 0.001), and those having no heat sensitivity (p = 0.004). For work capacity, significant predictors were low physical disability (EDSS), low fatigue, higher level of education, male sex and lower age. Those with work capacity showed significantly higher HRQoL than those who had no work capacity (p < 0.001). Levels of fatigue, cognition and emotional distress were found to be major contributing factors for HRQoL.
Work capacity and HRQoL among individuals diagnosed with MS are highly influenced by fatigue which can be considered as a key symptom. Work capacity was influenced by heat-sensitivity, cognitive difficulties and emotional distress and significant predictive factors besides fatigue, were physical disability (EDSS), age, sex, and level of education. Remaining at work also gives a better HRQoL.
PMCID: PMC3606119  PMID: 23497281
Cognition; Education; Emotional distress; Heat sensitivity; Regression analysis
OBJECTIVES—Health related quality of life (HRQOL) inventories are multi-dimensional measures of patient-centred health status developed for clinical research. The MS quality of life 54 (MSQOL-54) is an MS-specific HRQOL inventory originally devised for English speaking patients. It consists of a core measure, the 36-item short form health survey (SF-36) previously adapted into Italian, and 18 additional items exploring domains relevant to patients with MS (MS-18 module). The authors translated and culturally adapted into Italian the MS-18 module of the MSQOL-54 questionnaire, and clinically validated the whole questionnaire.
METHODS—The MS-18 module was translated following the methodology of the International Quality of Life Assessment (IQOLA) project. The MSQOL-54 was validated in 204 consecutive patients with MS seen between April and September 1997 at three participating centres. The questionnaire was explained by the physician who also administered the expanded disability status scale (EDSS) and mini mental status scale examination, and the patient filled in the MSQOL-54 and Beck depression inventory questionnaires (BDI), with assistance if required. The contribution of impairments and disabilities to MSQOL-54 scores were assessed, and mean scores were compared with normative data for the general Italian population, and with the original sample of United States MS patients.
RESULTS—The mean age of the 204 patients was 42 years; mean EDSS score was 4.5 (range 0-8.5). Patients' participation in the assessment was satisfactory, and all scales satisfied the usual psychometric standards. The characteristics of the United States sample matched those of our patients in all but gender (72% United States patients v 52% Italian patients were women), and education (90% United States patients and 44% Italian patients completed high school); MSQOL-54 profiles were also similar. The EDSS was significantly associated with the physical health composite but not with the mental health composite score. Multiple linear regression modelling showed that age and BDI independently predicted physical health composite (p < 0.001), and mental health composite (p < 0.001). Clinical worsening in the previous year had an independent effect on the physical health composite (p < 0.001).
CONCLUSIONS—The Italian version of MSQOL-54 is easy to administer and is well accepted by patients. Neurological impairment has a limited influence on perceived quality of life, while age and depressive symptoms has a major influence.

PMCID: PMC1736469  PMID: 10406981
Objective: To analyse the value of the INTERMED, a screening instrument to assess case complexity, compared with the Expanded Disability Status Scale (EDSS) and the Guy's Neurological Disability Scale (GNDS) to identify multiple sclerosis (MS) patients in need of multidisciplinary treatment.
Methods: One hundred MS patients underwent INTERMED, EDSS, and GNDS examinations. Patient care needs were assessed by a multidisciplinary team and a goal oriented treatment plan was defined. Correlations between INTERMED, individual INTERMED domains, EDSS, GNDS sum score, and total number of proposed disciplines involved in the treatment plan were studied.
Results: Mean (SD) age was 40.6 (10.1) years. Median scores were 14.0 for the INTERMED, 4.0 for the EDSS, and 13.5 for the GNDS sum score. Moderate correlations were found between the INTERMED sum score and EDSS (r=0.59) and GNDS sum score (r=0.60). The number of disciplines as proposed by the multidisciplinary team showed the highest statistically significant correlation with the INTERMED sum score (r=0.41) compared with EDSS (r=0.32) and GNDS sum score (r=0.34). No significant or only weak correlations were found between the psychological domain of the INTERMED and EDSS or GNDS.
Conclusion: The findings in this study show that there is an additional value of the INTERMED compared with the EDSS and GNDS in identifying MS patients in need of multidisciplinary treatment. The INTERMED domains show the area of the patient's vulnerability and care needs: especially the INTERMED's psychological and social domains may guide the clinician to deal with specific problems that complicate healthcare delivery.
PMCID: PMC1738178  PMID: 12486260

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