PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (628224)
Clipboard (0)
None

Related Articles

1.  Country, Sex, EDSS Change and Therapy Choice Independently Predict Treatment Discontinuation in Multiple Sclerosis and Clinically Isolated Syndrome 
Meyniel, Claire | Spelman, Timothy | Jokubaitis, Vilija G. | Trojano, Maria | Izquierdo, Guillermo | Grand’Maison, François | Oreja-Guevara, Celia | Boz, Cavit | Lugaresi, Alessandra | Girard, Marc | Grammond, Pierre | Iuliano, Gerardo | Fiol, Marcela | Cabrera-Gomez, Jose Antonio | Fernandez-Bolanos, Ricardo | Giuliani, Giorgio | Lechner-Scott, Jeannette | Cristiano, Edgardo | Herbert, Joseph | Petkovska-Boskova, Tatjana | Bergamaschi, Roberto | van Pesch, Vincent | Moore, Fraser | Vella, Norbert | Slee, Mark | Santiago, Vetere | Barnett, Michael | Havrdova, Eva | Young, Carolyn | Sirbu, Carmen-Adella | Tanner, Mary | Rutherford, Michelle | Butzkueven, Helmut | Kleinschnitz, Christoph
PLoS ONE  2012;7(6):e38661.
Objectives
We conducted a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in patients with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS).
Methods
The MSBASIS Study, conducted by MSBase Study Group members, enrols patients seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. We performed a multivariable survival analysis to determine factors within this dataset that predict first treatment discontinuation.
Results
A total of 2314 CIS patients from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. Over 40% of these patients stopped their first IMD during the observation period. Females were more likely to cease medication than males (HR 1.36, p = 0.003). Patients treated in Australia were twice as likely to cease their first IMD than patients treated in Spain (HR 1.98, p = 0.001). Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries. Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation.
Conclusion
In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation.
doi:10.1371/journal.pone.0038661
PMCID: PMC3387159  PMID: 22768046
Related Articles
2.  Treatment of multiple sclerosis with interferon β: an appraisal of cost-effectiveness and quality of life 
Parkin, D. | Jacoby, A. | McNamee, P. | Miller, P. | Thomas, S. | Bates, D.
Journal of Neurology, Neurosurgery, and Psychiatry  2000;68(2):144-149.
OBJECTIVE—To evaluate the cost-effectiveness of interferon beta-1b (IFβ-1b) for relapsing-remitting multiple sclerosis (RRMS).
METHODS—Construction of a cost-effectiveness model using published data on IFβ-1b effectiveness and the natural history of RRMS, and new data on costs and quality of life (QoL) from a sample of 102patients with RRMS and resident in northern England.
RESULTS—Poorer QoL was found for patients with multiple sclerosis compared with the general population; those who had had a relapse; those with worse states identified by a clinical measure (expanded disability status scale (EDSS)). Relapses have effects over several months. Health state valuations were higher than in the general population. Costs were higher in relapse than remission and for worse EDSS states. IFβ-1b costs were larger than cost savings. The best cost-effectiveness estimate was £28 700 per relapse avoided, which is £809 900 per QALY gained; or £328 300 per QALY gained allowing for effects of progression over 5 years. Estimates were robust to changes in assumptions.
CONCLUSIONS—The impact of multiple sclerosis on QoL is substantial. Future trials should base outcomes measurement on QoL and be better linked to natural history and cost data. IFβ-1b produces important occasional short term QoL gains, but small gains in QALYs overall and large additional costs.


doi:10.1136/jnnp.68.2.144
PMCID: PMC1736797  PMID: 10644777
Related Articles
3.  A post-marketing study on interferon ß 1b and 1a treatment in relapsing-remitting multiple sclerosis: different response in drop-outs and treated patients 
Milanese, C | La Mantia, L | Palumbo, R | Martinelli, V | Murialdo, A | Zaffaroni, M | Caputo, D | Capra, R | Bergamaschi, R
Journal of Neurology, Neurosurgery, and Psychiatry  2003;74(12):1689-1692.
Objectives: To evaluate the effectiveness of these agents on the basis of clinical experience in northern Italian multiple sclerosis centres.
Design: Clinical data on patients with relapsing-remitting multiple sclerosis were collected on an appropriate form from 65 centres in northern Italy. Intention to treat analysis was not possible, so patients who discontinued treatment (drop-outs) and who continued treatment (treated) were analysed separately. The main outcome measures were annual relapse frequency, number of relapse-free patients, mean change in extended disability status scale score (EDSS), and number of patients who worsened.
Results: 1481 patients were included; 834 were treated with Betaferon and 647 with Avonex for mean periods of 21.4 and 12.0 months, respectively. Basal EDSS was 2.37 and 2.17, respectively, and relapse frequency was 1.62 and 1.45. The annual relapse rate decreased by more than 60% with Betaferon and 55% with Avonex. The proportions of relapse-free, improved, and worsened patients were similar in the two groups. More patients interrupted treatment with Betaferon (41.1%) than with Avonex (15.3%); such patients showed more active disease at baseline and during treatment. The incidence of side effects was higher in Betaferon treated patients.
Conclusions: The effectiveness of Betaferon and Avonex is confirmed. There was a more marked effect than expected from the experimental trial results. This might reflect differences in inclusion criteria, or, more likely, loss of drop-outs, favouring selective retention of responders.
doi:10.1136/jnnp.74.12.1689
PMCID: PMC1757434  PMID: 14638892
Related Articles
4.  Evidence for grey matter MTR abnormality in minimally disabled patients with early relapsing-remitting multiple sclerosis 
Davies, G | Ramio-Torrenta, L | Hadjiprocopis, A | Chard, D | Griffin, C | Rashid, W | Barker, G | Kapoor, R | Thompson, A | Miller, D
Journal of Neurology, Neurosurgery, and Psychiatry  2004;75(7):998-1002.
Objectives: To establish whether magnetisation transfer ratio (MTR) histograms are sensitive to change in normal appearing grey matter (NAGM) in early relapsing-remitting multiple sclerosis (RRMS) in the absence of significant disability; and to assess whether grey or white matter MTR measures are associated with clinical measures of impairment in early RRMS
Methods: 38 patients were studied (mean disease duration 1.9 years (range 0.5 to 3.7); median expanded disability status scale (EDSS) 1.5 (0 to 3)), along with 35 healthy controls. MTR was determined from proton density weighted images with and without MT presaturation. SPM99 was used to generate normal appearing white matter (NAWM) and NAGM segments of the MTR map, and partial voxels were minimised with a 10 pu threshold and voxel erosions. Mean MTR was calculated from the tissue segments. Atrophy measures were determined using a 3D fast spoiled gradient recall sequence from 37 patients and 17 controls.
Results: Mean NAGM and NAWM MTR were both reduced in early RRMS (NAGM MTR: 31.9 pu in patients v 32.2 pu in controls; p<0.001; NAWM MTR: 37.9 v 38.3 pu, p = 0.001). Brain parenchymal fraction (BPF) correlated with NAGM MTR, but when BPF was included as a covariate NAGM MTR was still lower in the patients (p = 0.009). EDSS correlated with NAGM MTR (r = 0.446 p = 0.005).
Conclusions: In early RRMS, grey matter MTR abnormality is apparent. The correlation with mild clinical impairment (in this essentially non-disabled cohort) suggests that NAGM MTR could be a clinically relevant surrogate marker in therapeutic trials.
doi:10.1136/jnnp.2003.021915
PMCID: PMC1739100  PMID: 15201359
Related Articles
5.  Is inflammation important in early PPMS? a longitudinal MRI study 
Ingle, G | Sastre-Garriga, J | Miller, D | Thompson, A
Journal of Neurology, Neurosurgery, and Psychiatry  2005;76(9):1255-1258.
Background: Magnetic resonance imaging (MRI) studies in primary progressive multiple sclerosis (PPMS) have shown a reduced frequency of enhancement with the contrast agent gadolinium-DTPA (Gd-DTPA), in comparison with relapsing-remitting multiple sclerosis (RRMS), and it has been suggested that there may be a less important role for inflammation in its pathogenesis. However, the earliest clinical stages of PPMS have not been studied and thus it has not been possible to exclude the existence of an early inflammatory phase.
Objective: To study the presence, characteristics, and implications of inflammation in early PPMS.
Methods: 45 patients with a mean disease duration of 3.3 years had triple dose Gd enhanced MRI, expanded disability status scale (EDSS), and multiple sclerosis functional composite (MSFC) assessments at baseline. Repeat MRI was done at 1 and 2 months in 24 patients, and at 6 months in 38.
Results: Enhancing brain lesions were present in 42% of patients at baseline but enhancing cord lesions were uncommon (7%); 85% of enhancing lesions enhanced for one month or less. Patients with enhancing lesions had greater disability (EDSS, p = 0.027; MSFC, p = 0.026) and more MRI abnormalities (greater T2 load, p = 0.008; greater T1 hypointensity load, p = 0.001; and reduced partial brain volume, p = 0.012) than those without enhancement. Enhancement at 6 months was seen in 32% of patients and was restricted to a subset of patients who enhanced at baseline.
Conclusions: Enhancement is present in some cases of early PPMS and is associated with greater disease impact in terms of both clinical and MRI measures.
doi:10.1136/jnnp.2004.036590
PMCID: PMC1739783  PMID: 16107362
Related Articles
6.  Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors 
Hawkins, S | McDonnell, G
Journal of Neurology, Neurosurgery, and Psychiatry  1999;67(2):148-152.
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
Related Articles
7.  Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results 
Bowen, James D. | Kraft, George H. | Wundes, Annette | Guan, QingYan | Maravilla, Kenneth R. | Gooley, Theodore A. | McSweeney, Peter A. | Pavletic, Steven Z. | Openshaw, Harry | Storb, Rainer | Wener, Mark | McLaughlin, Bernadette A. | Henstorf, Gretchen R. | Nash, Richard A.
Bone Marrow Transplantation  2011;47(7):946-951.
The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). Total body irradiation, cyclophosphamide, and antithymocyte globulin were followed by transplantation of autologous, CD34-selected peripheral blood stem cells (PBSC). Neurological examinations, brain MRIs and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean EDSS=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥ 1.0 EDSS point was 0.52 (95% CI, 0.30 to 0.75). Five patients had an EDSS at baseline of ≤ 6.0; four of these had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.
doi:10.1038/bmt.2011.208
PMCID: PMC3276694  PMID: 22056644
multiple sclerosis; total body irradiation; cyclophosphamide; hematopoietic cell transplantation; oligoclonal bands
Related Articles
8.  Composite MRI Scores Improve Correlation with EDSS in Multiple Sclerosis 
Poonawalla, Aziz H. | Datta, Sushmita | Juneja, Vaibhav | Nelson, Flavia | Wolinsky, Jerry S. | Cutter, Gary | Narayana, Ponnada A.
Multiple sclerosis (Houndmills, Basingstoke, England)  2010;16(9):1117-1125.
Background
Quantitative measures derived from MRI have been widely investigated as noninvasive biomarkers in multiple sclerosis (MS). However, the correlation of single measures with Expanded Disability Status Scale (EDSS) is poor, especially for studies with large population samples.
Objective
To explore the correlation of MRI-derived measures with EDSS through composite MRI scores.
Methods
Magnetic resonance images of 126 patients with relapsing-remitting MS were segmented into white and gray matter, CSF, T2-hyperintense lesions, gadolinium contrast-enhancing lesions, T1-hypointense lesions (“black holes (BH)”). The volumes and average T2 values for each of these tissues and lesions were calculated and converted to a z-score (in units of standard deviation from the mean). These z-scores were combined to construct composite z-scores, and evaluated against individual z-scores for correlation with EDSS.
Results
Composite scores including relaxation times of different tissues and/or volumetric measures generally correlated more strongly with EDSS than individual measures. The maximum observed correlation of a composite with EDSS was r = 0.344 (p < 0.0001), which is an improvement over the highest-performing single MRI measure (BH; r=0.298, p<0.001).
Conclusion
Z-transformation permits construction of composite scores including volumetric and T2-relaxation measures. Inclusion of multiple MRI measures in the composite can provide a broader characterization of the disease process, resulting in more robust correlations with EDSS.
doi:10.1177/1352458510374892
PMCID: PMC2935291  PMID: 20813778
Multiple Sclerosis; EDSS; composite score; MRI; biomarkers
Related Articles
9.  The Treatment of Multiple Sclerosis with Inosine 
Markowitz, Clyde E. | Spitsin, Sergei | Zimmerman, Vanessa | Jacobs, Dina | Udupa, Jayaram K. | Hooper, D. Craig | Koprowski, Hilary
Journal of Alternative and Complementary Medicine  2009;15(6):619-625.
Abstract
Objective
The objective of this study is to evaluate the safety and tolerability of inosine in patients with relapsing–remitting multiple sclerosis (RRMS). The secondary objectives are to assess the effects of inosine administration on serum urate (UA) levels, the progression of neurologic disability, the cumulative number of new, active lesions on magnetic resonance imaging (MRI), and changes in serum levels for markers of inflammation.
Design
Oral administration of inosine was used to raise serum levels of the natural peroxynitrite scavenger UA in 16 patients with RRMS during a 1-year randomized, double-blind trial.
Outcome measures
The endpoints studied were relapse rate, disability assessed by the Kurtzke Expanded Disability Status Scale (EDSS), MRI, and analysis of serum levels of nitrotyrosine, and oxidative and proinflammatory makers.
Results
Increased serum UA levels correlated with a significant decrease in the number of gadolinium-enhanced lesions and improved EDSS. A number of MRI intensity-based parameters were altered by inosine treatment, in certain cases correlating with changes in serum UA levels. In a patient with low serum UA and high lesion activity, raising UA levels by inosine treatment decreased serum nitrotyrosine while increasing the ratio of Th2 to Th1 cytokines in circulating cells. The only side-effect correlated with inosine treatment was kidney stone formation in 4/16 subjects.
Conclusions
These data suggest that the use of inosine to raise serum UA levels may have benefits for at least some MS patients. The effect of this treatment is likely to be a consequence of inactivation of peroxynitrite-dependent free radicals. Close monitoring of serum UA levels as well as other measures are required to avoid the potential development of kidney stones.
doi:10.1089/acm.2008.0513
PMCID: PMC3189001  PMID: 19425822
Related Articles
10.  Venous Thrombosis in Multiple Sclerosis Patients after High-Dose Intravenous Methylprednisolone: The Preventive Effect of Enoxaparin 
Kalanie, Hossein | Harandi, Ali Amini | Alidaei, Shapoor | Heidari, Daryoosh | Shahbeigi, Saeed | Ghorbani, Mehdi
Thrombosis  2011;2011:785459.
Aim. This study was designed to examine the possible role of high-dose intravenous methylprednisolone (IVMP) in the development of venous thrombosis (VT). The cerebral one anecdotally had been reported in patients with relapsing remitting multiple sclerosis (RRMS) in acute attacks and the possible preventive role of enoxaparin. Material and Methods. From a pool of 520 patients, 388 patients with definite RRMS who fulfilled entry characteristics were selected and randomly received either a 5-day course of daily 1 gr IVMP or the aforementioned plus 5 days of daily subcutaneous 40 units of enoxaparin according to a predefined protocol. Results. Mean age, gender ratio, mean relapse rate, and EDSS were similar in both groups of patients (P > 0.05). Finally, 366 patients remained in the study. Of 188 patients treated with IVMP with 855 relapses, 5 developed VT (0.37% per patient per year and 0.58% per each course of IVMP) within 3 to 15 days of starting therapy. None of the 178 patients who experienced 809 relapses who received IVMP plus enoxaparin developed such complications. Conclusion. The study implies that high-dose IVMP in MS exacerbation may increase the risk of VT and prophylactic anticoagulant treatment in this setting is warranted.
doi:10.1155/2011/785459
PMCID: PMC3253479  PMID: 22242201
Related Articles
11.  Mycophenolate mofetil in combination with interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis: A preliminary study 
Etemadifar, Masoud | Kazemi, Mojtaba | Chitsaz, Ahmad | Hekmatnia, Ali | Tayari, Nazila | Ghazavi, Amirhossein | Maghzi, Amir Hadi
Journal of Research in Medical Sciences : The Official Journal of Isfahan University of Medical Sciences  2011;16(1):1-5.
BACKGROUND:
The efficacy of Mycophenolate mofetil (MMF) plus interferon beta-1a (IFNB-1a) in treatment of relapsing-remitting multiple sclerosis (RRMS) was evaluated.
METHODS:
This was a pilot study with randomized, double-blinded, placebo-controlled design. Patients with RRMS and Expanded Disability Status Scale score (EDSS) of < 6.0 were included. Those with relapse within the previous two months and prior use of immunomodulatory/immunosuppressive drugs were excluded. Patients were randomized into MMF (n = 13) and placebo (n = 13) groups and received weekly intramuscular IFNB-1a plus either MMF or placebo. MMF started by 500 mg/d for one week and weekly escalated by 500 mg/d, until target divided dose of 2000 mg/d and continued for 12 months. Radiologic and clinical assessments were performed at baseline and then at month 12.
RESULTS:
After one year of therapy, difference between the two groups in number of new T2 lesions was not statistically significant (0.54 ± 0.77 in MMF vs. 1.85 ± 3.2 in placebo group, p = 0.169). Two patients in the placebo group had gadoliniumenhanced lesions and one patient had relapse. There were 3 patients in each group with more than one point progression in EDSS. Common side effect in the MMF group included gastrointestinal upset, but no patient discontinued the treatment.
CONCLUSIONS:
Combination of MMF with IFNB-1a in patients with RRMS is well tolerated, but the efficacy of such combination was not statistically significant in this pilot study and deserves further investigation with a larger sample size and a longer follow-up.
PMCID: PMC3063426  PMID: 21448376
Mycophenolate Mofetil; Interferon Beta-1a; Immunosuppressive; Relapsing-Remitting Multiple Sclerosis
Related Articles
12.  Magnetisation transfer ratio in the normal appearing white matter predicts progression of disability over 1 year in early primary progressive multiple sclerosis 
Khaleeli, Z | Sastre‐Garriga, J | Ciccarelli, O | Miller, D H | Thompson, A J
Journal of Neurology, Neurosurgery, and Psychiatry  2007;78(10):1076-1082.
Background
Progression rates in primary progressive multiple sclerosis (PPMS) vary widely and brain magnetisation transfer imaging (MTI) has potential as an early prognostic indicator. We investigated the predictive value of MTI and the longitudinal changes developing over 1 year in early PPMS.
Aims
To determine (1) whether baseline brain MTI parameters in early PPMS predict clinical changes over 1 year, independent of brain volume and (2) whether a change in magnetisation transfer (MT) parameters occurs over 1 year, independent of atrophy.
Methods
30 patients with PPMS within 5 years of symptom onset and 15 controls underwent MT and volumetric imaging studies, at baseline and at 1 year. Patients underwent clinical assessment using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC), including the timed walk subtest (TWT). Normalised MT histograms were generated for whole brain, normal appearing brain tissue (NABT) and normal appearing white and grey matter (NAWM and NAGM) segments. Multiple regression analyses were performed to investigate whether baseline MTR parameters predicted clinical change over 1 year, adjusting for baseline brain volume. MTR changes over 1 year were assessed using paired t tests.
Results
In patients, lower baseline NAWM MTR predicted greater deterioration in EDSS and MSFC, particularly in walking ability measured by the TWT, independent of NAWM baseline volume (p = 0.001). NAGM MTR mean (p<0.001), and to a lesser extent NAWM mean (p = 0.011) and lesion MTR (p = 0.03), decreased over 1 year.
Conclusions
NAWM MTR may provide information on short term clinical prognosis in early PPMS. MTI is sensitive to brain tissue changes over 1 year in early PPMS, which were primarily seen in the NAGM.
doi:10.1136/jnnp.2006.107565
PMCID: PMC2117577  PMID: 17287235
Related Articles
13.  Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: results from the 15-year analysis of the US prospective open-label study of glatiramer acetate 
Ford, C | Goodman, AD | Johnson, K | Kachuck, N | Lindsey, JW | Lisak, R | Luzzio, C | Myers, L | Panitch, H | Preiningerova, J | Pruitt, A | Rose, J | Rus, H | Wolinsky, J
Multiple Sclerosis (Houndmills, Basingstoke, England)  2010;16(3):342-350.
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.
doi:10.1177/1352458509358088
PMCID: PMC2850588  PMID: 20106943
disability; Expanded Disability Status Scale; glatiramer acetate; long-term; relapsing-remitting multiple sclerosis; secondary progressive multiple sclerosis
Related Articles
14.  Predictors of Attack Severity and Duration in Multiple Sclerosis: A Prospective Study 
Naldi, P | Collimedaglia, L | Vecchio, D | Rosso, M.G | Perl, F | Stecco, A | Monaco, F | Leone, M.A
The Open Neurology Journal  2011;5:75-82.
Objective:
To evaluate predictors of severity and duration of early Multiple Sclerosis (MS) attacks.
Methods:
We analyzed 248 attacks in 95 patients in a prospective study. Severity: the difference between the EDSS score at the day of maximum worsening and the EDSS score before the onset of the attack. Duration: the time between the date of onset of the first symptom and the date of maximum improvement of the last symptom.
Results:
The number of involved Functional Systems (FS), FS type (brainstem and pyramidal), and total attack duration were linked to severity. Number of FS involved, FS type (sphincteric and sensory), and severity of the attack were related to duration. Neither severity nor duration were correlated to other predictors: gender, age and season at attack onset, speed of onset, infections in the preceding month, age at first attack, season of birth and first attack, CSF examination, first brain MRI, recovery from the first attack. In the multivariate analysis, the Odds Ratio (OR) and Confidence Intervals (CI) for severe attacks was 3.6, 1.7-7.7 for involvement of pyramidal FS, 2.6, 1.2-6.0 for brainstem and 2.5, 1.2-5.3 for long attack duration. Sphincteric (4.4; 1.7-11.0) and sensory FS (1.8; 1.0-3.2) were the only variables explaining duration. The probability of a second moderate/severe or long attack was not influenced by severity or duration of the first.
Conclusion:
FS are predictive of severity and duration of early MS attacks. Severity and duration of the first attack do not predict severity and duration of the second.
doi:10.2174/1874205X01105010075
PMCID: PMC3249638  PMID: 22216064
Course; Duration; Multiple sclerosis; Prognosis; Recovery; Attack; Relapse; Severity.
Related Articles
15.  Efficacy of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients with spinal symptoms 
Hellwig, Kerstin | Stein, Franz Josef | Przuntek, Horst | Müller, Thomas
BMC Neurology  2004;4:18.
Background
There are controversial results on the efficacy of the abandoned, intrathecal predominant methylprednisolone application in multiple sclerosis (MS) in contrast to the proven effectiveness in intractable postherpetic neuralgia.
Methods
We performed an analysis of the efficacy of the application of 40 mg of the sustained release steroid triamcinolone acetonide (TCA). We intrathecally injected in sterile saline dissolved TCA six times within three weeks on a regular basis every third day in 161 hospitalized primary and predominant secondary progressive MS patients with spinal symptoms. The MS patients did not experience an acute onset of exacerbation or recent distinct increased progression of symptoms. We simultaneously scored the MS patients with the EDSS and the Barthel index, estimated the walking distance and measured somatosensory evoked potentials. Additionally the MS patients received a standardized rehabilitation treatment.
Results
EDSS score and Barthel index improved, walking distance increased, latencies of somatosensory evoked potentials of the median and tibial nerves shortened in all MS patients with serial evaluation (p < 0.0001 for all variables). Side effects were rare, five patients stopped TCA application due to onset of a post lumbar puncture syndrome.
Conclusions
Repeated intrathecal TCA application improves spinal symptoms, walking distance and SSEP latencies in progressive MS patients in this uncontrolled study. Future trials should evaluate the long-term benefit of this invasive treatment.
doi:10.1186/1471-2377-4-18
PMCID: PMC535343  PMID: 15530171
Related Articles
16.  Computational classifiers for predicting the short-term course of Multiple sclerosis 
Bejarano, Bartolome | Bianco, Mariangela | Gonzalez-Moron, Dolores | Sepulcre, Jorge | Goñi, Joaquin | Arcocha, Juan | Soto, Oscar | Carro, Ubaldo Del | Comi, Giancarlo | Leocani, Letizia | Villoslada, Pablo
BMC Neurology  2011;11:67.
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2377-11-67
PMCID: PMC3118106  PMID: 21649880
Related Articles
17.  Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study 
Leocani, L | Rovaris, M | Boneschi, F M | Medaglini, S | Rossi, P | Martinelli, V | Amadio, S | Comi, G
Journal of Neurology, Neurosurgery, and Psychiatry  2006;77(9):1030-1035.
Background
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.
Objective
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.
Methods
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.
Results
Cross‐sectionally, the severity of each evoked potential score significantly correlated with the corresponding functional system (0.32
Conclusions
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.
doi:10.1136/jnnp.2005.086280
PMCID: PMC2077734  PMID: 16735397
Related Articles
Rashid, W | Davies, G R | Chard, D T | Griffin, C M | Altmann, D R | Gordon, R | Thompson, A J | Miller, D H
Journal of Neurology, Neurosurgery, and Psychiatry  2006;77(1):51-55.
Objectives
Previous studies have shown that upper cervical cord atrophy (UCCA) occurs in multiple sclerosis (MS), particularly in those disabled and with primary or secondary progressive disease. It is less clear how early it can be detected in relapsing‐remitting (RR) MS, and whether early cord atrophy relates to the concurrent or future clinical course.
Methods
Twenty seven RR MS patients (median disease duration 1.7 years, in all cases <3 years from onset) were recruited along with 20 controls. They were followed for up to 3 years with a yearly assessment of UCCA and clinical function measured by the Expanded Disability Status Scale (EDSS) and MS Functional Composite Score (MSFC). Clinical and MRI correlations were investigated. Statistical models adjusted for covariates including total intracranial volume.
Results
Longitudinal analysis showed a significant decrease in UCCA in patients both within the patient cohort (p<0.001) and in comparison with controls (p = 0.001). There was a significant increase in EDSS (p = 0.008) but no significant change in MSFC. The rate of UCCA loss did not correlate with clinical change or with change in brain volume.
Conclusions
In summary, serial UCCA measurement detects the development of spinal cord atrophy in clinically early RR MS.
doi:10.1136/jnnp.2005.068338
PMCID: PMC2117413  PMID: 16361592
atrophy; cord area; early disease; MRI; multiple sclerosis
Related Articles
Prosperini, Luca | Borriello, Giovanna | De Giglio, Laura | Leonardi, Laura | Barletta, Valeria | Pozzilli, Carlo
BMC Neurology  2011;11:26.
Background
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.
Purpose
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1186/1471-2377-11-26
PMCID: PMC3058026  PMID: 21352517
Related Articles
Achiron, Anat | Feldman, Anna | Magalashvili, David | Dolev, Mark | Gurevich, Michael | Villoslada, Pablo
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.
doi:10.1371/journal.pone.0046871
PMCID: PMC3470584  PMID: 23077530
Related Articles
Hardmeier, Martin | Schoonheim, Menno M. | Geurts, Jeroen J. G. | Hillebrand, Arjan | Polman, Chris H. | Barkhof, Frederik | Stam, Cornelis J. | Valdes-Sosa, Pedro Antonio
PLoS ONE  2012;7(7):e42087.
Background
Cognitive dysfunction in multiple sclerosis (MS) is frequent. Insight into underlying mechanisms would help to develop therapeutic strategies.
Objective
To explore the relationship of cognitive performance to patterns of nodal centrality derived from magneto-encephalography (MEG).
Methods
34 early relapsing-remitting MS patients (median EDSS 2.0) and 28 age- and gender-matched healthy controls (HC) had a MEG, a neuropsychological assessment and structural MRI. Resting-state functional connectivity was determined by the synchronization likelihood. Eigenvector Centrality (EC) was used to quantify for each sensor its connectivity and importance within the network. A cognition-score was calculated, and normalized grey and white matter volumes were determined. EC was compared per sensor and frequency band between groups using permutation testing, and related to cognition.
Results
Patients had lower grey and white matter volumes than HC, male patients lower cognitive performance than female patients. In HC, EC distribution showed highest nodal centrality over bi-parietal sensors (“hubs”). In patients, nodal centrality was even higher bi-parietally (theta-band) but markedly lower left temporally (upper alpha- and beta-band). Lower cognitive performance correlated to decreased nodal centrality over left temporal (lower alpha-band) and right temporal (beta-band) sensors, and to increased nodal centrality over right parieto-temporal sensors (beta-band). Network changes were most pronounced in male patients.
Conclusions
Partial functional disconnection of the temporal regions was associated with cognitive dysfunction in MS; increased centrality in parietal hubs may reflect a shift from temporal to possibly less efficient parietal processing. To better understand patterns and dynamics of these network changes, longitudinal studies are warranted, also addressing the influence of gender.
doi:10.1371/journal.pone.0042087
PMCID: PMC3407108  PMID: 22848712
Related Articles
Liu, C. | Blumhardt, L.
Journal of Neurology, Neurosurgery, and Psychiatry  1999;67(4):451-456.
OBJECTIVES—The commonly employed outcome measures on disability and relapse rates in treatment trials of relapsing-remitting multiple sclerosis have well demonstrated sensitivity to treatment effects, but their clinical interpretation is problematic. An alternative method of analysis, which is more clinically meaningful and statistically appropriate to a condition with a fluctuating disease course, uses the summary measure statistic "area under the disability/time curve (AUC)", to estimate each patient's total in trial morbidity experience.
METHODS—The AUC technique was applied in an intention to treat analysis of serial disability data derived from the expanded disability status scale (EDSS), the Scripps neurologic rating scale (SNRS), and the ambulation index (AI), collected during a double blind, randomised, placebo controlled, phase III trial of subcutaneous interferon β-1a (INFβ-1a) in relapsing-remitting multiple sclerosis (PRISMS Study). The results were compared with the often quoted "conventional" end point of mean change in rating scores from baseline to trial completion. Analyses were also carried out on subgroups with entry EDSS stratified above and below 3.5.
RESULTS—EDSS data analysed by AUC normalised to baseline scores disclosed that both doses of IFNβ-1a (22 or 44 µg) were superior to placebo (p= 0.008 and 0.013, respectively). In addition, the high dose (44 µg) was more beneficial than placebo using SNRS (p= 0.038) and AI data (p= 0.039). AUC analysis of SNRS scores also showed that for patients with baseline EDSS>3.5, the 44 µg (but not the 22 µg) dose was more advantageous than placebo (p=0.028).
CONCLUSIONS—Summary measure analysis using the AUC of serial disability/time plots, confirms and extends the results of conventional end point analysis of disability from the PRISMS Study data. AUC evaluations show that high dose INFβ-1a (44 µg three times weekly) was beneficial on all of the clinical rating scale scores used in this study. This method provides a statistically powerful and clinically meaningful assessment of treatment effects on in trial disability in patients with multiple sclerosis with fluctuating and highly heterogeneous disease courses.


PMCID: PMC1736573  PMID: 10486390
Related Articles
Politis, Marios | Giannetti, Paolo | Su, Paul | Turkheimer, Federico | Keihaninejad, Shiva | Wu, Kit | Waldman, Adam | Malik, Omar | Matthews, Paul M. | Reynolds, Richard | Nicholas, Richard | Piccini, Paola
Neurology  2012;79(6):523-530.
Objective:
Activated microglia are thought to play a major role in cortical gray matter (GM) demyelination in multiple sclerosis (MS). Our objective was to evaluate microglial activation in cortical GM of patients with MS in vivo and to explore its relationship to measures of disability.
Methods:
Using PET and optimized modeling and segmentation procedures, we investigated cortical 11C-PK11195 (PK11195) binding in patients with relapsing-remitting MS (RRMS), patients with secondary progressive MS (SPMS), and healthy controls. Disability was assessed with the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale (MSIS-29).
Results:
Patients with MS showed increased cortical GM PK11195 binding relative to controls, which was multifocal and highest in the postcentral, middle frontal, anterior orbital, fusiform, and parahippocampal gyri. Patients with SPMS also showed additional increases in precentral, superior parietal, lingual and anterior superior, medial and inferior temporal gyri. Total cortical GM PK11195 binding correlated with EDSS scores, with a stronger correlation for the subgroup of patients with SPMS. In patients with SPMS, PK11195 binding also correlated with MSIS-29 scores. No correlation with disability measures was seen for PK11195 binding in white matter. Higher EDSS scores correlated with higher levels of GM PK11195 binding in the postcentral gyrus for patients with RRMS and in precentral gyrus for those with SPMS.
Conclusions:
Microglial activation in cortical GM of patients with MS can be assessed in vivo. The distribution is not uniform and shows a relationship to clinical disability. We speculate that the increased PK11195 binding corresponds to enhanced microglial activation described in postmortem SPMS cortical GM.
doi:10.1212/WNL.0b013e3182635645
PMCID: PMC3413767  PMID: 22764258
Related Articles
Edgar, Chris | Jongen, Peter J | Sanders, Evert | Sindic, Christian | Goffette, Sophie | Dupuis, Michel | Jacquerye, Philippe | Guillaume, Daniel | Reznik, Regine | Wesnes, Keith
BMC Neurology  2011;11:68.
Background
There is need for a cognitive test battery that can be easily used in clinical practice to detect or monitor cognitive performance in patients with multiple sclerosis (MS). In order to conduct, in this patient group, a preliminary investigation of the validity and utility of a brief computerized battery, the Cognitive Drug Research (CDR) battery, we longitudinally assessed cognition in patients with relapsing remitting (RR) MS.
Methods
Forty-three mildly disabled, clinically active RRMS patients were repeatedly assessed with the Digit Symbol Substitution Test (DSST), Paced Auditory Serial Addition Test (PASAT) and five composite scores derived from the CDR computerized cognitive test system (CDR System): Power of Attention, Continuity of Attention, Quality of Working Memory, Quality of Episodic Memory and Speed of Memory. The Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) measured disability.
Results
The composite scores from the CDR battery generally showed excellent test-retest reliability over the repeated assessments, though was low on occasions for the Quality of Working Memory and Quality of Episodic Memory measures. The CDR measures tended to be highly correlated with other measures of cognition (DSST and PASAT) and were also strongly related to disability (EDSS and MSFC). Baseline scores indicated large impairments to visual information processing speed and attention (DSST, Cohen's d 1.1; Power of Attention d 1.4 [reaction time on tasks of focussed and sustained attention]), and a moderate impairment both to sustained attention (Continuity of Attention d 0.6) and complex information processing speed (Speed of memory d 0.7 [reaction time on tasks of working and episodic Memory]), when compared to normative data derived from healthy volunteers enrolled in a series of separate, prior clinical trials. Working memory (Quality of Working Memory) and episodic memory (Quality of Episodic Memory) were unimpaired.
Conclusions
Preliminary validation of the CDR System indicated that for most, but not all measures psychometric properties were adequate and the measures were related to disability (EDSS and MSFC) and other measures of cognition.
doi:10.1186/1471-2377-11-68
PMCID: PMC3128855  PMID: 21649910
Related Articles
Jasperse, Bas | Jakobs, Cornelis | Eikelenboom, M. Judith | Dijkstra, Christine D. | Uitdehaag, Bernard M. J. | Barkhof, Frederik | Polman, Chris H. | Teunissen, Charlotte E.
Journal of Neurology  2007;254(5):631-637.
Abstract
Background
Axonal degeneration is considered to play a major role in the development of clinical disability in multiple sclerosis (MS). N-AcetylAspartic Acid (NAA) is a neuron-specific marker constantly identified in MR-spectroscopy studies of the normal and MS brain. To our knowledge there are no studies available that evaluated NAA in cerebrospinal fluid (CSF) as a possible marker for disease severity.
Objective
To evaluate CSF concentrations of NAA in MS in relation to disease phenotype, clinical measures of disability and MRI markers of disease burden.
Methods
NAA concentrations were determined in CSF of 46 patients with MS (26 relapsing remitting (RRMS), 12 secondary progressive (SPMS) and 8 primary progressive (PPMS)). Prior to lumbar puncture, MS-patients underwent MRI and clinical examination, including the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). Additionally, CSF concentrations of NAA were determined in 12 patients with other neurological diseases (OND).
Results
Median CSF NAA concentration was 0.74 (IQR: 0.59-.94) in RRMS , 0.54 (IQR: 0.35-.73) in SPMS and 0.83 μmol/l (IQR: 0.56-.03) in PPMS patients. SPMS patients had a significantly lower NAA concentration than RRMS patients. NAA concentrations correlated with EDSS (r = )0.37, p = 0.016), MSFC (r = 0.41, p = 0.010), normalised brain volume (r = 0.49, p = 0.001), T2 lesion load (r = )0.35, p = 0.021) and black hole lesion load (r = )0.47, p = 0.002). No differences were observed between OND (median: 0.57 IQR: 0.28-.73) and MS patients.
Conclusion
CSF NAA concentration in MS patients is related to clinical performance and MRI measures of disease burden and may therefore be an important neuron specific marker of disease severity and possibly progression.
doi:10.1007/s00415-006-0415-5
PMCID: PMC2797839  PMID: 17415509
N-acetylaspartic acid; cerebrospinal fluid; multiple sclerosis; magnetic resonance imaging
Related Articles
Results 1-25 (628224)