bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical deficits in multiple sclerosis on the basis of subcortical lesions
Authors: Jeffery Douglas R , Absher John , Pfeiffer Frederick E , Jackson Hagan
Published: January 2007

Patients suffering from multiple sclerosis have a high frequency of cognitive deficits usually attributable to demyelination and axonal loss in the subcortical white matter. Neurologic abnormalities referable to cortical function are uncommon but have been described. The present study describes three patients with clinically definite MS with deficits in cognitive function referable to cortical location. Two of the patients underwent positron emission tomography and showed profound cortical hypometabolism adjacent to subcortical white matter lesions seen on MRI. This paper points out that neurologic deficits referable to cortical sites may be caused by subcortical white matter lesions and that cognitive dysfunction in patients with MS may progress rapidly in the absence of motoria deficits or other evidence of clinical deterioration.
Drop in relapse rate of MS by combination therapy of three different phosphodiesterase inhibitors
Authors: Suzumura Akio , Nakamuro Takuya , Tamaru Tsukasa , Takayanagi Tetsuya
Published: January 2007

Phosphodiesterase inhibitors (PDEIs), when used in combination, synergistically suppress TNFa production by various cells and also suppress experimental demyelination at very low concentrations. We conducted a pilot study to determine whether the combination of three PDEIs suppresses the relapse of MS at the usual therapeutic doses. Of the 12 relapsing remitting MS, the mean relapse rate/year dropped remarkably (from 3.08+3.32 to 0.92+1.86) after PDEI treatment. Seven out of 12 (58.3%) were relapse-free in the follow up period (499+142 days). The combination of three PDEIs can be safe and useful strategy for the future treatment of MS.
Leukotropic herpesviruses in multiple sclerosis
Authors: Hay Kathleen A , Tenser Richard B
Published: January 2007

Detection frequency of human herpesvirus 6 (HHV-6) and Epstein Barr virus (EBV) DNA in multiple sclerosis (MS) patient and controls was investigated. DNA of peripheral blood mononuclear leukocytes (PBL) was isolated and amplified by polymerase chain reaction techniques. EBV DNA was detected in all patients and controls. HHV-6 DNA was detected in 7% of MS patient and in 14% of controls. Result are compared with other investigations of HHV-6 DNA in PBL, serum, CSF and brain of patient with MS. Result of the present study and other investigations do not show an association between HHV-6 in PBL and MS.
Cytokine secretion profile of myelin basic protein-specific T cells in multiple sclerosis
Authors: Rohowsky-Kochan C , Molinaro D , Cook S D
Published: January 2007

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a presumed autoimmune pathogenesis involving autoantigen-specific CD4+ T cells and cytokines. A similar frequency of T cells responding to myelin basic protein (MBP), a putative target in MS, has been observed in MS patient and controls. To dissect the differences between MBP-specific T cells in patient and controls, we have analyzed the cytokine secretion profile of such autoreactive T cells. MBP-specific T cell clones (TCC) were isolated from the peripheral blood of MS patient and controls by limiting dilution. Expression of mRNA for interferon-γ (IFN-γ), interleukin (IL)-4, IL-10, tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) was assessed by polymerase chain reaction whereas secretion of cytokine protein was measured by ELISA. MBP-specific TCC exhibited a heterogeneous cytokine secretion profile with clones displaying Th1, Th2 and Th0 phenotypes. A significant difference in the distribution of the cytokine profile was noted between MS patients and controls. Although the frequency of Th1 secreting MBP-reactive TCC was similar between MS patients and controls, stable MS patient had a significant association with the Th0 phenotype whereas healthy individuals were associated with the Th2 phenotype. In comparison to control TCC, MBP-specific TCC from MS patients secreted increased amount of IFN-γ, IL-4 and IL-10 and decreased quantities of TGF-β. Thus, these studies suggest that there is a dysregulation in the balance between pro-inflammatory Th1 and anti-inflammatory Th2 cytokines in MS. It appears that the presence of Th1 secreting autoreactive T cells in healthy individuals may be counterbalanced by the presence of cells secreting Th2 cytokines and by the augmented production of the immunosuppressive cytokine TGF-β, whereas in MS there is a decrease in these anti-inflammatory agents.
Cost and health related quality of life consequences of multiple sclerosis
Authors: Grima D T , Torrance G W , Francis G , Rice G , Rosner A J , Lafortune L
Published: January 2007

Objectives: To (i) quantify the cost of multiple sclerosis (MS) to the Canadian health care system and society; (ii) measure health utility in MS patients, and (iii) examine the influence of disability on patient utility and health care costs.Materials and methods: A comprehensive patient survey and chart review of relapsing MS patient in remission, relapse and recalling a relapse.Results: Annual remission costs increased with EDSS level ($7596 at EDSS 1, $33 206 at EDSS 6). At all EDSS levels the largest costs were due to inability to work, which increased with EDSS. The average relapse cost for all EDSS levels was $1367. An inverse correlation was found between EDSS level and patient utility for patient in remission and relapse. The decrease in remission health utility from EDSS I to 6 was 0.24, which is 25% greater than the difference in health status between an average 25 and 85 year-old.Conclusions: This study demonstrates that MS produces substantial health care cost and reductions in patient quality of life and ability to work, losses that can be avoided or delayed if disease progression is slowed. These data provide health-care decision-makers with the opportunity to consider the full impact of MS when faced with budget allocation decisions.
Baclofen increases the soleus stretch reflex threshold in the early swing phase during walking in spastic multiple sclerosis patients
Authors: Nielsen Jørgen F , Anderson Jacob B , Sinkjær Thomas
Published: January 2007

The effect of baclofen on walking performance was examined in nine spastic multiple sclerosis patient. In addition, nine healthy subjects were tested as controls. The modulation of the short latency soleus stretch reflex was closer to normal with baclofen compared to the recordings without baclofen, the modulation index being 74% (range: 60-100) with baclofen and 62% (range: 20 -100) without baclofen, P=0.03. In healthy subject the modulation index was 100% (range: 52 -100). In the early swing phase the threshold of the soleus stretch reflex was significantly higher during baclofen medication being 139 degls (range: 63 -302) compared with 93 degls (range: 37-187) with out baclofen, P=0.004. The relation between the stretch velocity (input) and the amplitude of the stretch reflex (output) in early swing phase was unchanged being 0.27 μVs/deg (range: 0.1-1.51) in patient with baclofen and 0.24 μVs/deg (range: 0.08-0.79) without baclofen, P=0.25. Baclofen induced no change in input-output properties of the stretch reflex during walking compared with findings in a sitting position at matched EMG activity. There was a significant correlation between clinical spasticity score and stretch reflex threshold in the early swing phase (p=-0.61, P=0.04) and between clinical spasticity score and the slope of the best linear fit in the early swing phase (p=0.72, P=0.009).
Multiple sclerosis and tonsillectomy: no evidence for an influence on the development of disease or clinical phenotype
Authors: Broadley S A , Deans J , Chataway S JS , Sawcer S J , Compston D AS
Published: January 2007

The notion that cervical lymphatic surgery may influence the development of multiple sclerosis has been suggested before. Recent work in experimental allergic encephalomyelitis lends further support to this idea. We, therefore conducted a case: control study of tonsillectomy in multiple sclerosis. We found no evidence to suggest that tonsillectomy affect susceptibility to multiple sclerosis. This result support previous studies, which have largely failed to show any link between prior tonsillectomy and the subsequent development of multiple sclerosis. In addition, we failed to show any effect of tonsillectomy on the extent of cerebral demyelination as assessed clinically or with magnetic resonance imaging.
Modalities of fatigue in multiple sclerosis: correlation with clinical and biological factors
Authors: lriarte Jorge , Subirá María L , de Castro Purificación
Published: January 2007

Although different factors are probably involved in the etiology of fatigue in multiple sclerosis patient, no definite mechanism has been proposed. We have proposed that fatigue is a complex symptom that includes three clinical different entities (asthenia, fatigability and worsening of symptoms with effort). The goal of this study is to demonstrate if there is a peculiar mechanism for each of the different varieties of fatigue. A control sample of 155 patient (105 women, 50 men) with clinically definite MS was studied. Fatigue was measured using the Fatigue Descriptive Scale (FDS) and the Fatigue Severity Scale (FSS). Treatment depression, anxiety, sleep and cellular immune status were studied too. Fatigue was a symptom in 118 patient (76.13%Y.); 26 patient (22.03%) described it as asthenia (fatigue at rest); 85 patient (72.03%) as fatigability (fatigue with exercise), and seven patient (5.9%) as worsening of symptoms. The severity of pyramidal involvement was significantly more severe in patient suffering from fatigue some immunological parameters were associated with fatigue as well. The discriminant analysis of the data shows that some of the immunoactivation parameters are associated with asthenia (F2 1.5, P < 0.00 1), and pyramidal tract involvement is associated with fatigability (F=10.5, P<0.001). Sleep disorders, anxiety and depression were linked with fatigue in a few patients No relationship with treatment was proven. In conclusion, fatigue in MS seems to be a heterogeneous entity. Asthenia and fatigability may be different clinical entities. Certain immunoactivation parameters correlate with the presence of asthenia while pyramidal involvement is associated with fatigability.
Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern
Authors: Kroencke Dawn C , Lynch Sharon G , Denney Douglas R
Published: January 2007

In order to investigate the associations between fatigue and depression, disability, and disease subtype, 207 individuals with clinically definite Multiple Sclerosis (MS) were administered the Fatigue Severity Scale and the Zung Self-rating Depression Scale during a regular clinic appointment. Their current level of disability was established using the Expanded Disability Status Scale. Fatigue and depression were highly correlated (r=0.58) even when the depression measure was corrected for items overlapping with fatigue and other symptoms or consequences of MS (r=0.44). Fatigue and disability were also correlated (r=0.33). Multiple regression revealed that both depressed mood and disability were significant predictors of fatigue, together accounting for approximately 23% of the variance in patient' self-reported fatigue. The combined groups of primary progressive (n=45) and secondary progressive patient (n=25) appeared to have higher fatigue scores than relapsing-remitting patient (n=137). However an analysis of covariance revealed that this apparent difference was in fact attributable almost exclusively to differences in disability among the three subtypes of MS. Other reports of differences in fatigue between subtypes of MS should be re-examined in light of this finding.
T cell receptor β chain genotyping in Australian relapsing-remitting multiple sclerosis patients
Authors: Buhler Marc McW , Bennetts Bruce H , Heard Robert NS , Stewart Graeme J
Published: January 2007

This study focused on susceptibility to MS within the b-chain of the T-cell antigen receptor (TCRB locus, 7q35) in a cohort of 122 RR-MS patients compared with 96 normal individuals using biallelic polymorphisms across the bv8s1(Vb8.1) to bv11s1 (Vb11) TCRB subregion. The markers bv6s5, bv8s1, bv10s1, bv15s1 and bv3s1 were studied for allele and genotype frequencies; haplotypes were assigned with combinations of two of these markers and stratification for HLA-DR15 was also performed. Linkage disequilibrium was found between alleles of the bv8s1, bv10s1/bv15s1 and bv3s1 loci in both patients and controls. An increase among RR-MS patients in the allele frequency of bv8s1*2 (P=0.03) and the haplotype bv8s1*2/bv3s1*1 (P=0.006) was noted and both were found to be statistically significant. In the DR15-positive group, the association between TCRB and MS was seen with the bv8s1*2 allele (Puc=0.05) and the bv8s1*2/bv10s1 haplotypes (Puc=0.048), while the haplotype associations seen among DR15-negative RR-MS patients included the bv3s1*1 allele (bv10s1*1/bv3s1*1, Puc=0.022; bv8s1*2/bv3s1*1, Puc=0.048). These results support the involvement of the TCRB region in MS susceptibility and encourage further study of the variable gene segments in this region.
Lesion pattern in patients with multiple sclerosis and depression
Authors: Berg D , Supprian T , Thomae J , Warmuth-Metz M , Horowski A , Zeiler B , Magnus T , Rieckmann P , Becker G
Published: January 2007

To assess if a specific lesion pattern or changes of the basal limbic system as seen in primary depression and depression associated with neurodegenerative disorders might be identified in depressive multiple sclerosis (MS) patients, we submitted 78 MS patients to a MRI examination consisting of a quantitative measurement of lesions and of hyperintense signals from the pontomesencephalic midline (raphe). Furthermore relaxometry of the pontomesencephalic midline, a transcranial ultrasound examination rating its echogenicity semiquantitatively and a standardized neurological, neuropsychiatric and neuropsychological assessment were obtained. Thirty-one patients fulfilled the DSM-IV criteria for depression. Depressed MS patients had a significantly larger temporal lesion load than non-depressed MS patients, especially on the right side. A trend of difference was detected for lesions of the right parietal lobe, the right frontal lobe, the cerebellum and the total lesion load. Neither hyperintense signals or relaxometry nor echogenicity of the region at the level of the pontomesencephalic midline were significantly different between the groups. We conclude that depression in MS patients is not associated with an alteration of the basal limbic system at the brainstem as seen in Parkinson's disease or unipolar depression but with an increased lesion load of the projection areas of the basal limbic system.
New low-contrast vision charts: reliability and test characteristics in patients with multiple sclerosis
Authors: Balcer Laura J , Baier Monika L , Pelak Victoria S , Fox Robert J , Shuwairi Sarah , Galetta Steven L , Cutter Gary R , Maguire Maureen G
Published: January 2007

The quantitative assessment of visual function in multiple sclerosis (MS) clinical trials has been limited to Snellen visual acuity. The purpose of this study was to examine the inter-rater reliability and test characteristics of a new visual outcome measure, the Low-Contrast Sloan Letter Charts, in patients with MS and visually-asymptomatic volunteers. Contrast letter acuity scores (letter scores) were measured at each of four contrast levels (100, 5, 1.25 and 0.6%) by two independent raters. Inter-rater agreement was described with the intraclass correlation coefficient (ICC) and comparison of mean scores. Excellent inter-rater agreement (ICC=0.86-0.95) was demonstrated at each contrast level among MS patients (n=100) and visually-asymptomatic volunteers (n=33). Average letter scores at the lowest contrast level (0.6%) were highly variable in the MS group, even among patients with visual acuities of 20/20 or better, and among those who required no assistance for ambulation. Low-Contrast Sloan Letter Chart testing is a highly reliable method of visual assessment, and provides information on an aspect of neurologic impairment in MS which is not captured by Snellen visual acuity or ambulation status. This new method demonstrates excellent potential as a visual function outcome measure for future MS clinical trials.
Effect of precooling on physical performance in multiple sclerosis
Authors: White A T , Wilson T E , Davis S L , Petajan J H
Published: January 2007

Many individuals with MS experience heat sensitivity that may be associated with transient increases in the frequency of clinical signs and symptoms. Although physical activity may be beneficial for those with MS, induced thermal loads may preclude participation in exercise and other daily activities. This project was designed to evaluate the effects of precooling on physical function. Six thermosensitive MS patients were studied. Participants performed a graded exercise test to determine maximal oxygen uptake (VO2max) on a combined arm-leg ergometer. Thermal load was induced by 30 min of exercise under noncooled and precooled conditions at a workrate corresponding to 60% VO2max. Precooling consisted of 30 min lower body immersion in 16-178C water. Fatigue and 25-ft walk performance were assessed before, immediately after, and 30 min following exercise. No treatment differences in VO2 were observed. Rectal temperature, heart rate, and rating of perceived exertion (RPE) were significantly lower during the precooled exercise trial compared to the noncooled trial. Immediately following exercise, 25-ft walk performance and fatigue scores showed significantly greater deterioration in the noncooled condition. Precooling was effective in preventing gains in core temperature with physical work and may allow heat-sensitive individuals with MS to exercise with greater physical comfort.
Apoliprotein E and multiple sclerosis: impact of the epsilon-4 allele on susceptibility, clinical type and progression rate
Authors: Hùgh Peter , Oturai Anette , Schreiber Karen , Blinkenberg Morten , Jùrgensen Ole Steen , Ryder Lars , Paulson Olaf B , Sùrensen Per Soelberg , Knudsen Gitte Moos
Published: January 2007

The purpose of this study was to investigate the relation between APOE genotype and Multiple Sclerosis (MS) in a genetically homogeneous population. We examined 240 patients consulting the MS-clinic during a period of 3 years (1996-1999). The mean age of the patients was 41.7 years (range 19-80 Y, SD 10.0 Y). As a measure of the progression rate (PR) the last registered Expanded Disability Status Scale (EDSS) score was divided by the time span (years) from disease onset until the latest assessment. The APOE genotype was determined from saliva and/or blood samples using PCR-techniques. The prevalence of different APOE genotypes was compared with the allele-distribution in a population of 361 persons from a Danish cross-sectional population study. The frequency of APOE-e4/e4 homozygotes was significantly higher in the MS-group as compared to controls (P<0.05, odds ratio: 2.3), whereas the frequency distribution of other genotypes did not differ significantly. The rate of progression was significantly faster in the APOE-e4/e4 homozygotes compared to other genotypes in the MS group (P<0.05). This study suggests that the APOE-e4/e4 homozygotes have an increased risk of developing MS. MS patients with the APOE-e4/e4 allele may also have an increased rate of disease progression.
The precision of T1 hypointense lesion volume quantification in multiple sclerosis treatment trials: a multicenter study
Authors: Molyneux Paul D , Brex Peter A , Fogg Caroline , Lewis Sara , Middleditch Claire , Barkhof Frederik , Sormani Maria P , Filippi Massimo , Miller David H
Published: January 2007

The volume of hypointense lesions on T1 weighted brain MRI represents an increasingly used MR endpoint in phase III MS treatment trials. In this study we evaluated the reproducibility of hypointense T1 lesion volume quantification in a cohort of Multiple Sclerosis (MS) patients. The gadolinium enhanced T1 weighted brain MR images of 33 MS patients from three European centers were used in this study. These images were acquired as part of a phase III trial of interferon beta-1b in secondary progressive MS. The MRI machine manufacturers and imaging parameters varied according to the MRI acquisition center. Three experienced observers used a semi-automated local thresholding technique to quantify the hypointense T1 lesion volume on two occasions, separated by a delay. The intra and inter observer coefficients of variation were 3.7% and 4.9% respectively, with similar values derived for images obtained at all three sites. There was a generally high level of agreement between the lesion volumes obtained by the three raters. However, a modest but significant measurement drift was identified between the first and second sessions for one of the three raters, highlighting the very real possibility of measurement drift even for experienced observers. Our results support the increasing role for T1 hypointense lesion volume as an outcome measure in multicenter phase III MS treatment trials.
Visuoperceptual impairment in multiple sclerosis patients diagnosed with neuropsychological tasks
Authors: Vleugels Luc , Lafosse Christophe , van Nunen A n , Nachtergaele Saskia , Ketelaer Pierre , Charlier Marianne , Vandenbussche Erik
Published: January 2007

A comprehensive set of 31 binocular neuropsychological tasks assessing a series of spatial and non-spatial visuoperceptual abilities was used to study visuoperceptual impairment in a representative group of 49 MS-clinic patients exhibiting neither diagnosed ophthalmological afflictions nor major psychiatric diagnoses. Among these patients, true frequency rate of visuoperceptual impairment, i.e. of subjects failing four or more tasks, was estimated at 26%. The pattern of visuoperceptual impairment was non-uniform, non-selective, restricted and idiosyncratic. Only four tasks yielded significant rates of impairment. They concerned colour discrimination, the perception of the Müller-Lyer illusion and object recognition in two separate conditions. Each of the four factors identified by factor analysis had an important representative (with factor loading 40.35) among these four tasks. Failures on these tasks correlated poorly. Together, the four tasks satisfactorily predicted visuoperceptual impairment as defined by the comprehensive set of tasks (sensitivity 86.7%; specificity 81.3%), but with regard to an uncontaminated criterion, their aggregate sensitivity and specificity was only 75 and 56% respectively. Visuoperceptual neuropsychological task performance related significantly but weakly to cognitive status, physical disability and to pyramidal, cerebellar and brain stem neurological signs, and did not correlate with other clinical neurological signs, disease duration, type of MS, a history of optic neuritis, depression or medication status.
Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years
Authors: Johnson K P , Brooks B R , Ford C C , Goodman A , Guarnaccia J , Lisak R P , Myers L W , Panitch H S , Pruitt A , Rose J W , Kachuck N , Wolinsky J S ,   Copolymer 1 Multiple Sclerosis Study Group
Published: January 2007

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone®) reduced the relapse rate and slowed accumulation of disability for patients with relapsing-remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34-0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis.
A quantitative study of unpaid caregiving in multiple sclerosis
Authors: Carton H , Loos R , Pacolet J , Versieck K , Vlietinck R
Published: January 2007

Data on healthcare utilisation by MS patients of different grades of disability were collected using the method of a prospective diary. Professional care providers and unpaid caregivers noted during 4 weeks the time they spent and the types of support they provided. The total homecaring time of family and friends amounted to 4.6 and 12 h per day for the moderately and the severely disabled MS patients respectively. The time for unpaid core activities such as mobility help, nursing care and personal care of moderately and severely disabled patients amounted to 0.5 and 2 h per day, exceeding the time for professional medical and paramedical care at home. Eighty per cent of informal homecaring is provided by persons living with the patients, primarily the partner, who provides 60% of homecaring time. Severely disturbed bowel function and absence of a partner were associated with permanent institutionalisation.
The significant change for the Timed 25-Foot Walk in the Multiple Sclerosis Functional Composite
Authors: Kaufman M , Moyer D , Norton J
Published: January 2007

The Timed 25-Foot Walk is under evaluation as a clinical tool to follow patients with MS. Several approaches have been taken to define a clinically significant change in this measurement. This study was undertaken to define the range of values expected for the Timed 25-Foot Walk and to correlate prospectively the change in walk-time that occurs during an exacerbation of MS associated with subjective difficulty walking. Five results from this study are emphasized. (1) Patients who were minimally affected by MS frequently walked 25 feet between three and five seconds. (2) the walk-time variability, defined as the ratio of the longest to the shortest walk-time, minus 1, times 100%, for three consecutive trials was generally 20% or less; (3) if the two fastest walk-times obtained in three trials were compared, the walk-time variability was almost always 10% or less; (4) for clinically stable individuals, the walk-times of single trials separated by 12 months or less generally varied less than 20%; and (5) patients who complained of difficulty walking, but who did not have changes otherwise detectable by examination, generally had a prolongation of walk-time. These results suggest that an increase of more than 20% in the Timed 25-Foot Walk may indicate a significant change in gait.
pattern of cytokine secretion by peripheral blood cells of patients with multiple sclerosis in Brazil
Authors: da Costa Patrícia Mara , Yasuda Clarissa Lin , Scagliusi Silvia M , Diaz-Bardales Blanca Maria , Maciel Ernane , Damasceno Benito P , Blotta M Heloisa SL , Tilbery Charles P , Santos Leonilda MB
Published: January 2007

Autoimmune T cells play a key role as regulators and effectors of organ-specific autoimmune disease. In multiple sclerosis (MS), activated T cells specific for myelin components produce a plethora of inflammatory cytokines and mediators that contribute to myelin damage. The production of proinflammatory and regulatory cytokines by peripheral blood cells from patients with active and stable MS and healthy controls were examined. The results show that TNFa production was somewhat elevated in active MS with no significant increase in the level IFNg, whereas in the chronic phase the anti-inflammatory cytokines IL-10 and TGFb increased, accompanied by a reduction in IFNg when stimulated by myelin basic protein.
Interferon-beta treatment for patients with multiple sclerosis: the patients' perceptions of the side-effects
Authors: Gottberg K , Gardulf A , Fredrikson S
Published: January 2007

The aims of this study were to investigate (i) the self-reported frequency and intensity of systemic side-effects and their impact on the daily lives of patients suffering from Multiple Sclerosis (MS) and undergoing interferon-beta therapy and (ii) the self-reported frequency and perceptions of any local-tissue reactions. Forty patients aged 22-59 years (27 females) with relapsing/remitting MS were consecutively recruited for the study (17 on interferon-beta-1a and 23 on interferon-beta-1b). Two self-administered questionnaires were used before and after 1, 4, 8 and 16 weeks of therapy. The interferon therapy was found to be associated with flu-like symptoms. Most systemic side-effects were reported to be mild and to have little impact on the patients' daily lives. Asthenia and fatigue were more often rated as moderate or severe. The most frequently reported local-tissue side-effects were redness and local pain at the injection sites. A considerable inter-individual variation was found among patients regarding the perceptions of both the systemic and local side-effects. This suggests that it is of importance to identify early those patients who may need more support or other interventions to maintain a successful compliance.
MS-CANE: a computer-aided instrument for neurological evaluation of patients with multiple sclerosis: enhanced reliability of expanded disability status scale (EDSS) assessment
Authors: Cohen Y C , Hassin-Baer S , Olmer L , Barishev R , Goldhammer Y , Freedman L , Mozes B
Published: January 2007

Kurtzke's EDSS remains the most widely-used measure for clinical evaluation of MS patients. However, several studies have demonstrated the limited reliability of this tool. We introduce a computerized instrument, MS-CANE (Multiple Sclerosis Computer-Aided Neurological Examination), for clinical evaluation and follow up of patients with multiple sclerosis (MS) and to compare its reliability to that of conventional Expanded Disability Status Scale (EDSS) assessment. We developed a computerized interactive instrument, based on the following principles: structured gathering of neurological findings, reduction of compound notions to their basic components, use of precise definitions, priority setting and automated calculations of EDSS and functional systems scores. An expert panel examined the consistency of MS-CANE with Kurtzke's specifications. To determine the effect of MS-CANE on the reliability of EDSS assessment, 56 MS patients underwent paired conventional EDSS and MS-CANE-based evaluations. The inter-observer agreement in both methods was determined and compared using the kappa statistic. The expert panel judged the tool to be compatible with the basic concepts of Kurtzke's EDSS. The use of MS-CANE increased the reliability of EDSS assessment: Kappa statistic was found to be 0.42 (i.e. moderate agreement) for conventional EDSS assessment versus 0.69 (i.e. substantial agreement) for MS-CANE (P=0.002). We conclude that the use of this tool may contribute towards a standardized and reliable assessment of EDSS. Within clinical trials, this could increase the power to detect effects, thus reducing trial duration and the cohort size required.
Relationship between brain atrophy and disability: an 8-year follow-up study of multiple sclerosis patients
Authors: Fisher E , Rudick R A , Cutter G , Baier M , Miller D , Weinstock-Guttman B , Mass M K , Dougherty D S , Simonian N A
Published: January 2007

Brain atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in multiple sclerosis. The potential usefulness of atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between atrophy and disability. A follow-up study was performed to measure atrophy and disability scores in patients from the Multiple Sclerosis Collaborative Research Group's phase III trial of IFNb-1a (Avonex) in relapsing-remitting multiple sclerosis. New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization. The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a magnetic resonance imaging exam to calculate the brain parenchymal fraction. Brain parenchymal fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years). Furthermore, the change in BPF was correlated with the changes in disability scores from the end of the phase III trial to the follow-up exam. These data suggest that brain atrophy may be a useful and clinically relevant marker of disease progression in relapsing-remitting MS.
Olfactory dysfunction and extent of white matter abnormalities in multiple sclerosis: a clinical and MR study
Authors: Zorzon Marino , Ukmar Maja , Bragadin Luisa Monti , Zanier Francesca , Antonello Rodolfo M , Cazzato Giuseppe , Zivadinov Robert
Published: January 2007

Background: The relative contribution to the olfactory dysfunction of the lesions in the specific brain regions involved in olfaction compared with the lesions scattered all over the rest of the brain has not been fully clarified yet in patients with multiple sclerosis (MS). The concurrent use of Magnetic Resonance Imaging (MRI) and a standardized test of odor identification ability now permits to study the relation between smell loss and the extent of white matter abnormalities. Methods: We tested the olfactory function of 40 patients with definite MS and of 40 age-sex- and smoking-habit-matched healthy controls by using the Cross Cultural Smell Identification Test. We measured also the lesion load on T2-weighted images in the inferior-frontal and temporal lobes and in the rest of the brain in MS patients. Therefore, we tried to correlate measures of lesion load and smell test scores. Results: A robust correlation was demonstrated between MR measures of lesion load in the white matter of the olfactory brain region and smell loss (r=70.739, P50.0001). A significant relationship has been found even after taking potential confounding factors, such as sex, age, disease duration, disability, anxiety and depression, into account (r=70.90, P50.0001). Conclusions: Our findings show, in MS patients with stable neurological impairment and no recent disease exacerbation, a correlation between smell loss and the lesion load in the regions of the brain involved in olfaction and support the theory that the extent and severity of MRI abnormalities in specific brain regions are related to the presence of selective neurologic and neuropsychologic impairment.
Personality as a predictor of coping efforts in patients with multiple sclerosis
Authors: Rätsep T , Kallasmaa T , Pulver A , Gross-Paju K
Published: January 2007

The aim of the study was to explore personality traits as predictors of coping with disease-related distress in patients with multiple sclerosis (MS). All patients with clinically definite MS in a city with a population of approximately 100 000 were asked to complete the NEO Personality Inventory and a multidimensional coping inventory (COPE). There was an 83% response rate yielding 49 patients for the study population and 49 controls, matched for age, gender and educational level to the MS-patients, were used as comparison. Only Neuroticism correlated significantly with emotion-focused coping in both groups. Extraversion and Openness to Experience were linked to task-oriented coping strategies in normal controls but not in the MS-group. Agreeableness was associated with avoidance-oriented coping strategies only in the MS-group. Thus, the relation of certain personality characteristics to the choice of strategies for coping with the disease-related distress appear to differ from coping with stressful problems in everyday life. As dispositional characteristics may interfere with adaptive coping responses, analysis of personality traits and coping strategies could contribute while attempting to relieve the consequences of chronic disease on everyday life.
Raised cerebrospinal fluid nitrite and nitrate levels in patients with multiple sclerosis: no correlation with disease activity
Authors: Drulović J , Dujmović I , Mesaroš Š , Samardžić T , Maksimović D , Stojsavljević N , Lević Z , Stojković M Mostarica
Published: January 2007

A growing body of evidence implicates excessive generation of nitric oxide (NO) within the central nervous system (CNS) in multiple sclerosis (MS). The aim of our study is to analyse nitrite and nitrate as end products of NO in the cerebrospinal fluid (CSF) from MS patients and correlate the concentrations with clinical characteristics of the disease. CSF nitrite and nitrate concentrations were measured after reduction of nitrate, by Griess reaction, in 105 MS patients, 27 patients with non-inflammatory neurological disorders (NIND) and 13 individuals without neurological disorder (Co). Mean CSF nitrite and nitrate concentrations were significantly higher in patients with MS and NIND compared with the Co patients (9.44 and 8.68, respectively, versus 6.85 μM; P=0.0001 and P=0.031, respectively). There was no significant correlation between CSF nitrite and nitrate concentrations and activity, phase, severity and duration of MS. Our data are in agreement with the results of previous studies which have demonstrated raised concentrations of CSF NO metabolites in MS patients, providing further evidence for NO involvement in MS. The lack of correlation between NO metabolites and disease activity speaks in favour of the possible dual role of NO, as both immunoregulatory and proinflammatory molecule, in the pathogenesis of MS.
The predictive value of gadolinium enhancement for long term disability in relapsing-remitting multiple sclerosis-preliminary results
Authors: Losseff N A , Miller D H , Kidd D , Thompson A J
Published: January 2007

As short-term MRI studies are increasingly being used to monitor disease activity in multiple sclerosis (MS) it is vital to establish if short-term MRI activity is predictive of long term clinical outcome. We followed up after 5 years a group of 10 benign (relapsing-remitting MS with a disease duration 410 years and EDSS 43) and 10 early relapsing-remitting patients who previously had monthly serial MRI scans for 6 months. In the early relapsing-remitting group median EDSS at entry to the initial serial study was three and in the benign group 2.5. At 5-year follow up, five of these 20 patients had developed a definite deterioration in EDSS. The median number of new enhancing lesions detected originally in the group that had deteriorated was 11 (7-17) compared to 0 (0-5) new enhancing lesions, for those who had not deteriorated (P50.05). There was a trend towards a higher baseline T2 lesion load in the group with a definite change in EDSS but this was not significant. This study suggests that short-term measurement of the number of gadolinium enhancing lesions may predict long term outcome in relapsing-remitting MS.
Intra-observer, inter-observer and inter-scanner variations in brain MRI volume measurements in multiple sclerosis
Authors: Gasperini C , Rovaris M , Sormani M P , Bastianello S , Pozzilli C , Comi G , Filippi M
Published: January 2007

Introduction: Measurement of brain volume on magnetic resonance imaging (MRI) scans is regarded as an objective marker of multiple sclerosis (MS) severity with the potential to monitor treatment efficacy accurately. This study was performed to assess the variability of brain MRI volume measurements. Patients and methods: We studied nine patients with relapsing-remitting MS, who were imaged on two occasions (separated by an interval of 24 h) using two different MR scanners and fast fluid-attenuated inversion recovery (fast-FLAIR) sequences. The whole brain volume computed from each image was measured three times by three observers using a seed-growing technique based on signal intensity thresholding. Intra-observer, inter-observer and inter-scanner variabilities were expressed as coefficients of variations (COVs). The inter-scanner variability included not only the intra-observer variation but also the repositioning variability and the variation in observed brain volume caused by different scanner hardware and sequence implementations. Results: There was no statistically significant difference in patients' brain volume values between observers (P=0.82) or between scanners (P=0.30). The mean intra-observer COV was 1.2% (s.e.=0.4%), the mean inter-observer COV was 1.8% (s.e.=0.8%) and the mean inter-scanner COV was 2.4% (s.e.=1.2%). The intra-observer variance was not statistically different from those found between observers (P=0.83) or scanners (P=0.44). Conclusion: The intra-observer variability in brain volume measurements found in this study was within the range of intra-observer variability found in previous studies. This study shows that the use of different observers and MR scanners has only a small influence on the measured brain volume and does not affect the reproducibility of this measurement greatly.
United States open-label glatiramer acetate extension trial for relapsing multiple sclerosis: MRI and clinical correlates
Authors: Wolinsky Jerry S , Narayana Ponnada A , Johnson Kenneth P ,   Copolymer 1 Multiple Sclerosis Study Group and the MRI Analysis Center
Published: January 2007

After the placebo-controlled extension of the pivotal US trial of glatiramer acetate for the treatment of relapsing multiple sclerosis ended, 208 participants entered an open-label, long-term treatment protocol. Magnetic resonance imaging (MRI) was added to the planned evaluations of these subjects to determine the consequences of long-term treatment on MRI-defined pathology and evaluate its clinical correlates. Of the 147 subjects that remained on long-term follow-up, adequate images were obtained on 135 for quantitative MRI analysis. The initial imaging sessions were performed between June 1998 and January 1999 at 2447+61 days (mean+standard deviation) after the subject's original randomization. Clinical data from a preplanned clinical visit were matched to MRI within 3+51 days. At imaging, 66 patients originally randomized to placebo (oPBO) in the pivotal trial had received glatiramer acetate for 1476+63 days, and 69 randomized to active treatment with glatiramer acetate (oGA) were on drug for 2433+59 days. The number of documented relapses in the 2 years prior to entering the open-label extension was higher in the group originally randomized to placebo (oPBO=1.86+1.78, oGA=1.03+1.28; P=0.002). The annualized relapse rate observed during the open-label study was similar for both groups (oPBO=0.27, +0.45 oGA=0.28+0.40), but the reduction in rate from the placebo-controlled phase was greater for those beginning therapy with GA (oPBO reduced by 0.66+0.71, oGA reduced by 0.23+0.58; P=0.0002). One or more gadolinium enhancing lesions were found in 27.4% of all patients (number of distinct enhancements=1.16+2.52, total enhanced tissue volume=97+26 ml). The risk of having an enhancement was higher in those with relapses during the open-label extension (odds ratio 4.65, 95% confidence interval (CI) 2.0 to 10.7; P=0.001). The odds for finding an enhancement was 2.5 times higher for those patients originally randomized to placebo (CI 1.1 to 5.4; P=0.02) compared to those always on glatiramer acetate. MRI-metrics indicative of chronic pathology, particularly measures of global cerebral tissue loss (atrophy), were uniformly worse for those originally on placebo. These observations enrich our long-term follow up of the clinical consequences of treatment with glatiramer acetate to include its apparent effects on MRI-defined pathology. They show that the effect of glatiramer acetate on enhancements is definite, but modest, consistent with the drug's described mechanisms of action, and that a delay in initiating treatment results in progression of MRI-measured pathology that can be prevented.
Long-term therapy with glatiramer acetate in multiple sclerosis: effect on T-cells
Authors: Ragheb Samia , Abramczyk Sarah , Lisak Deena , Lisak Robert
Published: January 2007

Glatiramer acetate (GA) is an immunotherapeutic drug for multiple sclerosis (MS). Several mechanisms of action have been demonstrated which target and affect T-cells that are specific for myelin antigen epitopes. We measured the in vitro proliferation of GA-responsive T-cells from untreated MS patients and from normal healthy subjects; in addition, we determined the effect of prolonged GA therapy or interferon-b therapy on the in vitro proliferation of GA-responsive T-cells of MS patients. We found that GA induces the proliferation of T-cells isolated from individuals who have not been previously exposed to GA, and that long-term in vivo therapy of MS patients with GA abrogates the GA-induced proliferative response of T-cells. In GA-treated patients, there is no evidence of generalized immunosuppression; both tetanus toxoid and anti-CD3 induced proliferative responses remain unaffected. We propose that prolonged in vivo exposure to GA may result in the eventual induction of anergy or deletion of a population of GA-responsive cells that may also be T-cells that are pathogenic in MS. This mechanism of action, in addition to other mechanisms that have been demonstrated, suggests that GA has pleiotropic effects on the immune system in MS.
Disability and prognosis in multiple sclerosis: demographic and clinical variables important for the ability to walk and awarding of disability pension
Authors: Myhr K M , Riise T , Vedeler C , Nortvedt M W , Grønning M , Midgard R , Nyland H I
Published: January 2007

Objective: To evaluate disability and prognosis in an untreated population-based incidence cohort of multiple sclerosis (MS) patients. Methods: The Expanded Disability Status Scale (EDSS) score was recorded in 220 MS patients. Disease progression was assessed by life table analysis with different endpoints and multivariate Cox regression analysis was performed for evaluation of prognostic factors. Results: The probability of being alive after 15 years was 94.8+1.8% (s.e.), of managing without a wheelchair (EDSS57.0) 75.8+3.2%, of walking without walking assistance (EDSS56.0) 60.3+3.6%, and of not being awarded a disability pension 46.0+3.7%. The probability of still having a relapsing-remitting (RR) course after 15 years was 62.0+4.1%. A RR course and long interval between the initial (onset) and second episode (43 years) predicted favorable outcome. There was also a trend towards favorable outcome in patients with optic neuritis, sensory symptoms and low age at onset, but these factors were associated with the RR course. Motor symptoms and high age at onset indicated unfavorable outcome, but these factors were associated with the primary progressive course. Conclusions: A RR course and long inter-episode intervals in the early phase of the disease were associated with a better outcome. Other onset characteristics indicating a favorable outcome were associated with the RR course while characteristics indicating an unfavorable outcome were associated with the PP course.