bluuebunny/crossref_metadata_2025 huggingface dataset:
Water diffusion is elevated in widespread regions of normal-appearing white matter in multiple sclerosis and correlates with diffusion in focal lesions
Authors: Werring D J , Clark C A , Droogan A G , Barker G J , Miller D H , Thompson A J
Published: January 2007

Pathological changes in the normal-appearing white matter in multiple sclerosis are well recognised, but their relationship to pathology in focal lesions is not well understood. Magnetic resonance diffusion imaging is sensitive to abnormalities in the integrity, size and geometry of water spaces in brain tissue. This study investigated the anatomical distribution of normal-appearing white matter diffusion abnormalities and their relationship to diffusion in focal lesions in multiple sclerosis (MS). The average apparent diffusion coefficient (ADCav) was measured by three-axis echoplanar diffusion imaging in normal-appearing white matter regions and lesions throughout the brain in 40 patients, and in white matter in 14 matched controls. The correlation between the ADCav in normal-appearing white matter and lesions was determined. In controls and patients, diffusion was highest in the corpus callosum. Patients had a higher mean ADCav than controls in widespread regions including the corpus callosum, cerebellar, temporal and occipital normal-appearing white matter. Mean normal-appearing white matter ADCav correlated strongly with mean lesion ADCav (r=0.67, P < 0.001). This study demonstrates that water diffusion is elevated in widespread areas of normal-appearing white matter in MS, and is correlated with diffusion in lesions. These findings suggest that the pathogenetic mechanisms causing tissue damage in lesions and normal-appearing white matter are at least partly linked.
Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression
Authors: Huang Yu-Min , Kouwenhoven Mathilde , Jin Ya-Ping , Press Rayomand , Huang Wen-Xin , Link Hans
Published: January 2007

Dendritic cells (DC) are important antigen presenting cells (APC) and play a major role in initiating and orchestrating immune responses by priming T cells. Little is known about involvement of DC in multiple sclerosis (MS), where auto-aggressive T cells against myelin autoantigens are considered to contribute to inflammation and demyelination in the central nervous system. In this study, we compared phenotype and cytokine secretion of DC from patients with MS, other neurological diseases (OND) and healthy subjects. DC were generated from blood adherent mononuclear cells (MNC) by culture for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature myeloid lineage, comprising CD1a+ and CD11c+. The proportion of CD1a+ DC, being important for presentation of lipid antigens to T cells, was higher in MS patients compared to controls. The proportion of CD86+ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS. Low proportions of CD86+ DC were only observed in untreated MS patients but not in patients treated with IFN-b. Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls. These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.
Sodium fusidate (fusidin) ameliorates the course of monophasic experimental allergic encephalomyelitis in the Lewis rat
Authors: Di Marco Roberto , Puglisi Gaetano , Papaccio Gianpaolo , Nicoletti Alessandra , Patti Francesco , Reggio Arturo , Bendtzen Klaus , Nicoletti Ferdinando
Published: January 2007

We have evaluated the effect of the immunosuppressant sodium fusidate (fusidin) on the course of acute monophasic experimental encephalomyelitis (EAE) in male Lewis rats. Prophylactic treatment with fusidin, 80 or 120 mg/kg bd wt., markedly ameliorated the course of the disease in rats immunized with myelin basic proteins in complete Freund's adjuvant, entailing delayed onset of symptoms, lower clinical scores and more rapid recovery than PBS-treated control rats. The fusidin-treated, immunized rats exhibited milder mononuclear cell infiltration of brains and spinal cords than control animals. These data provide further evidence for the anti-inflammatory effect of fusidin and suggest that this drug may be valuable for the treatment of human multiple sclerosis.
Day-to-day variability of maximum walking distance in MS patients can mislead to relevant changes in the Expanded Disability Status Scale (EDSS): average walking speed is a more constant parameter
Authors: Albrecht H , Wötzel C , Erasmus L P , Kleinpeter M , König N , Pöllmann W
Published: January 2007

In this preliminary study we measured maximum walking distance and walking time on four consecutive days in 29 patients with clinically stable multiple sclerosis (MS). Patients were included in the study if they could achieve a maximum unaided walking distance of 100 up to 500 m. Our results showed a certain day-to-day variability of maximum walking distance, in some cases meaning changes up to 1.5 points in the expanded disability status scale (EDSS), which could be misinterpreted as a progression of the disease. Simultaneous measurements of maximum walking time showed a similar variability, unlike the mean walking speed which turned out to be more stable. Our results therefore suggest that scoring of MS patients should not be based on one single measurement of the maximum walking distance. The more reliable parameter appears to be the mean walking speed.
An assessment of the spectrum of disability and handicap in multiple sclerosis: a population-based study
Authors: McDonnell G V , Hawkins S A
Published: January 2007

Objectives: To establish the spectrum of disability and handicap in a population based sample of multiple sclerosis (MS) patients. Background: Much knowledge exists about the epidemiology of MS but, despite its importance for health and social service planning, there remains relatively little data on the extent and nature of disability and handicap in this population. Methods: In a prevalence study in the north-east of N. Ireland, 288 patients (Poser criteria) were identified. Disability and handicap were assessed using the Incapacity Status Scale and Environmental Status Scale of the Minimal Record of Disability for MS. Results: Both scales were completed for 248 (86%) of patients. Just 71 (29%) are fully independent in all basic ADL's of bathing, dressing, grooming and feeding. Fifty-seven (23%) are unable to climb a flight of stairs and 102 (42%) acknowledge problems with sexual function. Sixty-one (25%) were working essentially full-time and 53 (21%) had no external financial support. Forty-five (18%) had changed residence due to MS, 12 (5%) were institutionalised and 86 (35%) required assistance for at least 1 h/day with ADL's. Eighty-one (33%) were unable to drive a car or use public transport. Forty-two (17%) access community services for at least 1 h/day on average. Conclusions: This data gives a clear indication of the considerable range of basic health and social issues in a typical MS community. Further work is required to establish patient perceptions of the adequacy of care provision and whether standards of care for MS patients are being met.
Recovery following acute exacerbations of multiple sclerosis: from impairment to quality of life
Authors: Bethoux Francois , Miller Deborah M , Kinkel R Philip
Published: January 2007

To observe the pattern of recovery after treatment with intravenous Methylprednisolone (i.v. MP) for a relapse of multiple sclerosis (MS), and to determine the best time to plan further interventions such as rehabilitation, we assessed consecutive outpatients (n=24) treated with i.v. MP for a relapse over a period of 12 weeks. Outcomes measures used were the Expanded Disability Status Scale (EDSS), the Incapacity Status Scale (ISS), the MOS Short Form-36 (SF-36), the Mental Health Inventory (MHI), and the MS-Related Symptom Checklist (MSSCL). There was statistically significant early improvement of EDSS and ISS scores, which was sustained until week 12, and significant improvement of MHI and MSSCL scores between 4 and 12 weeks. Although trends for improvement of scores reflecting the same pattern of recovery were observed with the SF-36 physical and mental composites, these changes did not reach statistical significance. Our results suggest that improvement of impairments and disability after treatment with i.v. MP for a relapse of MS occurs early, while improvement of subjective health status is delayed. Even after maximum improvement is reached, patients are left with multiple symptoms and functional limitations, and may benefit from additional rehabilitative interventions.
Analysis of an interferon-γ gene dinucleotide-repeat polymorphism in Nordic multiple sclerosis patients
Authors: Dai Y , Masterman T , Huang W X , Sandberg-Wollheim M , Laaksonen M , Harbo H F , Oturai A , Ryder L P , Soelberg-Sørensen P , Svejgaard A , Hillert J
Published: January 2007

The proinflammatory cytokine interferon (IFN)-γ has been shown to influence the course of multiple sclerosis (MS). The IFN-γ (IFNG) contains a multiallelic dinucleotide repeat in intron l. To investigate whether alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyses on 100 sibling pairs from four Nordic countries, and case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls. To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases. We also measured IFN-γ mRNA levels in unstimulated peripheral blood mononuclear cells from 46 MS patients and 27 controls grouped according to IFNG intron l genotype. Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results. Genotype frequencies for intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the benign-MS octile differ significantly from those in the severe-MS octile. Comparison of IFN-γ mRNA levels in genotype-conditioned subgroups revealed no significant differences. Thus, alleles at the IFNG intron l dinucleotide repeat appear to affect neither MS susceptibility and severity nor IFN-γ mRNA expression in vivo.
Self-administered Expanded Disability Status Scale with functional system scores correlates well with a physician-administered test
Authors: Bowen James , Gibbons Laura , Gianas Ann , Kraft George H
Published: January 2007

Background: Patient-administered measures are needed to assess disability cost-effectively in large epidemiological studies. Setting: An outpatient clinic in a large multiple sclerosis center. Methods: A self-administered EDSS questionnaire was developed (EDSS-S). Consecutive patients with clinically definite multiple sclerosis completed the EDSS-S (n=95). During the same visit, a physician completed an EDSS (EDSS-P). Scores below 4.0 were determined using functional system (FS) scores. Scores above 4.0 were calculated by two methods, using gait alone and using gait and functional system scores combined. Results: EDSS-P scores ranged from 0-9.5 (mean 5.1, median 5.0, 78% female, age 17-78, mean age 45). Mean EDSS-P, EDSS-S and intraclass correlation coefficients of agreement were: EDSS using ambulation alone (4.6, 5.1, 0.89), EDSS using ambulation and FS scores (4.6, 5.3, 0.87), bowel/bladder FS scores (1.6, 1.7, 0.79), pyramidal FS scores (2.1, 2.4, 0.67), sensory FS scores (1.6, 2.1, 0.60), cerebellar FS scores (1.1, 1.6, 0.55), brainstem FS scores (0.5, 1.2, 0.45), vision FS scores (1.9, 1.3, 0.38), cerebral FS scores (0.6, 2.3, 0.27). Conclusions: Very good correlation was seen between patient and physician scores for EDSS and the bowel/bladder FS score. Four other FS scores correlated moderately. In general, patients scored themselves more disabled than physicians.
Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS
Authors: Chen M , Gran B , Costello K , Johnson K , Martin R , Dhib-Jalbut S
Published: January 2007

Glatiramer acetate (GA) is an approved treatment for multiple sclerosis (MS). The proposed mechanism of action is the induction of GA-specific T cells characterized by protective anti-inflammatory Th2 response. We tested this hypothesis in 11 MS patients treated with GA from 1-19 months. Interferon-g and IL-5 (markers of Th1 and Th2 responses respectively) were assayed by ELISA in GA-specific T-cell lines (TCL) supernatants. Th1/Th2 bias was defined based on the ratio of IFN-γ/IL-5 secretion. Fifty-eight pre-treatment, and 75 on-treatment GA-specific TCL were generated. On-treatment mean IL-5 levels in GA-TCL increased significantly, whereas those for IFN-g were markedly reduced. Consequently, the ratio of IFN-γ/IL-5 also shifted in favor of a Th2 response. The percentage of GA-TCL classified as Th1 was decreased, whereas those classified as Th2 increased on-treatment as compared to pre-treatment. Some GA-specific TCL, (approximately 25%) generated during treatment secreted predominantly IL-5 in response to MBP and the immunodominant MBP peptide 83-99, indicating that these crossreactive antigens can act as partial agonists for GA-reactive TCL. These results strongly suggest that the mechanism of action of GA in MS involves the induction of crossreactive GA-specific T cells with a predominant Th2 cytokine profile.
Physiologic studies of male sexual dysfunction in multiple sclerosis
Authors: Yang C C , Bowen J D , Kraft G H , Uchio E M , Kromm B G
Published: January 2007

Objective: We conducted this investigation to better define the neural disruptions that result in sexual dysfunction in men with multiple sclerosis (MS), using genital electrodiagnostic testing and nocturnal penile tumescence and rigidity monitoring. Methods: Thirteen men with MS and sexual dysfunction were recruited for the study. Twelve healthy, sexually potent men were enrolled as controls. All underwent pudendal somatosensory evoked potential (SEP) testing using standard methods, and a new modification to isolate the right and left dorsal nerves of the penis. RigiScan testing was performed on the MS subjects to assess nocturnal erectile function. Results: Unilateral and bilateral DNP SEPs were able to be performed on the control subjects. In all but one MS subjects, DNP SEP abnormalities were found. Three men had normal latency bilateral DNP SEP latencies, but on unilateral DNP testing, abnormalities were identified. Seven men, including those with abnormal or absent SEP latencies, had normal nocturnal erectile activity. There was no correlation between overall functional status, presence of abnormal or absent SEP, and quality of nocturnal erectile activity. Conclusions: Genital SEP abnormalities are common in men with MS and sexual dysfunction. Unilateral DNP SEP testing was more sensitive in identifying abnormalities than the standard method of pudendal SEP testing. One of the causes of sexual dysfunction in men with MS may be due to genital somatosensory pathway disruption, with sparing of the efferent tracts in some men.
Multiple sclerosis and oligodendroglioma
Authors: Green Ari J , Bollen Andrew W , Berger Mitchel S , Oksenberg Jorge R , Hauser Stephen L
Published: January 2007

Two cases of multiple sclerosis (MS) and oligodendroglioma are reviewed, increasing the total number of reported cases to 11. In this series, the clinical onset of MS preceded the discovery of the tumor by a mean of 15 years. No distinguishing features of oligodendroglioma were characteristic of MS-associated cases. However, there was an overrepresentation of benign MS. Although this could result from biased ascertainment, other possibilities, including effective remyelination mediated by mitotically active oligodendrocytes, or secretion of immunosuppressive cytokines by the tumor tissue, cannot be excluded. It is likely that the coexistence of MS and oligodendroglioma is due to chance alone, nonetheless the possibility that glioma derived factors can moderate the disease course in MS is deserving of further study.
Diffusion tensor imaging in early relapsing-remitting multiple sclerosis
Authors: Griffin Colette M , Chard Declan T , Ciccarelli Olga , Kapoor Raj , Barker Gareth J , Thompson Alan J , Miller David H
Published: January 2007

Diffusion tensor magnetic resonance imaging (DTI) indices are abnormal in patients with established multiple sclerosis (MS). The objective of this study was to examine the diffusion characteristics of MS lesions, normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) in MS patients with early relapsing-remitting disease. A further objective was to investigate the relationship between three DTI parameters (fractional anisotropy (FA), mean diffusivity (MD) and volume ratio (VR)) and clinical outcome measures (Kurtzke expanded disability status scale (EDSS) and MS Functional Composite Measure) in early disease. DTI was performed in 28 patients and 27 controls. Analysis was carried out using a region of interest (ROI) approach. ROIs were placed in 12 NAWM and nine NAGM regions. Significant differences were found in FA, MD and VR between lesions and NAWM (P<0.001 for all three DTI parameters). No significant differences were found between patients and controls when examining NAWM or NAGM, although there was a trend for abnormal NAWM FA and VR in some regions. No correlation was found between DTI parameters in lesions, NAWM or NAGM and the clinical outcome measures. The lack of significant DTI abnormality in the NAWM and NAGM may reflect a lack of pathological change or a limited sensitivity of DTI using ROI methodology. Previous studies have shown abnormalities in T1 relaxation time, magnetisation transfer ratio (MTR) and N-Acetyl aspartate (NAA) in this cohort of patients, and as such, DTI using a region of interest (ROI) approach may not be as sensitive as other MR techniques in detecting subtle changes in normal appearing brain tissue in early disease.
Modelling new enhancing MRI lesion counts in multiple sclerosis
Authors: Sormani M P , Bruzzi P , Rovaris M , Barkhof F , Comi G , Miller D H , Cutter G R , Filippi M
Published: January 2007

Magnetic resonance imaging (MRI) has been established as the most relevant paraclinical tool for diagnosing and monitoring multiple sclerosis (MS). In this context, counting the number of new enhancing lesions on monthly MRI scans is widely used as a surrogate marker of MS activity when evaluating the effect of treatments. In this study, we investigated whether parametric models based on mixed Poisson distributions (the Negative Binomial (NB) and the Poisson-Inverse Gaussian (P-IG) distributions) were able to provide adequate fitting of new enhancing lesion counts in MS. We found that the NB model gave good approximations in relapsing7remitting and secondary progressive MS patients not selected for baseline MRI activity, whereas the P-IG distribution modelled better new enhancing lesion counts in relapsing-remitting MS patients selected for baseline activity. This study shows that parametric modelling for MS new enhancing lesion counts is feasible. This approach should provide more targeted tools for the design and the analysis of MRI monitored clinical trials in MS.
Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease
Authors: Spitsin S , Hooper D C , Leist T , Streletz L J , Mikheeva T , Koprowski H
Published: January 2007

Peroxynitrite has been implicated in the pathogenesis of multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). Previously, we have shown that administration of uric acid (UA), a peroxynitrite scavenger, is therapeutic in EAE. We have also shown that MS patients have lower levels of serum uric acid than healthy individuals or those with other neurological diseases. The aim of this investigation was therefore to raise serum UA levels in MS patients. Oral administration of UA failed to increase low serum UA levels, evidently due to its degradation by gastrointestinal bacteria. However, serum UA could be raised and maintained at elevated levels for a year and more without reported side-effects by oral administration of its precursor inosine. Three of 11 patients given inosine showed some evidence of clinical improvement and there was no sign of disease progression in the remaining patients. Gadolinium-enhanced lesions, observed in two patients before receiving inosine, could not be detected after either 10 or 15 months inosine treatment. These data provide evidence that serum UA levels can be readily manipulated and that the benefit of higher levels to individuals with MS should be studied further in greater number of patients.
Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability
Authors: Flachenecker Peter , Reiners Karlheinz , Krauser Miriam , Wolf Annalaska , Toyka Klaus V
Published: January 2007

Background: Autonomic dysfunction is frequently observed in patients with multiple sclerosis (MS) but the evolution over time and the relationship to clinical characteristics are not yet established. Objectives: We investigated the correlation of disease activity and progression of disability with composite scores of cardiovascular autonomic dysfunction and serum levels of catecholamines in a cross-sectional study of patients with clinically active and clinically stable MS. In a longitudinal study of clinically active MS patients, we performed cardiovascular reflex tests for up to 2 years. Methods: Twenty-six patients with clinically active relapsing-remitting MS, age 33.0+7.3 years, and nine patients with clinically stable MS, age 41.3+10.9 were studied. Twenty-four healthy volunteers served as controls. Standard autonomic tests were repeated at 3, 6, 12, 18 and 24 months in 18 of the 26 active patients participating in a placebo-controlled trial with interferon-b-1a. Parasympathetic dysfunction was assessed by heart rate response to the Valsalva manoeuvre, deep breathing and active change of posture, while sympathetic dysfunction was analysed by blood pressure response to active change of posture and to sustained handgrip, and by measuring levels of norepinephrine and epinephrine in serum obtained in the supine position. Results: In the cross-sectional study, the number of patients with at least one abnormal sympathetic test was higher in the `active' patient group (39%) than in healthy controls (8%, P50.02) or `stable' patients (0%, P50.04), while no difference was seen in the parasympathetic score. Median catecholamine levels were significantly lower in `active' MS patients than in those with stable disease (norepinephrine, 204 ng/l (interquartile range 158-310 ng/l) vs 363 ng/l (269-507 ng/l), P50.02 and epinephrine, 23 ng/l (16-28 ng/l) vs 32 ng/l (24-107 ng/l), P50.04). In the subgroup of patients studied longitudinally, parasympathetic but not sympathetic dysfunction increased slightly during the follow-up period, with a significant correlation to the increase in clinical disability (r=0.7, P50.002). No difference was seen for any of the autonomic scores between patients treated with interferon-b (n=12) and those receiving placebo (n=6). During acute exacerbations, only parasympathetic dysfunction tended to increase in parallel with a deterioration in the EDSS. Conclusions: Parasympathetic dysfunction was closely related to the progression of disability in patients with MS. In contrast, sympathetic dysfunction was associated to the clinical activity of MS. This is in line with previous observations suggesting that the autonomic nervous system may be intimately linked with the disordered immune regulation in MS.
Quality of life in multiple sclerosis: the impact of depression, fatigue and disability
Authors: Amato M P , Ponziani G , Rossi F , Liedl C L , Stefanile C , Rossi L
Published: January 2007

This study deals with the assessment of quality of life and its main clinical and demographical determinants in a clinical series of 103 patients with multiple sclerosis (MS) (37 men; 66 women; mean age 44.89 years; mean disease duration 12.40 years; mean EDSS score 4.07). We used the MSQOL-54 inventory, a disease-specific instrument recently validated in an Italian population. Each patient underwent a complete clinical assessment, including that of disability status (Expanded Disability Status Scale), cognitive function (Mini Mental State Examination), depression (Hamilton Rating Scale for Depression) and fatigue (Fatigue Severity Scale). In terms of Pearson's correlations, there was a moderate inverse relationship between disability level and the MSQOL-54 physical composite score, and a moderate to strong inverse correlation between depression or fatigue severity and both the physical and mental composite scores. In a stepwise linear regression analysis, depression, fatigue and disability level were confirmed to be significant and independent predictors of quality of life. Quality of life instruments can help to provide a broader measure of the disease impact and to develop a care program tailored to the patient's needs.
Early prediction of a benign course of multiple sclerosis on clinical grounds: a systematic review
Authors: Ramsaransing Geeta , Maurits Natasha , Zwanikken Cornelis , De Keyser Jacques
Published: January 2007

Background: There is growing consensus that neurologists should consider disease-modifying therapies early in multiple sclerosis (MS). However, there is a subgroup with a natural benign course, in which treatment could be postponed. We sought to determine the frequency of benign MS and early clinical factors that may predict a benign course. Methods: We performed a systematic review of the existing literature on benign MS, which was defined as minimal or no disability equivalent to a score on the Expanded Disability Status Scale (EDSS) 43.0 at least 10 years after disease onset. Results: Only a small number of studies of adequate quality was available. In total there were nine published studies representing 2204 patients. The estimated frequency of benign MS was 26.7%. Onset with optic neuritis, onset before the age of 40 years, absence of pyramidal signs at presentation, duration of first remission more than 1 year, and only one exacerbation in the first 5 years after onset of MS, were associated with a benign course. Conclusions: From the existing literature a set of unrelated clinical characteristics emerged that was associated with a benign course of MS. However, there is a need for prospective studies to define more precisely clinical and paraclinical predictors of benign MS.
A prospective, open-label treatment trial to compare the effect of IFNβ-1a (Avonex®), IFNβ-1b (Betaseron®), and glatiramer acetate (Copaxone®) on the relapse rate in relapsing-remitting multiple sclerosis: results after 18 months of therapy
Authors: Khan Omar A , Tselis Alexandros C , Kamholz John A , Garbern James Y , Lewis Richard A , Lisak Robert P
Published: January 2007

We previously reported results of a 12 month prospective, non-randomized, open-label treatment trial of immunomodulatory therapy in patients with relapsing-remitting multiple sclerosis (RRMS). We now report the results after 18 months of follow-up. Our primary objective was to compare the effect of INFβ-1a (Avonex®), IFNβ-1b (Betaseron®), and Glatiramer Acetate (GA, Copaxone®) to no treatment on the relapse rate in patients with RRMS. One hundred and fifty-six consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 18 months. Prior 2-year relapse history and available chart information was carefully reviewed at the time of enrollment. Thirty-three of 156 elected no treatment at enrollment; 40 elected IFNβ-1a, 41 IFNβ-1b, and 42 chose GA. There were no statistically significant differences among the four groups at enrollment. After 18 months of treatment, 122 patients remained in their original treatment group. Compared to the untreated group (1.02), mean annualized number of relapses was significantly reduced only in the GA (0.49, P40.0001) and IFNβ-1b groups (0.55, P=0.001) in contrast to the IFNβ-1a treated patients (0.81, P=0.106) who did not show a significant reduction. Despite limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment naïve RRMS patients.
Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine
Authors: Rossini P M , Pasqualetti P , Pozzilli C , Grasso M G , Millefiorini E , Graceffa A , Carlesimo G A , Zibellini G , Caltagirone C
Published: January 2007

Previous studies suggest that aminopyridine may play a role in the symptomatic treatment of fatigue in multiple sclerosis. Although the mechanism underlying the beneficial effect on fatigue remains unclear, it has been proposed that aminopyridines may help to improve conduction in demyelinated central pathways, implicating both axonal and synaptic mechanisms. The objective of the present study is to determine whether 4-AP decreases daily-living fatigue in progressive multiple sclerosis. The effect of 4-AP on other neurophysiological and neuropsychological parameters was also considered. A `double-blind', randomized, `placebo-controlled', crossover trial was conducted on 54 patients with progressive multiple sclerosis. All patients received treatment with placebo and 32 mg per day of 4-AP, each for 6 months. The main outcome measure was the Fatigue Severity Scale. Secondary measures were EDSS, cognitive functions and neurophysiological parameters. Forty-nine patients (91%) completed the study. Changes in fatigue scores, EDSS and cognitive functions were not significantly different between 4-AP and placebo. However, when patients treated with 4-AP were divided into two groups according to the serum level of 4-AP, a significant effect on fatigue compared with placebo was observed in the `high level' (430 ng/ml) group (P=0.05). Synchronization of motor evoked potentials improved during 4-AP with respect to placebo (P=0.019) and this correlated positively with fatigue reduction (P=0.010). No relevant side effects were observed.
Isolated demyelinating syndromes: comparison of CSF oligoclonal bands and different MR imaging criteria to predict conversion to CDMS
Authors: Tintoré M , Rovira A , Brieva L , Grivé E , Jardí R , Borrás C , Montalban X
Published: January 2007

Aim of the study: To evaluate and compare the capacity of oligoclonal bands (OB) and three sets of MR imaging criteria to predict the conversion of clinically isolated syndromes (CIS) to clinically definite multiple sclerosis (CDMS). Patients and methods: One hundred and twelve patients with CIS were prospectively studied with MR imaging and determination of OB. Based on the clinical follow-up (conversion or not conversion to CDMS), we calculated the sensitivity, specificity accuracy, positive and negative predictive value of the OB, and MR imaging criteria proposed by Paty et al, Fazekas et al and Barkhof et al. Results: CDMS developed in 26 (23.2%) patients after a mean follow-up of 31 months (range 12-62). OB were positive in 70 (62.5%) patients and were associated with a higher risk of developing CDMS. OB showed a sensitivity of 81%, specificity of 43%, accuracy of 52%, positive predictive value (PPV) of 30% and negative predictive value (NPV) of 88%. Paty and Fazekas criteria showed the same results with a sensitivity of 77%, specificity of 51%, accuracy of 57%, positive predictive value of 32% and negative predictive value of 88%. Barkhof criteria showed a sensitivity of 65%, specificity of 70%, accuracy of 69%, PPV of 40% and NPV of 87%. The greatest accuracy was achieved when patients with positive OB and three or four Barkhof's criteria were selected. Conclusions: We observed a high prevalence of OB in CIS. OB and MR imaging (Paty's and Fazekas' criteria) have high sensitivity. Barkhof's criteria have a higher specificity. Both OB and MR imaging criteria have a high negative predictive value.
Changes in motor cortex activation after recovery from spinal cord inflammation
Authors: Cramer S C , Fray E , Tievsky A , Parker R A , Riskind P N , Stein M C , Wedeen V , Rosen B R
Published: January 2007

Diseases of the spinal cord are associated with reactive changes in cerebral cortex organization. Many studies in this area have examined spinal cord conditions not associated with recovery, making it difficult to consider the value of these cortical events in the restoration of neurological function. We studied patients with myelitis, a syndrome of transient spinal cord inflammation, in order to probe cortical changes that might contribute to recovery after disease of the spinal cord. Seven patients, each of whom showed improvement in hand motor function after a diagnosis of myelitis involving cervical spinal cord, were clinically evaluated then studied with functional MRI. During right and left index finger tapping, activation volumes were assessed in three cortical motor regions within each hemisphere. Results were compared with findings in nine control subjects. Compared to the control group, myelitis patients had larger activation volumes within contralateral sensorimotor as well as contralateral premotor cortex. The degree of daily hand use showed a significant correlation with the volume of activation in contralateral sensorimotor cortex. Recovery from myelitis is associated with an enlarged activation volume in contralateral motor cortices. This change in motor cortex function is related to behavioral experience, and thus may contribute to motor improvement. The expanded activation in motor cortex, seen with several forms of spinal cord insult, may have maximal utility when corticospinal tract axons are preserved.
Chlamydia pneumoniae in the cerebrospinal fluid of patients with multiple sclerosis and neurological controls
Authors: Sotgiu S , Piana A , Pugliatti M , Sotgiu A , Deiana G A , Sgaramella E , Muresu E , Rosati G
Published: January 2007

Chlamydia pneumoniae infection is a common event in neurological patients and recovery of C. pneumoniae DNA in the cerebrospinal fluids (CSF) of multiple sclerosis (MS) patients could represent an epiphenomenon. We assessed the relevance of C. pneumoniae infection in 62 CSF samples from 32 MS patients and 30 neurological controls by means of PCR, immunofluorescence microscopy, enzyme-linked fluorescence and antibody detection. Multiple sclerosis (9.3%) and neurological controls (13.3) had similar percentage of anti-C. pneumoniae antibodies. However, C. pneumoniae DNA was only detectable in MS patients' CSF (9.3%). Our data support the hypothesis that C. pneumoniae persistence in some MS patients may be the result of an impaired clearance within the central nervous system.
Baló's concentric sclerosis: surviving normal myelin in a patient with a relapsing-remitting clinical course
Authors: Moore G RW , Berry K , Oger J JF , Prout A JE , Graeb D A , Nugent R A
Published: January 2007

Baló's concentric sclerosis is a demyelinating disorder in which bands of demyelination alternate with concentric bands of myelin preservation. The pathogenesis of the lesion is unknown. Previous reports using modern histopathologic techniques have shown the bands of myelin preservation to be comprised of remyelinated or partially demyelinated myelin. Here we report a case of Baló's concentric sclerosis in a 24-year-old East Indian patient with a previous history of relapsing-remitting multiple sclerosis (MS). Pathologically, the bands of myelin preservation showed myelin sheaths of normal thickness, with focal areas of demyelination. The findings, taken together with those of previously reported cases, suggest that Baló's concentric sclerosis is a variant of MS, and the concentric lesion may be an intermediary form in evolution of a chronic active MS plaque. The pathogenesis of this concentric lesion may be explained by periodic suppression of demyelination in the rapidly expanding border, allowing remyelination or only transient incomplete demyelination to occur.
Visuoperceptual impairment in MS patients: nature and possible neural origins
Authors: Vleugels L , Lafosse C , van Nunen A , Charlier M , Ketelaer P , Vandenbussche E
Published: January 2007

Failures on visuoperceptual neuropsychological tasks (on neuropsychological tests of visuo-spatial perception or on tests concerning semantic properties of visual objects), may indicate focal deficits of visuoperceptual function, or could be the result of (an)other (peripheral) visual deficit(s), or be the effect of a more general cognitive decline. In multiple sclerosis (MS) patients exhibiting sufficient visual acuity and not showing severe cognitive deterioration, impairment on a comprehensive set of 31 visuoperceptual neuropsychological tasks was compared with spatial resolution deficits (SRD), temporal resolution deficits (TRD) for visual stimuli, abnormal pattern shift visual evoked potential (PSVEP) responses, and failing scores on neuropsychological tasks other than visuoperceptual tasks. Impairment on the visuoperceptual neuropsychological tasks was highly independent from the other abnormal visual and cognitive neurological impairments examined, suggesting that it mostly represented focal deficits. Only TRD in both eyes related to this impairment and this relationship was rather weak. Thus in some MS patients a slowed visual information processing may be one of the combined deficits underlying visuoperceptual neuropsychological task impairment. Given that SRD and TRD were not related to another stage of MS and reflect disturbances of a P (parvocellular channel and ventral stream projections) and M (magnocellular channel and dorsal stream projections) visual-system function respectively, demyelination of a certain M pathway may become a co-determinant of visuoperceptual neuropsychological task impairment more rapidly than damage to a certain P pathway.
Paroxysmal attacks in multiple sclerosis
Authors: Tüzün E , Akman-Demir G , Eraksoy M
Published: January 2007

Paroxysmal attacks are short, frequent and stereotyped symptoms that can be observed in multiple sclerosis (MS) patients. We evaluated retrospectively the clinical and neuroradiological findings of patients, who developed any paroxysmal attacks during the course of their disease. EDSS scores, MS clinical types and disease durations of 59 patients with paroxysmal attacks (Group 1) were compared to 586 consecutive patients without paroxysmal attacks recorded in our MS database (Group 2). Anatomical and clinical correlation was attempted in 31 of the patients who had MRI examinations performed within 6 months of the paroxysmal attacks. EDSS scores of patients in Group 1 at the time of the paroxysmal attacks were significantly lower than the scores at their last clinic visit, whereas there were no significant differences for other parameters. Our results demonstrate that paroxysmal attacks occur early in the course of the disease, when there is little or no neurologic disability and associated tissue damage.
Protein markers of brain damage
Authors: Thompson E J , Green A JE
Published: January 2007

Brain proteins are released into body fluids in a fashion which reflects the underlying pathogenetic mechanisms for individual diseases. It is therefore important to distinguish not only different protein markers (reflecting various brain cells from which they have been released), but also their metabolism at different sites within the body (e.g. reticulo-endothelial system vs renal clearance) which will have an important bearing on whether fragments of the protein are found in urine or blood. It is clear that different patterns of protein abnormalities would be helpful in differential diagnosis of the individual diseases which afflict the nervous system. It would also be useful to monitor these proteins either as surrogate markers of the natural history of the condition or in the various therapies for each disease.
The cytokine storm in multiple sclerosis
Authors: Link Hans
Published: January 2007

MS is associated with a cytokine storm characterized by the parallel upregulation of proinflammatory (IFN-g, TNF-a, and b, and IL-12) and immune response-down-regulating (TGF-b, IL-10) cytokines. Also IL-6 and the cytolytic molecule perforin are upregulated. Even when evaluated in individual MS patients over the disease course, no Th1/Th2 dichotomy is obvious but, instead, upregulation of Th1+Th2+Th3 cytokines simultaneously, probably reflecting the complex pathology of MS in lesion size, time and distribution in the indiviual patient. Few correlations have been observed between cytokines and clinical MS variables, though upregulation of TGF-b seems to correlate with benign course and minor disability. Both pro- and antiinflammatory cytokines are also produced by microglia and astrocytes, constituting a CNS-cytokine network that interacts with the cytokine network of the immune system. This complexity is to be kept in mind when searching for cytokine abnormalities in MS.
Soluble Intercellular Adhesion Molecule-1 (sICAM-1) in serum and cerebrospinal fluid of demyelinating diseases of the central and peripheral nervous system
Authors: Trojano M , Avolio C , Ruggieri M , De Robertis F , Giuliani F , Paolicelli D , Livrea P
Published: January 2007

Serum and cerebrospinal fluid (CSF) soluble Intercellular adhesion molecule-1 (ICAM-1) levels were evaluated (ELISA) in 22 untreated and 13 corticosteroid-treated active relapsing remitting (RR) Multiple Sclerosis (MS), in 10 untreated and 10 corticosteroid-treated Guillain-Barré syndrome (GBS) and in 17 non-inflammatory neurological diseases (NIND). Twenty-eight clinically inactive RR MS were assayed for serum sICAM-1 before and after 3 months treatment of 8 MIU rIFNb-1b taken s.c. every other day. High sICAM-1 serum levels above the NIND values were found in untreated clinically active MS and in untreated GBS (P50.05) but not in the untreated clinically inactive MS group. The active MS group showed significantly (P=0.0001) higher sICAM-1 serum levels if compared to the inactive group. Corticosteroid-treated active MS and GBS patients showed lower (P50.05) serum sICAM-1 levels than the corresponding untreated groups. Serum sICAM-1 levels after 3 months of rIFNb-1b treatment (P50.0001, paired t-test) resulted increased compared to pretreatment values in MS. The mean values of CSF/serum sICAM-1: CSF/serum Albumin ratios (sICAM-1 Index) in active untreated MS patients were higher compared to NIND (P50.005) and to corticosteroid-treated MS group (P=0.01). sICAM Index values in GBS did not differ from those in NIND. The results seem to suggest potential roles for serum sICAM-1 in downregulating the ongoing inflammatory response at the blood-brain barrier level and for CSF sICAM-1 in the maintenance of a central nervous system local immune response.
Detection of JC virus DNA in cerebrospinal fluid from multiple sclerosis patients
Authors: Ferrante P , Omodeo-Zorini E , Caldarelli-Stefano R , Mediati M , Fainardi E , Granieri E , Caputo D
Published: January 2007

JC virus (JCV), the causative agent of progressive multifocal leukoencephalopathy (PML), has been proposed as a possible aetiopathogenic factor in multiple sclerosis (MS). We performed a study to search the LT region of JCV genome by nested PCR in cerebrospinal fluid (CSF), peripheral blood mononuclear cell (PBMC) and urine samples collected from 121 MS patients, 24 patients with other neurological disorders (OND), 30 non neurological patients (NND) and in PBMCs and urine of 40 healthy subjects. JCV DNA has been found in the CSF of 11 MS patients (9%) while all the CSFs from the 24 OND and the 30 NND cases were negative. No significant differences have been observed as regard to the frequency of JCV DNA detection in PBMCs and urine between the MS patients and the control groups. Nucleotide sequences analysis of seven JCV CSF isolates showed that five strains were identical the prototypal strain, while the other two had a base mutation (T→C) in 4286 nucleotide (nt). The finding of JCV DNA in the CSF of MS patients suggest that JCV could play a role in the triggering and/or in the maintenance of MS aetiopathogenic process, and therefore it should be taken in consideration when monitoring this disease.
Interferon beta-1b injection site reactions and necroses
Authors: Gaines Ann Reed , Varricchio Frederick
Published: January 2007

We conducted a comprehensive review of selected adverse event reports that were submitted to the Food and Drug Administration (FDA) for interferon beta-1b during the first 30 months following licensure. The adverse events reviewed were injection site reactions, injection site necroses, and non-injection site necroses. These adverse events were selected because of the relative frequency of injection site reactions and because of the severity and sequelae of certain injection site and non-injection site necroses. Our review enabled us to characterize the clinical presentation and the treatment received, which were not described in the package insert or by the IFNB (interferon beta-1b) Multiple Sclerosis Study Group publication. The time of onset of the adverse events ranged from 1-29 months after initiation of interferon beta-1b treatment, with a mean of 1 month. In general, the more clinically significant adverse events (i.e., injection site necrosis and non-injection site necrosis) developed more slowly than the injection site reactions. Greater than 85% of the adverse events presented with one or two signs/symptoms, although the number of signs/symptoms ranged from 1-8. No predominance of treatments for the adverse events was observed. The most striking finding was that the overall sex ratio, which could be due to reporting artifacts, was 8.1: 1 female: male.
The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis
Authors: Reiber H , Ungefehr S , Jacobi Chr
Published: January 2007

We report an extended set of neuroimmunological data detected in cerebrospinal fluid (CSF) from n=267 patients with definite multiple sclerosis (MS). Known frequencies of oligoclonal IgG (98%), frequencies of intrathecal fractions of IgG, IgA and IgM (72%, 9% and 20%, respectively) were confirmed and quantitated as intrathecal fractions, IgIF or CSF concentrations, IgLoc. Eighty-nine per cent of the patients had a combined `MRZ-reaction', i.e. intrathecal antibody synthesis (Antibody Index, AI > 1.4) against measles, rubella and/or varicella zoster virus. Frequencies of single antibodies decreased from measles (78%) to rubella (60%), VZV (55%) and HSV (28%). This MRZ-reaction, indicating a chronic autoimmune type disease already at time of first clinical symptoms, is less sensitive but more specific than detection of oligoclonal IgG. With increasing intrathecal IgG synthesis the number of different locally synthesized antibody species were increased as well as the amount per species (increased mean AI values). The concentration of MRZ antibodies in CSF represents together about 2% of intrathecally synthesized total IgG. But, as a very particular result the ratio of intrathecally synthesized specific antibody/intrathecally synthesized JgG was 5-fold higher (0.24-0.85%) compared to the corresponding ratio in blood (0.06-0.17%) of MS patients. This difference between brain ratio and blood ratio is discussed to be indicative for the anti-MRZ antibody forming B-lymphocyte subset in blood migrating into brain at earlier time of pathophysiological start of disease. These results give a concise explanation of neuroimmunological aspects in MS, not understood so far.