bluuebunny/crossref_metadata_2025 huggingface dataset:
Myelin basic protein in CSF as indicator of disease activity in multiple sclerosis
Authors: Lamers K JB , de Reus H PM , Jongen P JH
Published: January 2007

There is an evident need for a quantitative laboratory marker for ascertaining disease activity and treatment effects in multiple sclerosis (MS) patients. Activity of the disease process in MS is accompanied by myelin breakdown and appearance of myelin basic protein (MBP) in cerebrospinal fluid (CSF). In this paper MBP in CSF of relapsing-remitting (RR) MS patients is reviewed. MBP in CSF is a fragment containing an epitope corresponding to aminoacid residues 45-89 of the native molecule. From several relevant studies about CSF MBP in RR MS the following relations can be concluded: CSF MBP levels in active MS patients are frequently increased (45-100%), remain increased until 5 to 6 weeks after onset symptoms and are higher in polysymptomatic exacerbations and correlate with number of gadolinium-enhanced (Gd) lesions on MRI, severity of relapses, EDSS score and CSF intrathecal IgM synthesis. After an intravenous methylprednisolone treatment the increased CSF MBP levels return to normal values and reduction in CSF MBP is related to reduction in EDSS score, number of Gd lesions and CSF intrathecal IgM synthesis.
MBP, anti-MBP and anti-PLP antibodies, and intrathecal complement activation in multiple sclerosis
Authors: Sellebjerg Finn , Christiansen Michael , Garred Peter
Published: January 2007

Intrathecal immunoglobulin synthesis and activation of the complement cascade occurs in patients with multiple sclerosis (MS). The present study aimed at further studying the relation between intrathecal immunoglobulin synthesis and complement activation. We compared total intrathecal synthesis of lgA, IgG, and IgM, the number of cells secreting anti-myelin basic protein (MBP) and anti-proteolipid protein (PLP) antibodies of the IgG isotype and intrathecal activation of the complement cascade in patients with possible onset symptoms of MS (n=18) or clinically definite MS (n=30). Early activation of the complement cascade correlated with intrathecal synthesis of IgM. Intrathecal IgG, lgA and IgM synthesis also correlated weakly with the presence of cells secreting anti-MBP or anti-PLP autoantibodies. Full activation of the complement cascade did not correlate with any measures of intrathecal antibody synthesis. These findings suggest a complex relation between different immunoglobulin isotypes and complement activation which may have similarly complex roles in the pathogenesis of MS.
Can CSF predict the course of optic neuritis?
Authors: Frederiksen J L
Published: January 2007

To discuss the implications of CSF abnormalities for the course of acute monosymptomatic optic neuritis (AMON), various CSF markers were analysed in patients being randomly selected from a population-based cohort. Paired serum and CSF were obtained within a few weeks from onset of AMON. CSF-restricted oligoclonal IgG bands, free kappa and free lambda chain bands were observed in 17, 15, and nine of 27 examined patients, respectively. Sixteen patients showed a polyspecific intrathecal synthesis of oligoclonal IgG antibodies against one or more viruses. At 1 year follow-up five patients had developed clinically definite multiple sclerosis (CDMS); all had CSF oligoclonal IgG bands and virus-specific oligoclonal IgG antibodies at onset. Due to the relative small number studied at the short-term follow-up, no firm conclusion of the prognostic value of these analyses could be reached. CSF Myelin Basic Protein-like material was increased in only two of 29 patients with AMON, but may have potential value in reflecting disease activity, as the highest values were obtained among patients with CSF sampled soon after the worst visual acuity was reached, and among patients with severe visual impairment. In most previous studies of patients with AMON qualitative and quantitative analyses of CSF IgG had a predictive value for development of CDMS, but the results are conflicting.
Data on cytokine mRNA expression in CSF and peripheral blood mononuclear cells from MS patients as detected by PCR
Authors: Monteyne Philippe , Sindic Christian JM
Published: January 2007

Reverse transcription polymerase chain reaction (RT-PCR) was used to amplify the mRNA coding for different cytokines in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) cells from 18 multiple sclerosis (MS) patients as compared with 21 other neurological patients. mRNA levels were quantitated by radioactive hybridization of the PCR products. Expression of tumor necrosis factor (TNF)-a, interferon (IFN)-g, and interleukin (IL)-10 mRNA was elevated in CSF cells of MS patients. In many MS patients, both proinflammatory and immunoregulatory cytokine messages were detected in the CSF compartment. Such immune reactivity of CSF cells, as opposed to PBMC, was not associated with higher clinical activity of the disease. Expression of the B7.1 accessory molecule mRNA was similarly investigated. In the CSF, it was detected only in some clinically active MS cases and in other inflammatory diseases.
Therapy with antibodies against CD40L (CD154) and CD44-variant isoforms reduces experimental autoimmune encephalomyelitis induced by a proteolipid protein peptide
Authors: Laman J D , Maassen C BM , Schellekens M M , Visser L , Kap M , de Jong E , van Puijenbroek M , van Stipdonk M JB , van Meurs M , Schwärzler C , Günthert U
Published: January 2007

Interactions between mononuclear cells are required for the formation of inflammatory infiltrates in the CNS and the activation of cellular effector functions provoking demyelination in MS. Membrane-expressed costimulatory molecules are crucial to such interactions. We therefore investigated whether two costimulatory molecules, CD40L (CD154, expressed on activated CD4-possible T cells) and selected CD44-variant isoforms (expressed on activated CD4-positive T cells), are targets for immunotherapy in MS. The model of experimental autoimmune encephalomyelitis (EAE) induced in SJL-mice by immunization with a peptide derived from the proteolipid protein (PLP139-151) was optimized to address these questions. A previous observation that anti-CD40L (CD154) monoclonal antibodies can effectively prevent EAE in this model was confirmed, and extended by demonstrating that CD40 is expressed by cells of the monocytic lineage infiltrating the spinal cord. In vivo treatment with antibody against the standard isoform of CD44 (CD44s or CD44H) did not affect disease burden. In contrast, combined treatment with antibodies against the isoforms CD44v6, v7 and v10, which are thought to be involved in inflammatory processes, reduced the disease burden considerably. In addition, CD44v10- expressing cells were detected in the spinal cord. These data support the idea that CD40-CD40L interactions form a target for immunotherapy of MS, and indicate that cells expressing CD44v6, v7 and/or v10-containing isoforms have such potential as well.
T cell receptor Vb5 and Vb17 clonal diversity in cerebrospinal fluid and peripheral blood lymphocytes of multiple sclerosis patients
Authors: Lozeron P , Chabas D , Duprey B , Lyon-Caen O , Liblau R
Published: January 2007

To better characterize the cellular immune response taking place in the MS central nervous system, we investigated the blood and CSF T cell receptor (TCR) Vβ5 and Vb17 repertoire in HLA-typed patients with recently diagnosed MS or other neurological diseases (OND). Using a RT-PCR based technique, we analysed directly ex vivo the CDR3 size of TCR β chains utilizing Vβ5 (eight patients with MS and one with OND) or Vβ17 (eight patients with MS and six with OND) gene segments on paired blood-CSF samples. Globally, the analysis of Vβ5-Jβ and Vβ17-Jβ repertoire showed a less diverse pattern in the CSF samples than in the corresponding peripheral blood lymphocytes both in MS and in OND patients. However, we did not detect any recurrent clonal expansion within the Vb5+ T cells in MS patients, underlining the potential limits of Vβ5- based immunotherapy in MS. We found an expanded T cell population using the same Vβ17-Jβ1.6 combination with identical CDR3 length in the CSF of three MS patients and none of the control patients. These results suggest selective expansion of T cells expressing this segment gene in the MS central nervous system.
Correlation of soluble adhesion molecules in blood and cerebrospinal fluid with magnetic resonance imaging activity in patients with multiple sclerosis
Authors: Rieckmann Peter , Altenhofen Bernd , Riegel Antje , Kallmann Boris , Felgenhauer K
Published: January 2007

Several studies have reported a positive correlation between levels of soluble adhesion molecules in serum or cerebrospinal fluid and cranial MRI activity. We performed a cross-sectional study in 46 patients with newly diagnosed MS and determined levels of soluble intercellular adhesion molecule-1 (sICAM-1) as well as vascular cell adhesion molecule-1 (sVCAM-1) in correlation to the number and area of gadolinium enhancing lesions on cranial magnetic resonance images (MRI). The data revealed a significant positive correlation between sVCAM-1 serum levels and gadolinium enhancing lesions. In addition, CSF to serum ratios for sICAM-1 and sVCAM-1 correlated to MRI activity. In patients with a single enhancing lesion (SEL) there was a negative correlation between the QsCAM and the distance of the SEL to the ventricles. As these adhesion molecules are stable and markers of disease activity in MS, we further investigated sVCAM-1 serum levels during treatment with interferon beta-1b (Betaferon®). Significant increases in serum levels for sVCAM-1 in patients receiving Betaferon were associated with a favourable treatment response after 1 year in 17 out of 19 patients and correlated to decreased MRI activity, whereas stable or reduced sVCAM-1 levels occured more often in non-responders (five out of six patients). Therefore it can be hypothezised that soluble adhesion molecules are released from cerebral endothelial cells as an early immunoregulatory activity of the immune system to reduce cellular traffic across the blood brain barrier and this is further enhanced by IFN-beta treatment.
In vitro cytokine profiles as indicators of relapse activity and clinical course in multiple sclerosis
Authors: Schluep Myriam , van Melle Guy , Henry Hugues , Städler Claudio , Roth-Wicky Béatrice , Magistretti Pierre J
Published: January 2007

In vitro production of tumor necrosis factor-a (TNF-a), interleukin-2 (IL-2), IL-4, IL-6, IL-10 and oligoclonal IgG (IgG OB) was evaluated in the aim to investigate their profile in correlation with multiple sclerosis (MS) clinical activity and clinical course. Whole blood stimulation with lipopolysaccharide or concanavalin A was performed in 61 patients presenting with relapsing-remitting, relapsing-progressive or chronic progressive MS; treatments received were: none, azathioprine (AZA), cyclosporin, cyclophosphamide, subcutaneous interferon-b 1a (IFN-b 1a) and corticosteroids (CST). The cinetics of cytokine production showed that (i) in the absence of treatment, TNF-a and IL-6 dropped respectively after and during the periods surrounding relapse, while IL-4 was increasing before and IL-10 after relapse; (ii) with AZA, TNF-a and IL-6 lowered before exacerbation, IL-4 prolonged high levels after and IL-10 before relapse; (iii) with IFN-b 1a, IL-10 was already increasing before relapse, and TNF-a was higher after relapse. When cytokine levels were analysed independently from MS clinical activity, the use of AZA inhibited IgG OB and TNF-a synthesis (P=0.002) but increased IL-4 (P=0.0024), whereas IFN-b 1a stimulated TNF-a and inhibited IgG OB and IL-4 production. CST inhibited TNF-a, IL-6, IL-4 and IgG OB synthesis. This study stresses both the weight of clinical parameters and of methodology used in results obtained in cytokine analysis in MS.
The potential role of nitric oxide in multiple sclerosis
Authors: Giovannoni G , Heales S J.R. , Land J M , Thompson E J
Published: January 2007

Nitric oxide (.NO) and its reactive derivative peroxynitrite (ONOO7) have been implicated in the pathogenesis of multiple sclerosis (MS). They are cytotoxic to oligodendrocytes and neurones in culture by inhibiting the mitochondrial respiratory chain (complexes II/III and IV) and inhibiting certain key intracellular enzymes. Recently .NO has been implicated as a possible aetiological factor in reversible conduction block in demyelinated axons. Inducible nitric oxide synthase (iNOS) is upregulated in the central nervous system of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. In some EAE models inhibiting iNOS activity decreases disease severity whilst in other models disease activity is exacerbated. Raised levels of nitrate and nitrite, stable end-products of .NO/ONOO7, are found in the cerebrospinal fluid, serum and urine of patients with MS. CSF levels of nitrate and nitrite correlate with blood-brain-barrier dysfunction, which suggests that .NO may play a role in inflammatory blood-brain-barrier dysfunction. In a longitudinal study on 24 patients with relapsing remitting and secondary progressive MS, raised serum nitrate and nitrite levels correlated with a relapsing course and infrequent relapses. However, no correlation was found between raised serum levels of nitrate and nitrite and MRI activity, disease progression, or the development of cerebral atrophy. In autoimmune mediated CNS demyelinating disease .NO may be a double-edged sword, mediating tissue damage on the one hand and on the other hand modulating complex immunological functions which may be protective.
Are there indicators of remyelination in blood or CSF of multiple sclerosis patients?
Authors: Massaro A R
Published: January 2007

Knowing the mechanisms and the times of remyelination is not only an intriguing scientific challenge but it has also important consequences on the therapeutic approach to multiple sclerosis (MS). The neural-cell adhesion molecule (N-CAM) shows tempting suggestions about its possible involvement in reparative mechanisms, and, finally, in remyelination. In fact, its levels progressively increase in the cerebrospinal fluid (CSF) of acute MS patients, paralleling the progressive clinical improvement after the attack. Some information is also given about the ciliary neurotrophic factor (CNTF), whose CSF levels were found to be increased in MS patients who were recovering from an acute exacerbation.
Myelin basic protein-like material in the urine of multiple sclerosis patients: relationships to clinical and neuroimaging changes
Authors: Whitaker John N
Published: January 2007

Urinary myelin basic protein-like material (MBPLM) represents material which is cross-reactive with a cryptic epitope in peptide 84-89 of human myelin basic protein. While normally present at moderate levels in the adult, these levels rise higher in patients who have secondary progressive multiple sclerosis (MS). The increase in urine MBPLM correlates with the burden of disease detected by T2-weighted cranial magnetic resonance imaging. There is no correlation between urinary MBPLM and acute disease activity in relapsing-remitting MS. The first major need for improving the clinical utility of measurements of MBPLM in urine in MS patients is to delineate its exact chemical features so that assays may be improved and a potential biological role of the MBPLM better understood. The second major task is to apply the group data accumulated and apply them to individual patients. This could prove to be means to individually direct treatment and determine its effectiveness.
T1 hypointense lesion load in secondary progressive multiple sclerosis: a comparison of pre versus post contrast loads and of manual versus semi automated threshold techniques for lesion segmentation
Authors: O'Riordan J I , Cain M Gawne , Coles A , Wang L , Compston D AS , Tofts P , Miller D H
Published: January 2007

Magnetic resonance imaging (MRI) is increasingly being used as a monitoring tool for disease activity in therapeutic trials in multiple sclerosis. There is, however, only a limited relationship between MRI findings and clinical outcome measurements. It has been suggested that hypointense lesion load on T1 weighted imaging has a better correlation with disability than the more conventional T2 hyper intense lesion load. This study was undertaken to (i) evaluate different measurement techniques used to quantify T1 hypointense lesion load, and (ii) to compare lesion load as measured using different parameters and disability. Twenty-five patients with secondary progressive multiple sclerosis, mean age of 40 years (23-57), mean EDSS 5.7 (4-7) were analysed. T2 lesion load on FSE correlated well with both the hypointense lesion load on T1 pre-gadolinium (r=0.8, P50.0001) and T1 post-gadolinium (r=0.8, P50.0001) but less so with the enhancing lesion load (r=0.4, P50.05). There was a very strong correlation with T1 hypo-intense lesion volume pre and post gadolinium (r=0.96, P50.001). However, the EDSS was not correlated with the T2 lesion load (r=70.27, P=0.2), T1 pre-gadolinium load (r=70.3, P=0.1), T1 post gadolinium load (r=70.4, P=0.7) and enhancing lesion load (r=70.28, P=0.2), or with the degree of hypointensity of T1 weighted images determined using the threshold technique. There is a strong correlation between T1 hypointense lesion volume both pre and post gadolinium and also between T1 and T2 lesion volumes.
Oxidative damage to DNA in plaques of MS brains
Authors: Vladimirova Olga , O'Connor John , Cahill Alan , Alder Hansjuerg , Butunoi Catalin , Kalman Bernadette
Published: January 2007

A major cause of clinical disability in multiple sclerosis (MS) is related to a degenerative process in the central nervous system (CNS) which ultimately develops from a potentially reversible inflammation and demyelination. The mechanism of this degenerative process within MS lesions is not completely understood. We hypothesize that oxidative damage to DNA secondary to inflammation may contribute to irreversible tissue alterations in a plaque. To test this assumption, we determined the level of a DNA oxidative marker, 8-hydroxy-deoxy-guanosine (8-OH-dG) in the normal appearing white matter (NAWM), plaque and cortical regions of cerebella from MS patients who suffered from severe cerebellar symptoms during the course of the disease, and in NAWM and cortical regions of cerebella from non-neurological controls. We found a significant increase in DNA oxidation within plaques compared to NAWM specimens in MS cerebella. A tendency for increase of oxidative markers in normal appearing cortical tissues located in the proximity of MS plaques was also observed when compared to those in control cortical specimens. Oxidative damage to DNA in MS lesions, and in neuron rich areas located in the proximity of these lesions is likely related to the release of reactive oxygen species (ROS) and nitric oxide (NO) during inflammation in the brain. This biochemical impairment of DNA and of other macromolecules may contribute to the development of severe clinical disability through the induction of degenerative changes within and outside of plaques in MS brains.
Impairments of attention in individuals with Multiple Sclerosis
Authors: Paul Robert H , Beatty William W , Schneider Ronni , Blanco Carlos , Hames Karen
Published: January 2007

To investigate the status of attention in multiple sclerosis (MS) we administered tests of focused and divided attention to 39 MS patients and 18 age- and education-matched control subjects. In addition, a test of vigilance and a test of automatic information processing was administered. MS patients performed as well as controls on the automatic processing task and on most measures of focused and divided attention when accuracy but not speed was the dependent variable. By contrast, the MS patients performed significantly worse than controls on the more effortful measures of attention, especially those that engaged working memory or emphasized speeded responding. These results indicate that deficits of attention in MS patients are most likely to be evident on tasks which require concentrated cognitive effort.
Correlates of coping style in patients with multiple sclerosis
Authors: Beatty William W , Hames Karen A , Blanco Carlos R , Williamson Sandra J , Wilbanks Susan L , Olson Karen A
Published: January 2007

To examine certain correlates of patterns of coping with stress, 43 patients with multiple sclerosis (MS) read a vignette describing a stressful social situation and completed the Ways of Coping Checklist, describing how they would cope with the stressful situation. Performance on a test of solving problems in everyday living was positively correlated with the total number of coping responses and with the number of problem-focused strategies, but neither vocabulary nor verbal abstract reasoning were related to coping patterns. In agreement with earlier work, increases in psychological distress were positively correlated with endorsement of emotion-focused coping strategies but unrelated to the use of other coping responses.
A questionnaire to assess neurological impairment in multiple sclerosis
Authors: Goodin Douglas S
Published: January 2007

This study assessed the feasibility of using a self-report questionnaire to measure neurological impairment in multiple sclerosis (MS). Thirty patients aged 21-67 years participated. Each patient was examined and scored on three commonly used impairment scales; the extended disability status scale (EDSS), the neurologic rating scale (NRS) and the ambulation index (AI). Two other scales were also determined; the sum of the EDSS functional scores (SFS), and a five point scale rating functional status (FS). The physician also filled out a copy of the questionnaire based on interview and examination of the patient. All of these scores were determined and the physicial questionnaire filled out blind to the patient's answers on their self-report questionnaire. The first 15 consecutive patients served as the pilot group to develop a computer program to convert answers on the questionnaire into predicted scores on each of the five scales. The second 15 patients served as the independent test group to assess the validity of the computer program. Using this program, both patient and physician questionnaires accurately predicted (r40.87) the scores on each of the five scales measured manually. In addition, the scores on all five scales were highly cross-correlated (r40.85) suggesting that, in fact, each measured a similar attribute of MS (i.e., impairment). Therefore, the five scales were combined into a single measure, the mean disability score (MDS), which showed the highest correlations (r40.95) of any scale between the predicted scores and the actual scores determined by examination. The results of this study indicate that the self-report questionnaire is a valid measure of neurological impairment in MS and, thus, that it can be used to survey this health outcome in an MS population. Moreover, this questionnaire can be filled out by a physician (based directly on the neurological examination) and, together with the computer program for scoring each patient, can be used to provide consistent scoring in clinical trials.
Comparing the ability of various compositive outcomes to discriminate treatment effects in MS clinical trials
Authors: Goodkin D E , Priore R L , Wende K E , Campion M , Bourdette D N , Herndon R M , Fischer J S , Jacobs L D , Cookfair D L , Rudick R A , Richert J R , Salazar A M , Granger C V , Simon J H , Alam J J , Bartoszak D M , Braiman J , Brownscheidle C M , Coats M E , Cohan S L , Dougherty D S , Kinke R P , Mass M K , Munschauer F E , Pullicino P M , Scherokman B J , Weinstock-Guttman B , Whitham R H ,   The Multiple Sclerosis Collaborative Research Group (MSCRG)
Published: January 2007

We compared the ability of the Kurtzke Expanded Disability Status Scale (EDSS) and a composite outcome of non-physician-based measures of time to ambulate 25 feet (TA) and manual dexterity (the Box and Block Test [BBT], and 9-Hole Peg Test [9HPT]) to discriminate treatment effects in the Phase III study of interferon beta-1a. A log-rank comparison of Kaplan-Meier curves by treatment group showed the non-physicianbased composite of BBT, 9HPT, and TA was of comparable sensitivity (P=0.013) in discriminating sustained treatment failure as the EDSS alone (P=0.029). The composite of BBT, 9HPT, TA, and EDSS was more sensitive (P=0.009) in discriminating sustained treatment failure than the EDSS alone. Compositive outcomes of the EDSS and non-physician-based measures of manual dexterity and timed ambulation provide an appealing strategy to reduce the number of patients required to discriminate treatment effects in MS clinical trials.
Side effect profile and adherence to in the treatment of Multiple Sclerosis with interferon beta-la
Authors: Mohr David C , Likosky William , Boudewyn Arne C , Marietta Peter , Dwyer Pat , Van Der Wende Judy , Goodkin Donald E
Published: January 2007

This study examines the course of patient-reported side effect during the first 4 months of treatment for multiple sclerosis (MS) with interferon beta-Ia (IFNβ-Ia), and the relationship of those side effects to discontinuation of medication. Flu-like symptoms, muscle aches and chills decreased over the first 2 months of treatment but did not change over the second 2 months. Loss of feeling or numbness, tingling and depression increased over 4 months, however these side effects were generally mild. Loss of feeling or numbness and tingling at 2 month follow-up were significantly related to discontinuation of IFNβ-Ia by 4 month follow-up.
Human Herpesvirus-6 (HHV-6) infection in multiple sclerosis: a preliminary report
Authors: Ablashi D V , Lapps W , Kaplan M , Whitman J E , Richert J R , Pearson G R
Published: January 2007

We examined cerebra! spinal fluid (CSF) from multiple sclerosis (MS) patients and patients with other neurological diseases (OND) for antibody specific for Human Herpesvirus-6 (HHV-6) and for HHV-6 DNA detectable by PCR. CSF from MS patients had a higher frequency of IgG antibody to HHV-6 late antigens (39.4%) compared with CSF from OND (7.4%). In contrast, the frequency of detectable IgG antibody in CSF from MS patients specific for Epstein-Barr Virus (EBV) (12.1%) and Human Cytomegalovirus (HCMV) (6.1%) was much lower. Two of 12 MS CSFs (16.7%) also contained HHV-6 DNA detected by PCR. None of four OND CSF were positive for HHV-6 DNA. Plasma from 16 patients with MS, eight with OND and 72 healthy donors were tested for antibodies by ELISA to HHV-6 early (p41/38) and late (gp 110) proteins. Although no differences in ant-gp 110 IgG antibody were detected between MS patients, patients with other neurological diseases, and normals, IgG antibody to early protein p41/38 was detected in > 68% of the plasma from MS patients, 12.5% from OND patient and 27.8% of the controls. IgM antibody to p41/38 was present in >56% of MS patients, 12.5% of OND patients, and 19% of controls. These data suggest that more than half of the MS patients had active, ongoing HHV-6 infections. HHV-6 was also isolated from peripheral blood mononuclear cells (PBMC) from 3/5 MS patients who were in relapse or had progressive disease and was identified as HHV-6 Variant B. These preliminary results support the hypothesis that HHV-6 may be a co-factor in the pathogenesis of some cases of MS.
The fatigue descriptive scale (FDS): a useful tool to evaluate fatigue in multiple sclerosis
Authors: Iriarte J , Katsamakis G , De Castro P
Published: January 2007

Although fatigue is common among multiple sclerosis (MS) patients, evaluation of this symptom is difficult due to the subjectivity and variability of the complaint. We proposed the Fatigue Descriptive Scale (FDS) as a tool to evaluate the severity and quality of fatigue in a group of patients suffering from MS. As a way to demonstrate the usefulness of this scale we applied the FDS in a group of 155 patients (105 women and 50 men) with clinically-definite multiple sclerosis, as outlined according to Poser’s criteria. Age was 36.2±11.1 years (range 12-62) and time of evolution was 8.3±9.4 years (range 1-44). The Fatigue Severity Scale (FSS) was also used. Descriptive statistics techniques and techniques for nonparametric distribution (Spearman Rank, Kruskal-Wallis ANOVA) were used. One hundred and eighteen patients reported fatigue (73 spontaneously, 45 when questioned). All descriptions of fatigue were ranked according to FDS categories. Eighty-five patients defined the symptom as fatigue with exercise, 26 as asthenia and seven as the worsening of other symptoms. Fatigue by itself produced limited or disrupted activity in 78 patients; work-related functions were limited in 48 patients; social relations were limited in 29 patients; and self-care was difficult for one patient. Fifty-six patients suffered fatigue daily. FDS score was 4.9±3.9 (range 0-13). FSS was 3.1±1.7 (range 0.2-6.6). FDS and FSS of Krupp were highly correlated (R=0.87, p<0.001). Therefore, in comparison with other scales, the FDS shows remarkable usefulness in classifying, periodicity, and severity of fatigue in MS patients. The high correlation with the FSS implies that it is a valid method to measure the severity of fatigue, as was demonstrated in our paper proposing the FDS. The importance of this new scale is its ability to inform the clinicians in a very quick, easy, and at the same time complete way, how severe the fatigue really is and how it affects the patient.
Survey of multiple sclerosis in Northern California
Authors: Goodin Douglas S ,   Northern California MS Study Group
Published: January 2007

A random sample of 493 multiple sclerosis (MS) patients registered with the Northern California Chapter of the National MS Society was surveyed by mail and subsequently interviewed with regard to their MS, life style, diet, medical treatment, family history, and insurance coverage. Of this sample, 168 patients (34%) returned completed questionnaires. The answers on the questionnaire were entered into a database and scores on the extended disability status scale (EDSS), the neurologic rating scale (NRS), the ambulation index (AI), and the mean disability scale (MDS) were determined from the patient's answers to a portion of the questionnaire using a previously validated conversion program. This survey population of 168 patients seemed to represent well both the random sample and the frame population from which it was drawn. Patients commonly experienced symptoms for which there are medical treatments currently available such as bladder symptoms, fatigue, spasticity, pain, and depression. Surprisingly, however, with the exception of spasticity, patients were only infrequently treated for these complaints. In addition, despite the recent approval of the beta-interferons and copolymer 1 in the treatment of MS, only 74% of the appropriate candidates for such treatment had these options discussed with them and only 45% ever actually received such treatment. Certain clinical features and dietary habits were strongly associated with both EDSS scores and total disability. Not unexpectedly, either a progressive disease course or the presence of neurological dysfunction in any one of a number of functional areas (e.g. bladder, vision, cognitive change, etc.) correlated with higher EDSS scores and greater total disability. Fatigue was also strongly correlated with disability. Indeed, fatigue accounted (in whole or in part) for 65% of the disability experienced by patients; an observation which only underscores the fact that fewer than one third of the patients who experience fatigue have ever been tried on medications. Interestingly, the only factors associated with lower EDSS scores and less total disability were exercise and alcohol consumption. Such associations from a single survey, however, do not establish causation. It is the purpose of this study to establish a baseline level of function within this survey population so that future surveys in the same set of individuals can allow a prospective assessment of how health outcome has influenced different aspects of the patient's medical care, lifestyle, and insurance coverage.
Recent developments in drug therapy for multiple sclerosis
Authors: Smith Paul F , Darlington Cynthia L
Published: January 2007

Symptomatic treatment of multiple sclerosis (MS) includes a diverse range of drugs intended to relieve the specific symptoms with which a patient may present at a particular point in the progression of the disease. These drugs, not specifically designed for the treatment of MS, may include antispastic agents (e.g. baclofen), drugs to reduce tremor (e.g. clonazepam), anticholinergics (e.g. oxybutynin) which relieve urinary symptoms, anti- epileptics (e.g. carbamazepine) to control neuralgia, stimulants to reduce fatigue (e.g. amantadine), and antidepressants (e.g. fluoxetine) to treat depression. The treatment of acute relapses or exacerbations is dominated by corticosteroids such as methylprednisolone. The most active area of current investigation is the development of drugs which will inhibit the progression of the disease process itself, and in this category the beta- and alpha-interferons are the most effective drugs currently available, although many new treatments are currently in trials, including immunoglobulin, copolymer-1, bovine myelin, T-cell receptor (TCR) peptide vaccines, platelet-activating factor (PAF) antagonists, matrix metallo-proteinase inhibitors, campath-1, and insulin-like growth factor (IGF).
Chromosome 19 locus apolipoprotein C-II association with multiple sclerosis
Authors: Zouali Hamed , Faure-Delanef Laurence , Lucotte Gérard
Published: January 2007

We have used a PCR based method to analyze allelic frequencies in a (TG)n(AG)m microsatellite marker located in the first intron of the apolipoprotein C-II gene in French MS patients and controls. Samples were collected from 74 MS patients and from 102 controls. The distribution of microsatellite alleles differed between patients and controls (w2=7.82), showing a significant effect (P50.04) with MS due to the increased frequency of the allele 6 and a decrease frequency (P50.03) of allele 1. Our study confirms that the apolipoprotein C-II region may influence susceptibility to MS.
Reduced visual evoked responses in multiple sclerosis patients with optic neuritis: Comparison of functional magnetic resonance imaging and visual evoked potentials
Authors: Gareau P J , Gati J S , Menon R S , Lee D , Rice G , Mitchell J R , Mandelfino P , Karlik S J
Published: January 2007

The limited application of functional magnetic resonance imaging (fMRI) for investigations of multiple sclerosis (MS) patients has already shown that deficits of the motor, cognitive and visual systems may be identified by differences in the patterns of activation in response to a suitable stimulus. In MS patients with unilateral optic neuritis, the area of activation in the primary visual cortex, measured by fMRI techniques, is dramatically reduced in response to stimulation of the affected eye. The latency of the major positive component of the visual evoked potential (VEP) recorded upon stimulation of the affected eye is significantly increased in these patients, as compared to the unaffected eye and normal volunteers. We have found a correlation between the neural response measured using fMRI and the latency of the VEP. fMRI signal responses have the potential to provide more detailed topographic information relating to functional deficits in MS.
Sensory symptoms of multiple sclerosis: a hidden reservoir of morbidity
Authors: Rae-Grant Alex D , Eckert Nancy J , Bartz Sharon , Reed James F
Published: January 2007

Objective: To assess the frequency and quality of sensory symptoms in a population of patients with Multiple Sclerosis (MS) and compare them with controls. Design: Survey to target population and control group evaluating demographic data, data on disease course, presence of various symptoms of MS. Setting: Neurological practices affiliated with a tertiary community hospital. Participants: 224 patients with MS, 93 controls of similar age and sex. Results: Sensory symptoms were more common in MS patients than in controls, and differed in severity and quality. Fifty per cent described brief (seconds to hours) episodes of neurological dysfunction, significantly more often than in controls (P=0.001). Pain was present at some time in similar percentages in patients and controls, but active pain problems were present more often in MS patients (P=0.001). The qualitative description of pain in MS patients was more often neuropathic, with burning, itching, electric and formicatory pain, as opposed to throbbing, sharp or muscular pain. Pain was localized to arms, legs, trunk, hands, feet and face more often in the MS group. Lhermitte's phenomenon was present in two-thirds of patients at some time in their disease course. Twenty per cent of the patients identified themselves as having respiratory problems (Controls 7.5%, P=0.005). Fatigue limited activity in 78% of patients, but only in 17% of controls (P=0.001). Dizziness, memory dysfunction, and restless legs symptoms were all more frequent in patients. The self-rated `worst' symptoms of MS was pain in 12%, fatigue in 17% and dizziness in 5%, a total of 34% of `worst' symptoms. Sensory symptoms were present in patients with early disease and without disability as often as in disabled patients and in those with longer disease duration. There was however a strong correlation between the total number of sensory symptoms reported and the presence of disability in the MS patients. Conclusions: Sensory symptoms are common in MS patients. Pain syndromes, transient neurologic events, Lhermitte's phenomenon, fatigue, respiratory symptoms and vertigo were present significantly more frequently in patients with MS than in a control population and contributed to subjective morbidity. Future clinical trials assessing therapy in MS might include sensory symptoms as secondary endpoints to capture this `hidden reservoir' of disease morbidity.
Nasal administration of transforming growth factor-β1 induces dendritic cells and inhibits protracted-relapsing experimental allergic encephalomyelitis
Authors: Ishikawa Mikio , Jin Yuxuen , Guo Hong , Link Hans , Xiao Bao-Guo
Published: January 2007

Cytokines have a crucial role in initiation and perturbation of EAE that represents an animal model of multiple sclerosis (MS). Administration of transforming growth factor-β1 (TGF-β1) to EAE mice improves clinical EAE and prevents relapses by unknown mechanisms. Administering low doses of TGF-β1 nasally, we confirmed that TGF-β1 inhibited development and relapse of protracted-relapsing EAE (PR-EAE) in DA rats. Infiltration of CD4+ T-cells and macrophages within the central nervous system was clearly reduced, while proliferation and IFN-g secretion of mononuclear cells (MNC) was augmented in TGF-β1-treated EAE rats compared to PBS-treated control EAE rats. TGF-β1 administered nasally also increased nitric oxide production and CD4+ T cell apoptosis. TGF-β1 treated rats showed augmented proliferation of dendritic cells (DC) compared to MNC. These data imply that low doses of TGF-β1 given by the nasal route prevent PR-EAE and upregulate DC functions that may be involved for disease prevention.
Treatment adherence and patient retention in the first year of a Phase-III clinical trial for the treatment of multiple sclerosis
Authors: Mohr David C , Goodkin Donald E , Masuoka Lorianne , Dick Leah P , Russo David , Eckhardt Jannelle , Boudewyn Arne C , Bedell Lisa
Published: January 2007

The purpose of this study was to examine the relationship between patient management strategies employed by study personnel, and patient retention and adherence to treatment in the first year of a Phase III clinical trial of interferon beta-1b for treatment of secondary progressive multiple sclerosis (MS). Study staff from each of 35 sites were interviewed regarding patient management practices. Sites which were rated as more empathetic, as instilling a sense of purpose in the patient, and promoting less formal relationships with patients had high rates of adherence to treatment. In addressing specific patient concerns, attention to patients' emotional status and patients' expectations of trial participation were related to better adherence.
Databases in MS research: pitfalls and promises
Authors: Weinshenker Brian G
Published: January 2007

A database is an organized repository of data. Prospective collection of patient information in a database (`databasing') has been attempted by a few consortia of MS investigators over the past 10 years. This approach promises to facilitate epidemiologic research in MS and investigation of the natural history of the disease and how it might be altered by long-term treatments such as interferon beta. Databasing has some advantages over clinical trials in assessing new therapies, primarily because the focus is on long-term effectiveness in an entire population rather than short-term statistical significance in a highly selected population. The limitations of databasing and strategies to overcome these limitations are addressed.
The Guy's Neurological Disability Scale (GNDS): a new disability measure for multiple sclerosis
Authors: Sharrack Basil , Hughes Richard AC
Published: January 2007

A postal survey showed that the majority of 49 leading international neurologists involved with multiple sclerosis research felt that currently existing outcome measures for this illness were inadequate, and that there was a need for a new measure which should be patient orientated, multidimensional, and not biased towards any particular disability. The Guy's Neurological Disability Scale (GNDS) was subsequently devised as a simple and user-friendly clinical disability scale capable of embracing the whole range of disabilities which could be encountered in the course of multiple sclerosis. It has 12 separate categories which include cognition, mood, vision, speech, swallowing, upper limb function, lower limb function, bladder function, bowel function, sexual function, fatigue, and `others'. The GNDS was found to be acceptable to neurologists and patients, reliable, responsive, and valid as a measure of disability. The scale was also found to be valid when applied by non-neurologists, over the phone, or via a postal questionnaire.
Assessment of cognitive and psychological functions in patients with multiple sclerosis: considerations for databasing
Authors: Beatty William W
Published: January 2007

Test batteries for use in studying cognition and depression in patients are briefly but critically reviewed. Suggestions for a new battery that contains tests that are related to rehabilitation and work status are proposed.
The Multiple Sclerosis Functional Composite measure (MSFC): an integrated approach to MS clinical outcome assessment
Authors: Fischer J S , Rudick R A , Cutter G R , Reingold S C ,   National MS Society Clinical Outcomes Assessment Task Force
Published: January 2007

Clinical outcome assessment in Multiple Sclerosis (MS) is challenging due to the diversity and fluctuating nature of MS symptoms. Traditional clinical scales such as the EDSS are inadequate in their assessment of key clinical dimensions of MS (e.g., cognitive function), and they have psychometric limitations as well. Based on analyses of pooled data from natural history studies and from placebo groups in clinical trials, the National MS Society's Clinical Outcomes Assessment Task Force recently proposed a new multidimensional clinical outcome measure, the MS Functional Composite (MSFC). The MSFC comprises quantitative functional measures of three key clinical dimensions of MS: leg function/ambulation, arm/hand function, and cognitive function. Scores on component measures are converted to standard scores (z-scores), which are averaged to form a single MSFC score. Preliminary analyses confirm that: (1) the three clinical dimensions of the MSFC are relatively independent; (2) the MSFC is sensitive to clinical changes over 1- and 2-year intervals; and (3) the MSFC has acceptable criterion validity (i.e., predicts both concurrent and subsequent EDSS change). The advantages and potential limitations of incorporating quantitative functional outcome measures such as the MSFC into collaborative databases are discussed.
Recent developments in the assessment of quality of life in Multiple Sclerosis (MS)
Authors: Fischer J S , LaRocca N G , Miller D M , Ritvo P G , Andrews H , Paty D
Published: January 2007

Multiple sclerosis (MS) and its treatment have broad-ranging effects on quality of life. This article reviews recent efforts to assess the impact of MS on activities of daily living (ADLs) and health-related quality of life (HRQL), and describes the development of the Multiple Sclerosis Quality of Life Inventory (MSQLI). The MSQLI is a modular MS-specific HRQL instrument consisting of a widely-used generic measure, the Health Status Questionnaire (SF-36), supplemented by nine symptom-specific measures (covering fatigue, pain, bladder function, bowel function, emotional status, perceived cognitive function, visual function, sexual satisfaction, and social relationships). Content validation consisted of evaluating its adherence to a conceptual model of the impact of MS, and review by MS specialists (neurologists and allied health professionals), HRQL experts, patients, and caregivers. The reliability and construct validity of the MSQLI were rigorously evaluated in a field test with 300 North American patients (198 female, 102 male) with definite MS (Poser criteria) and a broad range of physical impairment (EDSS=0.0-8.5). This article concludes by comparing the MSQLI with two other MS-specific HRQL measures (MS Quality of Life-54 (QOL-54) and Functional Assessment of Multiple Sclerosis (FAMS)) and discussing key issues to consider in selecting an HRQL instrument for a collaborative database.
Measuring handicap in multiple sclerosis
Authors: Thompson A J
Published: January 2007

Handicap, shortly to be renamed participation, is a well defined though somewhat neglected entity which addresses an important aspect of the impact disease has on the individual. It is particularly relevant in Multiple Sclerosis (MS) which has such a major impact on issues such as employment, relationships, transport and social integration. Few validated measuring tools exist, and the generic London Handicap Scale is probably the best currently available but is only appropriate for group comparison. Handicap should be monitored in MS and is particularly appropriate in the evaluation of rehabilitation strategies.
Measuring evoked responses in multiple sclerosis
Authors: Comi Giancarlo , Leocani Letizia , Medaglini Stefania , Locatelli Tiziana , Martinelli Vittorio , Santuccio Giuseppe , Rossi Paolo
Published: January 2007

Evoked potentials (EPs) have been widely utilised in Multiple Sclerosis (MS) patients to demonstrate the involvement of sensory and motor pathways. Their diagnostic value is based on the ability to reveal clinically silent lesions and to objectivate the central nervous system damage in patients who complain frequently of vague and indefinite disturbances which frequently occurs in the early phases of the disease. The advent of magnetic resonance imaging (MRI) techniques has greatly reduced the clinical utilisation of EPs, which is not fully justifiable, as the information provided by EPs are quite different from those provided by MRI. The abnormalities of evoked responses reflect the global damage of the evoked nervous pathway and are significantly correlated with the clinical findings, while the vast majority of MRI lesions are not associated to symptoms and signs. Transversal and longitudinal studies have demonstrated that EP changes in MS are more strictly related to disability than MRI lesion burden. On the contrary, MRI is more sensitive than EPs in revealing the disease activity. Evoked responses modifications observed in MS are not disease-specific; moreover longitudinal studies showed latency and morphology changes of evoked responses not always related to clinical changes. Such a dissociation can be explained both by technical factors and by subclinical disease activity. To reduce the negative impact of technical aspects, only reproducible parameters of the evoked responses should be used to monitor disease evolution and therapeutic interventions.