bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple sclerosis, disease modifying treatments and depression: a critical methodological review
Authors: Feinstein Anthony
Published: January 2007

Background: Major depression affects one in two patients with multiple sclerosis (MS) during the course of their lifetime. This adds to the morbidity associated with the disorder and may contribute to an increased mortality rate because of suicide. Over the past few years, with the advent of disease modifying treatments for MS, a new concern with respect to mood has arisen, namely the possibility that some of these drugs may have depression as a clinically significant side effect. Objective: To ascertain whether disease modifying treatments in MS are associated with the development of depression or the worsening of a depressive illness. Methodology: A MEDLINE and PSYCHLIT search focusing on depression and disease modifying treatments going back to 1993 (the publication date of the results of the first randomised, placebo controlled trial). The methodology pertaining to the assessment of depression is critically reviewed. Furthermore, a critical summary is provided of treatment modalities for the depressed MS patient. Results: There are conflicting data that depression may occur with some disease modifying drugs, particularly interferon beta-1b. However, all studies reveal limitations with respect to the assessment of mood. Some reports, despite omitting details of how mentation was assessed, still comment on the presence or absence of depression. Others suffer from one or more of the following shortcomings: a failure to assess premorbid risk factors for mood disorder; a reliance on one question to assess depression; the utilisation of self report mood rating scales of questionable validity; neglecting to distinguish depression as a symptom from depression as a syndrome (i.e. major depression as defined by the DMS-1V). Conclusions: Given the many methodological pitfalls inherent in all studies to date, it is premature to conclude that disease modifying drugs are associated with depression. Evidence suggests that treatment of depression, irrespective of a putative association with a disease modifying agent, is frequently effective. This applies to pharmacotherapy or psychotherapy, although the former may be preferred should depression arise during a course of treatment with a disease modifying agent.
Long term azathioprine fails to prevent onset of multiple sclerosis: report of two cases
Authors: Constantinescu C S , Whiteley A , Blumhardt L D
Published: January 2007

Azathioprine is an immunosuppressive drug widely used in the treatment of chronic inflammatory diseases, including Multiple Sclerosis (MS). We report two patients who developed the first manifestations of clinically definite multiple sclerosis while on long term (3.5 and 10 years, respectively) treatment with azathioprine for Crohn's disease. Both patients developed the first MS symptoms during a quiescent phase of their inflammatory bowel disease. These cases show that long term azathioprine, while possibly maintaining inflammatory bowel disease under control, could not prevent the onset of MS.
Brain atrophy in relapsing multiple sclerosis: relationship to relapses, EDSS, and treatment with interferon β-1a
Authors: Rudick Richard A , Fisher Elizabeth , Lee Jar-Chi , Duda Jeffrey T , Simon Jack
Published: January 2007

Brain atrophy is a relevant surrogate marker of the disease process in multiple sclerosis (MS) because it represents the net effect of various pathological processes leading to brain tissue loss. There are various approaches to quantifying central nervous system atrophy in MS. We have focused on a normalized measure of whole brain atrophy, the brain parenchymal fraction (BPF). BPF is defined as the brain parenchymal volume, divided by the volume within the surface of the brain. We applied this method to an MRI data set generated during a phase III clinical trial of interferon β-1a (AVONEX). The purpose of the current study is to further explore clinical and MRI correlates of the BPF, particularly as they relate to relapse rate and Kurtzke's Expanded Disability Status Score (EDSS); and to further explore the therapeutic effects observed in interferon β-1a recipients. Of all demographic and disease measures in the clinical trial data base, T2 lesion volume most closely correlated with BPF in cross sectional studies, and was the baseline factor most closely correlated with progressive brain atrophy in the subsequent 2 years. We also observed that change in T2 lesion volume was the disease measure most closely correlated with change in BPF during 2 years of observation. Of interest, relapse number and EDSS change during 2 years were only weakly correlated with BPF change during the same period. Disability progression, defined as sustained worsening of at least 1.0 EDSS points from baseline, persisting at least 6 months, was associated with significantly greater brain atrophy progression. We observed a therapeutic effect of interferon β-1a in the second year of the clinical trial, and this beneficial effect was not accounted for by change in gadolinium enhanced lesion volume, or by corticosteroid medication within 40 days of the final MRI scan. The BPF is an informative surrogate marker for destructive pathological processes in relaping MS patients, and is useful in demonstrating treatment effects in controlled clinical trials. The significance of progressive brain atrophy during relapsing MS will be assessed by measuring clinical and MRI changes in prospective follow up studies.
Acute pulmonary oedema: presenting symptom of multiple sclerosis
Authors: Crawley F , Saddeh I , Barker S , Katifi H
Published: January 2007

Acute pulmonary oedema and headache are both common. The former is usually cardiogenic in origin. Severe headache of sudden onset in a young person may be suggestive of subarachnoid headache. We describe a 24-year-old man who presented with headache and pulmonary oedema, finally ascribed to multiple sclerosis. This is the first report of neurogenic pulmonary oedema as the first symptom of multiple sclerosis. We review the neuroanatomical basis and experimental evidence for neurogenic pulmonary oedema.
Clinical, radiological, immunological and pathological findings in inflammatory CNS demyelination-possible markers for an antibody-mediated process
Authors: Brück Wolfgang , Neubert Katrin , Berger Thomas , Weber Joerg R
Published: January 2007

The present report describes immunopathological, radiologcal and serological characteristics of antibody-mediated demyelination in a multiple sclerosis (MS) case with the main findings: (1) immunoglobulin and complement deposits in areas of active demyelination accompanied by massive macrophage activation; (2) ring-enhancing lesions in T1-weighted MRI after gadolinium application; (3) high titers of serum anti-myelin antibodies; and (4) signs of macrophage activation in the serum. Plasmapheresis may be a successful treatment for the type of inflammatory demyelination shown in the present case.
Interferon β-1a and depression in relapsing - remitting multiple sclerosis: an analysis of depression data from the PRISMS clinical trial
Authors: Patten S B , Metz L M
Published: January 2007

Depression is a suspected side effect of multiple sclerosis (MS) treatment with interferon β-1a. However, this has not been confirmed by rigorous studies. Several psychological symptom rating scales were completed during the PRISMS clinical trial of subcutaneous interferon β-1a (Rebif®) for relapsing - remitting MS. We conducted an analysis of these data in order to determine whether symptom elevations were associated with treatment. The PRISMS clinical trial included 560 subjects from 22 centres in nine countries. There were two active treatment arms (44 mcg × 3 and 22 mcg × 3 subcutaneously three times per week) and a placebo group. Two hundred and sixty-seven of these subjects were enrolled at English speaking study centres, where psychiatric symptom ratings were obtained at baseline, 6, 12, 18 and 24 months using the Center for Epidemiological Studies Depression Rating Scale (CES-D), the General Health Questionnaire (GHQ) and the Beck Hopelessness Scale (BHS). After randomization, the groups completing these scales were similar in terms of age, gender, EDSS, duration of illness and employment status. Median CES-D scores in the high dose, low dose and placebo groups at baseline were also similar: 8.0, 7.0 and 8.0, respectively. After 6 months of treatment, the median change in CES-D score was zero in all three groups. The proportion of subjects exceeding the traditional CES-D cut-point for clinically significant depression (>15) after 6 months of treatment was strongly associated with pre-treatment depression (RR 2.9, 95% C.I.: 1.8 - 4.7), but not with treatment group (chi-square=1.64, d.f.=2, P=0.44). The results were comparable at 12, 18 and 24 months and when ratings from the other scales were evaluated. This analysis confirms that depression is common in persons with MS: the incidence of CES-D depression in the first 6 months of follow-up was 15.6%. However, no evidence of increased depressive symptomatology was observed in association with interferon b-1a (Rebif®).
The Brief Repeatable Battery of Neuropsychological Tests: normative values allow application in multiple sclerosis clinical practice
Authors: Boringa J B , Lazeron R HC , Reuling I EW , Adèr H J , Pfennings L EMA , Lindeboom J , de Sonneville L MJ , Kalkers N F , Polman C H
Published: January 2007

The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) is a sensitive measure of cognitive impairment in multiple sclerosis (MS) patients. It consists of the Selective Reminding Test, the 10/36 Spatial Recall Test, the Symbol Digit Modalities Test, the Paced Auditory Serial Addition Test and the Word List Generation Test. We administered one of two parallel versions of the test battery to 140 healthy subjects to produce normative values for both versions. As expected, test scores were influenced by certain variables like age, gender and education. Although constructed as two equivalent versions, for some tests the two versions showed significant differences in test scores, which could not be explained by differences in these variables.
Randomized study of antibodies to IFN-g and TNF-a in secondary progressive multiple sclerosis
Authors: Skurkovich S , Boiko A , Beliaeva I , Buglak A , Alekseeva T , Smirnova N , Kulakova O , Tchechonin V , Gurova O , Deomina T , Favorova O O , Skurkovich B , Gusev E
Published: January 2007

Studies of cytokines in multiple sclerosis (MS) have shown that immune mechanisms connected with disturbance of the synthesis of cytokines probably play critical roles in the initiation and prolongation of MS. In a double-blind, placebo-controlled trial, 45 patients with active secondary progressive MS were randomized to three groups of 15 patients, each receiving a short course of antibodies to IFN-g, to tumor necrosis factor (TNF)-a, or a placebo. After 12 months with analysis of disability (Expanded Disability Status Scale scores), accompanied by interval determinations of lymphocyte subpopulations, cytokine production levels, MRI, and evoked potentials, it was found that only patients who received antibodies to IFN-g showed statistically significant improvement compared to the placebo group-a significant increase in the number of patients without confirmed disability progression. This was supported by MRI data (a decrease in the number of active lesions) and systemic changes in cytokine status (a decrease in IL-1b, TNF-a, and IFN-g concentrations in supernatants of activated blood cells of these MS patients and an increase in TGF-b production). Neutralization of IFN-g could be a new approach to treating secondary progressive MS. Long-term administration of humanized monoclonal antibodies to IFN-g and simultaneous use of antibodies to IFN-g together with IFN-b products are planned.
Cardiovascular autonomic dysregulation and fatigue in multiple sclerosis
Authors: Merkelbach S , Dillmann U , Kölmel C , Holz J , Müller M
Published: January 2007

Both cardiovascular disturbances and fatigue are frequent in multiple sclerosis (MS). We investigated their relationship in 84 MS patients (mean age 39.9+8.9 years) using five established autonomic tests and three different fatigue questionnaires. 64.2% of the patients were categorised as being fatigued. Fatigue perception was weakly related to EDSS. Moderate cardiovascular disturbances were found in 16.6% of the patients, and 10.7% had severe cardiovascular autonomic abnormalities. Cardiovascular dysfunction was slightly related to age and to EDSS. In 19.4% of all patients signs of autonomic failure and fatigue were co-existent. Using correlation analysis, we found only weakly significant correlation coefficients between some single autonomic test parameters and fatigue scores, which were confounded by age effects. The analysis of dichotomised data revealed slightly significant differences in fatigue experience between patients with and without abnormalities regarding the handgrip test and the Valsalva reaction. Thus, autonomic disturbances might contribute to fatigue symptoms in a MS subgroup, but the overall influence of the autonomic cardiovascular regulation towards fatigue experience seems to be of minor relevance.
The relationship between disability and depression in multiple sclerosis: the role of uncertainty, coping, and hope
Authors: Lynch Sharon G , Kroencke Dawn C , Denney Douglas R
Published: January 2007

The relationship between disability and depression was studied in 188 patients with clinically definite multiple sclerosis (MS). Patients were administered the Zung Self-Rating Depression Scale, Ways of Coping, Uncertainty of Illness Scale, and Hope Scale during their regular clinic appointments. Their current level of disability was rated by the attending physician using the Expanded Disability Status Scale. Even when the depression measure was corrected for items overlapping with other symptoms or consequences of MS, depression was correlated with disability. Depression was also correlated with an array of psychological variables, including uncertainty concerning ones illness, hope, and the use of various emotion-centered, though not problem-centered coping strategies. Multiple regression analyses revealed that none of these psychological correlates mediated or moderated the relationship between disability and depression. Instead, disability, uncertainty, hope, and emotion-centered coping were significant independent predictors of depression, together accounting for approximately 40% of the variance in patients' self-reported depression. The relationship between disability and depression in MS is usually interpreted as evidence that depression is psychogenic and reactive to the demands and limitations of this disease. The demonstration that this relationship is not diminished when an array of potentially intervening psychological variables are included in the analysis raises questions concerning the validity of this interpretation.
Intrathecal synthesis of virus-specific oligoclonal IgG, and of free kappa and free lambda oligoclonal bands in acute monosymptomatic optic neuritis. Comparison with brain MRI
Authors: Frederiksen Jette L , Sindic Christian JM
Published: January 2007

Twenty-seven patients with acute monosymptomatic optic neuritis were randomly selected from a population-based cohort of patients extensively screened for known etiologies of ON. Paired serum and CSF obtained median 20 days from onset were examined for oligoclonal IgG, free kappa and free lambda chains, and virus-specific oligoclonal IgG antibodies by an affinity-mediated capillary blot technique. CSF-restricted oligoclonal IgG bands, free kappa and free lambda chain bands were observed in 17, 15 and nine patients, respectively. In addition, 16 patients showed a polyspecific intrathecal synthesis of oligoclonal IgG antibodies against one or more viruses (12 measles, nine varicella zoster, six rubella, six mumps) compared to all the 18 examined patients with definite multiple sclerosis (P=0.0014). The presence of virus-specific oligoclonal IgG was significantly related to the results of oligoclonal IgG (P=0.0034), free kappa chain bands (P=0.0020), and brain MRI abnormalities (P=0.0402). At 1 year follow-up five patients had developed clinically definite multiple sclerosis; all had virus-specific oligoclonal IgG antibodies, oligoclonal IgG and abnormal MRI at onset.
Computerized color perimetry in multiple sclerosis
Authors: Accornero N , Rinalduzzi S , Capozza M , Millefiorini E , Filligoi G C , Capitanio L
Published: January 2007

Color visual field analysis has proven highly sensitive for early visual impairments diagnosis in MS, yet it has never attained widespread popularity usually because the procedure is difficult to standardize, the devices are costly, and the test is fatiguing. We propose a computerized procedure running on standard PC, cost effective, clonable, and easy handled. Two hundred and sixty-four colored patches subtending 18 angle of vision, with selected hues and low saturation levels are sequentially and randomly displayed on gray equiluminous background of the PC screen subtending 2486408 angle of vision. The subject is requested to press a switch at the perception of the stimulus. The output provides colored maps with quantitative information. Comparison between normals and a selected population of MS patients with no actual luminance visual field defects, showed high statistical difference.
Integrated care pathways in multiple sclerosis rehabilitation: completing the audit cycle
Authors: Rossiter D A , Edmondson A , Al-Shahi R , Thompson A J
Published: January 2007

The rehabilitation of progressive neurological disorders, such as Multiple Sclerosis (MS) requires comprehensive, expert management which is demanding of both time and resources. Mechanisms to monitor and audit both process and outcome are therefore essential. Integrated care pathways (ICPs) which detail the expected interventions during a given episode of clinical care, provide such a mechanism. In this study three cohorts of patients (totalling 125 episodes) with clinically definite progressive MS underwent a rehabilitation programme audited through ICPs. The cohorts were similar in relation to disability and age. Variations (departures from the expected pathway) were documented for both the rehabilitation process and goal achievement. Duration of stay reduced from 28 days for the first cohort to 18 days for the third and there was greater multidisciplinary input and carer involvement over time. Goal achievement increased from 79% for the first cohort to 87% for the third and there was an increased emphasis on cognitive function and fatigue management in relation to goals set. ICPs provide an excellent mechanism for closing the audit loop and have the potential to play an important role in improving service provision in MS.
Cerebrospinal fluid - physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases
Authors: Reiber Hansotto
Published: January 2007

The state of the art in routine CSF analysis is reviewed with particular reference to multiple sclerosis regarding: (1) The physiology and pathophysiology of blood-CSF barrier function and dysfunction with the CSF flow rate as main modulator of blood- and brain-derived protein concentrations in CSF; (2) The neuroimmunological aspects regarding (a) patterns of disease-related immunoglobulin class response (IgG, lgA, IgM) in actual Reiber graphs with reference to specific parameters and optional tests, and (b) the oligoclonal, polyspecific antibody synthesis in brain; (3) Particular marker proteins in CSF and blood for differential diagnosis of neurological diseases; (4) Mathematical base for evaluations of CSF data with an example of a multiple sclerosis patient for calculation of intrathecal immunoglobulin and antibody synthesis as well as Antibody Index.
Composite cerebrospinal fluid score in relapsing-remitting and secondary progressive multiple sclerosis
Authors: Jongen P JH , Floris S , Doesburg W H , Lemmens W AJG , Hommes O R , Lamers K JB
Published: January 2007

We investigated whether cerebrospinal fluid (CSF) analysis may differentiate between relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS). In 17 RR and 16 SP patients we determined: albumine CSF/PB ratio; mononuclear cell (MNC) number, CD4+, CD8+, and B1+ subsets, CD4+/CD8+ ratio; IgG, IgG index, IgM, IgM index, complement components C3 and C4, and C3 and C4 indexes; myelin basic protein; neuron-specific enolase (NSE); S100; and lactate. For each parameter the statistical distance was calculated. Then, using linear discriminant analysis, we computed a discriminant score, including only variables with a P value less than or equal to 0.15: albumin CSF/PB ratio, MNC number, IgM, IgM index, C3, C4, NSE, S100, and lactate. The discriminant score allocated all 17 RR patients to the RR group and 15 of 16 SP patients to the SP group. We conclude that RR and SP MS patients differ with respect to CSF profile and that in individual patients a composite CSF score may differentiate between RR and SP MS.
Are there any body fluid markers of brain atrophy in multiple sclerosis?
Authors: Giovannoni G , Green A JE , Thompson E J
Published: January 2007

The weak correlation between inflammatory activity and disease progression in patients with multiple sclerosis has shifted the emphasis from inflammatory monitoring to the investigation of the pathological processes of demyelination, axonal loss, and gliosis. New magnetic resonance imaging (MRI) techniques that have been developed to measure these processes appear very promising. This paper will briefly discuss potential body fluid markers of axonal loss, gliosis and demyelination, as the pathological substrates of brain atrophy, their function and the principles behind their future study in patients with multiple sclerosis.
Relapse markers in multiple sclerosis: are in vitro cytokine production changes reflected by circulatory T-cell phenotype alterations?
Authors: Debruyne Jan , Philippé Jan , Dereuck Jacques , Willems Annick , Leroux-Roels Geert
Published: January 2007

In vitro tumor necrosis factor-a (TNF-a), interferon-g (IFN-g) and interleukin-2 (IL-2) production, serum neopterin levels, and T-lymphocyte subpopulations were determined on a monthly basis in 22 MS patients. We found increased in vitro TNF-a production from 4 weeks on prior to the day of an exacerbation. There was a significant correlation with in vitro IFN-g release, the absolute blood monocyte count and the serum neopterin levels, suggesting that monocytes stimulated by IFN-g play an important role in the TNF-a production. Serial analysis of in vitro TNF-a production proved to be a helpful tool in predicting relapses in MS patients. Furthermore, elevated levels of IFN-g and IL-2 after stimulation with OKT3 during exacerbations were demonstrated. These increases were not reflected by changes in T-lymphocyte subpopulations. However, significant differences in T-cell subsets were observed between controls and relapsing progressive patients.
Myelin reactive T cells in the autoimmune pathogenesis of multiple sclerosis
Authors: Stinissen Piet , Medaer Robert , Raus Jef
Published: January 2007

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination. Although it is widely accepted that demyelination in MS results from an active inflammatory process, the cause of the inflammation is still not completely resolved. Findings in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and observations in human MS have led to the hypothesis that MS is an autoimmune disease mediated by autoreactive T cells with specificity for myelin antigens. The identity of the brain antigen(s) which is (are) the primary target(s) of the autoimmune process is not known, but current evidence indicates that myelin basic protein (MBP) is a likely candidate. In this paper we will overview some of the experimental evidence suggesting that MBP reactive T cells hold a central position in the pathogenesis of MS, and discuss some of the currently tested therapeutic strategies in MS which are directed towards the pathogenic MBP reactive T cells. Although there appears to be no direct correlation between anti-MBP T cell responses and clinical disease activity, some recent observations suggest that monitoring of anti-MBP T cell responses could be helpful to study immunological efficacy of experimental immunotherapies in MS.
Disease activity and the immune set in multiple sclerosis: blood markers for immunotherapy
Authors: Coles A J , Wing M G , Compston D AS
Published: January 2007

There is no established immunological marker of multiple sclerosis activity, which reflects the poor understanding of the immunopathogenesis of multiple sclerosis. Passive measurement of the levels of soluble inflammatory markers, whose half lives are usually measured in minutes and hours, can only indicate the extent of instantaneous inflammation, which is known to fluctuate in multiple sclerosis. We favour measurement of immune responses in vitro. As healthy individuals have T cell reactivities to myelin proteins that are postulated to be pathogenic in multiple sclerosis,1,2we prefer non-antigen specific mitogen and recall antigen assays as immunological markers. We illustrate their use in the treatment of 27 patients with multiple sclerosis using a pulse of humanised anti-lymphocyte (CD52) antibody that caused prolonged T cell depletion. The mitogen-induced proliferation, and secretion of IFN-g, from peripheral blood mononuclear cells in vitro was significantly reduced after treatment, suggesting that immune responses had been modulated. Such observations will only gain credence as an outcome measure if they are shown to correlate with clinical or radiological measures of multiple sclerosis activity. Perhaps more importantly, aspects of the pathogenesis of multiple sclerosis may be revealed by close immunological surveillance of patients undergoing experimental treatments.
The expression of integrins on activated T-cells in multiple sclerosis. Effect of intravenous methylprednisolone treatment
Authors: Luján S , Masjuan J , Roldán E , Villar L M , González-Porqué P , Álvarez-Cermeño J C
Published: January 2007

We studied the effect of intravenous methylprednisolone (MP) on the expression of the integrins, LFA-1 and VLA-4, on activated blood T-lymphocytes in 17 patients with relapses of clinically definite relapsing-remitting MS. MP treatment did not induce changes in the expression of CD3, CD4, DR, LFA-1 or VLA-4 markers when measured in the total population of lymphocytes in MS patients in relation to treatment. Treatment influenced neither the LFA-1 nor VLA-4 positive cells within the CD3+ population. MP treatment clearly decreased the DR+ CD3+ cells (P50.01) and the percentage of DR+ CD3+ lymphocytes bearing VLA-4 (P50.01). However, this was not the case when we studied the percentage of lymphocytes which expressed LFA-1. Glucocorticoids did not influence the mean intensity of the expression of the two integrins quantified in either total or DR+ CD3+ lymphocytes. Although, further research seems warranted to investigate a possible effect of MP on lymphocyte integrin function, this work corroborates the idea that MP treatment may interfere with the mechanisms of T-cell migration into CNS, thus modulating the activity of multiple sclerosis.
Urinary markers of disease activity in multiple sclerosis
Authors: Giovannoni G , Thompson E J
Published: January 2007

Numerous markers of disease activity, representing different aspects of the inflammatory cascade and pathogenic process in multiple sclerosis, can be detected in the urine. Urinary monitoring provides distinct advantages over blood and cerebrospinal fluid: it is easier to collect, allows frequent sampling and acts as a natural integrator by capturing the excretion of a substance over a prolonged period of time. We will discuss the principles, advantages, and pitfalls of urinary monitoring in relationship to multiple sclerosis.
Determinants of Gd-enhanced MRI response to IFN-β-1a treatment in relapsing-remitting multiple sclerosis
Authors: Koudriavtseva T , Pozzilli C , Fiorelli M , Gasperini C , Bagnato F , Galgani S , Frontoni M , Ciccarelli O , Bastianello S
Published: January 2007

The decision to use interferon beta (IFN-b) as a treatment for relapsing-remitting multiple sclerosis (RRMS) is based on both clinical characteristics and course of the disease. To better identify the profile of responders, the relationships between baseline clinical/MRI characteristics and therapeutical response was analyzed in 49 patients with RRMS randomly assigned to receive subcutaneously 3 or 9 MIU of IFN-b-1a. The therapeutical response was evaluated as a per cent change in the mean number and volume of monthly Gd-enhancing lesions in both first (early response) and second (late response) 6-month period of treatment, compared to the 6-month pre-treatment period. A better early response was seen in patients with a lower number of relapses during the pre-treatment period, while the late response was favourably influenced by a lower baseline EDSS and the high dose. Our findings suggest that the effect of IFN-b-1a on disease MRI activity is dose-related and dependent on the relapse rate and the level of disability before treatment.
Patient perception of quality of care provided by specialists and generalists
Authors: Schwartz Carolyn E , Brotman Sally , LaRocca Nicholas , Lee Hang
Published: January 2007

Efforts to control medical care costs have focused on reducing the number of specialists directing patient care. This cross-sectional survey evaluated multiple sclerosis patient perceptions of the quality of care across three patterns of care: primary care (n=156), single specialty care (n=338), and comprehensive care (n=75). The pattern of medical care received by the patient was defined by: (1) whether the MS provider was a primary care physician or (2) a neurologist; (3) whether the patient reported using other specialty services, such as psychological, rehabilitation, or social work services. Process indicators of quality of care were measured by subscales for interpersonal aspects of care, access to care, and perceived action plan. The MSQOL-54 was used to measure health-related quality of life. Pattern of care was not related to the Interpersonal or Access dimensions of care, after adjusting for health status and sociodemographic characteristics. Patients in the Single Specialty and Comprehensive Care patterns of care were, however, more likely to report their MS provider having and implementing an action plan. We conclude that MS patients who receive Single Specialty and Comprehensive Care are more likely to get diagnostic and treatment-related tests, as well as immunotherapeutic and experimental treatments.
Familial multiple sclerosis: volumetric assessment in clinically symptomatic and asymptomatic individuals
Authors: Fulton Jennifer C , Grossman Robert I , Mannon Lois J , Udupa Jayaram , Kolson Dennis L
Published: January 2007

A genetic basis for clustering of multiple sclerosis (MS) cases, based on studies of MS families, has been proposed for decades. Few reports provide detailed neurological as well as neuroradiological findings on these patients. We report total T2-weighted intracranial lesion volumes on members of three familial MS cohorts: a mother and father with conjugal MS with one affected son and a neurologically normal son and daughter, one pair of monozygotic twin sisters with MS, and a female sibling pair with MS. We hypothesized that asymptomatic siblings in a family with two affected parents and another affected child might demonstrate clinically silent T2-weighted lesions; and that monozygotic twins with MS are more likely to express similar T2-weighted lesion volumes than non-twin sibling pairs. We found clinically silent lesions in unaffected children of the symptomatic parent couple, with a significant difference in total T2 lesion volume between these unaffected siblings and their parents, as well as their affected brother. In our other sibling pairs, T2 lesion volumes were similar between the twins and significantly different in the non-twin pair, despite similar levels of clinical functioning as determined by EDSS scoring. These results suggest that foci of demyelination might be expected in clinically normal offspring of parents with MS, possibly reflecting a genetic predisposition to subsequent development of MS.
Multiple sclerosis: a preliminary study of selected variables affecting rehabilitation outcome
Authors: Langdon D W , Thompson A J
Published: January 2007

Problem: The diversity of physical and cognitive impairments seen in progressive multiple sclerosis (MS), make it difficult to identify the factors that influence neurorehabilitation outcome. Improvements in a motor disability scale must be considered in the context of the patient's physical and cognitive starting points, if the process of neurorehabilitation is to be properly understood. Method: Data was collected from 38 patients (mean age 41 years, 16 men and 22 women) with clinically definite MS (of whom all but one were in the progressive phase of the disease), who were consecutively admitted to a neurorehabilitation unit. Patients' physical disability was assessed on the motor scale of the Functional Independence Measure (FIM) on admission and discharge. Cognitive and neurological assessments were completed on admission. The cognitive battery comprised the WAIS-R, NART, RMT, CVLT CMT, GNT, GDA, and VOSP (some in short form). Emotional measures were the STAI, STAXI and BDI. Results: The mean improvement on the FIM was 6 points. A multiple regression analysis was performed to determine which cognitive and neurological variables related to reduced disability after neurorehabilitation. To take account of each patient's starting point, the model included their FIM admission score. This variable, together with vocabulary skills and cerebellar function accounted for 57% of the variance in the patients' improvements. These results suggest that verbal intelligence and cerebellar function are influential in determining rehabilitation outcome. Although these findings will be unsurprising to clinicians, this is the first quantitative demonstration of these effects.
Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis
Authors: Matusevicius D , Kivisäkk P , He B , Kostulas N , Özenci V , Fredrikson S , Link H
Published: January 2007

Myelin-directed autoimmunity is considered to play a key role in the pathogenesis of multiple sclerosis (MS). Increased production of both pro- and anti-inflammatory cytokines is a common finding in MS. Interleukin-17 (IL-17) is a recently described cytokine produced in humans almost exclusively by activated memory T cells, which can induce the production of proinflammatory cytokines and chemokines from parenchymal cells and macrophages. In situ hybridisation with synthetic oligonucleotide probes was adopted to detect and enumerate IL-17 mRNA expressing mononuclear cells (MNC) in blood and cerebrospinal fluid (CSF) from patients with MS and control individuals. Numbers of IL-17 mRNA expressing blood MNC were higher in patients with MS and acute aseptic meningoencephalitis (AM) compared to healthy individuals. Higher numbers of IL-17 mRNA expressing blood MNC were detected in MS patients examined during clinical exacerbation compared to remission. Patients with MS had higher numbers of IL-17 mRNA expressing MNC in CSF compared to blood. This increase in numbers of IL-17 mRNA expressing MNC in CSF was not observed in patients with AM. Our results thus demonstrate increased numbers of IL-17 mRNA expressing MNC in MS with higher numbers in CSF than blood, and with the highest numbers in blood during clinical exacerbations.
Quantification of impairment in MS: discussion of the scales in use
Authors: Amato Maria Pia , Ponziani Giuseppina
Published: January 2007

Accurate, efficient measurement of disease status has become a key issue in MS clinical practice and research. Despite some perceived problems, the Expanded Disability Status Scale (EDSS) remains the most widely used comprehensive measure of impairment. There is also a place for more restricted scales of impairment which focus on some aspects of neurological function in more detail than the EDSS e.g. measures of ambulation, arm function and cognitive function. Improvements in scales of impairment in the future is likely to result from the use of more quantitative tests of selected components of the neurological examination.
Magnetic resonance imaging in the monitoring of disease progression in multiple sclerosis
Authors: Stevenson V L , Miller D H
Published: January 2007

Disease progression and irreversible disability in multiple sclerosis results from incomplete recovery from relapses, but most importantly from insidious disease progression. Although magnetic resonance imaging parameters, such as new lesion rate and gadolinium enhancement, reflect inflammation and disease activity they have no bearing on disease progression. Until now the T2 lesion load or disease burden has been relied upon for this, despite its poor relationship with disability measures. This paper looks at the mechanisms responsible for disease progression and discusses the MR techniques now available to reflect these pathological processes.
Normal-appearing white matter changes in multiple sclerosis: the contribution of magnetic resonance techniques
Authors: Filippi Massimo , Tortorella Carla , Bozzali Marco
Published: January 2007

Several magnetic resonance (MR) techniques have proved to be sensitive enough to detect the subtle pathological changes that post-mortem studies showed to occur in the normal-appearing white matter (NAWM) from patients with multiple sclerosis (MS). Although these abnormalities can be detected in other neurological conditions, they seem to be more frequent and diffuse in MS. However, the contribution of NAWM changes to the diagnosis is still unclear. Their nature is also unknown and perhaps differs in different phases and clinical manifestations of the disease. Nevertheless, the extent and severity of NAWM damage seems to be relevant in causing disability and influencing the clinical evolution in MS patients. This review will summarize the present knowledge about MR-detected NAWM changes in MS and their relevance to the diagnosis and the understanding of disease evolution.
Magnetisation transfer of normal appearing white matter in primary progressive multiple sclerosis
Authors: Leary S M , Silver N C , Stevenson V L , Barker G J , Miller D H , Thompson A J
Published: January 2007

Patients with primary progressive multiple sclerosis may develop severe disability despite a paucity of lesions on conventional magnetic resonance imaging, raising the possibility that intrinsic changes in normal appearing white matter (NAWM) contribute to disability. This study has measured magnetisation transfer ratio (MTR), an index of tissue damage, of NAWM in 52 patients with primary progressive multiple sclerosis and 26 healthy controls. Absolute values of MTR were obtained from the genu of the corpus callosum and pons, and mean values were calculated from bilateral regions in the centrum semiovale, frontal white matter, parieto-occipital white matter and posterior limb of the internal capsule. The median MTR was lower in all regions in patients compared to controls. Median values (per cent units) were significantly lower in corpus callosum (39.73 vs 40.63; P=0.01), frontal white matter (39.11 vs 39.59; P=0.01) and centrum semiovale (37.21 vs 37.82; P50.05). This study has demonstrated small but widespread decreases in MTR in NAWM in primary progressive multiple sclerosis supporting the hypothesis that there are intrinsic changes in NAWM which may contribute to disability in this patient group.
Impaired interleukin-12 production in multiple sclerosis patients
Authors: Rohowsky-Kochan C , Molinaro D , Choudhry A , Kahn M , Cook S D
Published: January 2007

Multiple sclerosis (MS), a disease of the human central nervous system, is believed to be a T cell mediated autoimmune disorder with genetic and environmental influences. Interleukin-12 (IL-12), a proinflammatory cytokine produced primarily by antigen presenting cells is a potent inducer of interferon-g (IFN-g) and other Th1 cytokines that may play an important role in MS pathogenesis. We have investigated IL-12 production induced by the T cell independent pathway in untreated and IFN-b treated MS patients, healthy individuals and other neurological disease (OND) patients in response to the human pathogen Staphylococcus aureus. We report that peripheral blood mononuclear cells (PBMC) from untreated MS patients produce normal amounts of the biologically active IL-12 p70 heterodimer but significantly less free IL-12 p40 heavy chain than PBMC from both healthy and disease controls when challenged in vitro with Staphylococcus aureus. Both mRNA expression of the inducible IL-12 p40 chain and protein levels were found to be reduced in untreated MS patients. No decrease in the production of the IL-12 p40 was seen in MS patients on IFN-b therapy. The decreased production of IL-12 p40 heavy chain is not attributed to increased IL-10 secretion, a defect in the production of cytokines by macrophages or the number of cytokine producing cells. The factor(s) responsible for the decrease in p40 remain to be determined. Since IL-12 p40 antagonizes the biological activity of IL-12 in vitro and in vivo, identification of a defect in the `natural' antagonist of IL-12, may provide the basis for immune therapy.
Sexual dysfunction in multiple sderosis: a case-control study. 1. Frequency and comparison of groups
Authors: Zorzon M , Zivadinov R , Bosco A , Bragadin L Monti , Moretti R , Bonfigli L , Morassi P , Iona L G , Cazzato G
Published: January 2007

Sexual dysfunction is a very important but often overlooked symptom of multiple sclerosis. To investigate the type and frequency of symptoms of sexual dysfunction in patient suffering from multiple sclerosis, we performed a case-control study comparing 108 unselected patient with definite multiple sclerosis, 97 patient with chronic disease and 1 10 healthy individuals with regard to sexual function, sphincteric function, physical disorders impeding sexual activity and the impact of sexual dysfunction on social life. Information has been collected from a face-to-face structured interview performed by a doctor of the same gender as the patient. The disability, the cognitive performances, the psychiatric conditions and the psychological profile of patien t a nd co ntrols have bee n assessed. Sexul a dysfu nction was prese nt in 73.1% of cases, in 39.2% of chronic disease co ntrols and in 12.7% of h e althy co ntrols (P < 0.000 1). Male cases reported symptoms of sexual dysfunction more freq ue ntly th an female cases (P <0.002). Symptoms of sexual dysfunction more commonly reported in patient with multiple scerosis were anorgasmia or hyporgasmia (37.1%), decreased vaginal lubrication (35.7%) and reduced libido (31.4%) in women, and impotence or erectile dysfunction (63.2%), ejaculatory dysfunction and/or orgasmic dysfunction (50%) and reduced libido (39.5%) in men. Seventy-five per cent of cases, 51.% of chronic disease controls and 28.2% of healthy controls (P <0.0001) experienced symptoms of sphincteric dysfunction. In conldusion, a substantial part of our sample of patient with multiple sclerosis reported symptoms of sexual and sphincteric dysfunction. Both sexual and sphincteric dysfunction were significantly more common in patient with multiple sclerosis than in either control group. Our findings suggest that a peculiar damage of the structures involved in sexual function is responsible for the dysfunction in patient with multiple scerosis, but the highly significant lower frequency of symptoms of depression and anxiety in healthy controls may also imply a possible causative role of psychological factors.
The reliability of leg circumference assessment: a comparison of spring tape measurements and optoelectronic volumetry
Authors: Labs Karl-Heinz , Tschoepl Martin , Gamba Giancesare , Aschwanden Markus , Jaeger Kurt A
Published: January 2007

The purpose of this study was to compare the reliability of repeated spring tape measurements with optoelectronic volumeter measurements for the assessment of lower leg circumferences. The limb circumferences at mid-calf and ankle level of both legs were measured three times using a spring tape measure as well as an optoelectronic volumeter. In all, 30 healthy volunteers participated in the study. Test reliability and repeatability were described through the process-related and between-subject variances and variance-derived parameters such as the reliability coefficient (intraclass correlation coefficient, RC), the relative precision (RP), and the coefficient of repeatability (CR). A higher value for the RC and a lower value for the RP indicate that the test variability is predominantly due to between-subject variance and not to test process-related variance. RCs for both methods, independent of whether measurements were taken at calf or at ankle level, always exceeded 0.95. RPs were in the same order of magnitude for both methods but lower for measurements at calf than at ankle level (range: RPcalf 6.36-8.74%; range: RPankle 12.49-18.56%). CRs for both methods were low and of comparable magnitude (CR range: 4.8-7.7), although slightly smaller for the spring tape. When measurement results from the spring tape and the volumeter were compared, results achieved with the volumeter were significantly longer than those from the spring tape (p, 0.05). Results from both methods were linearly in good agreement and there was no proportional bias; differences shown were due to a significant constant bias regarding the volumeter. Circumference measurements taken by spring tape and by optoelectronic volumetry are both characterized by a comparably high reliability. However, these methods cannot be used in an interchangeable way because a constant bias exists for volumetry, resulting in significantly larger circumferences compared with those measured using the spring tape.
Non-invasively determined ambulatory venous pressure
Authors: Fronek Arnost , Kim Reuben , Curran Barbara
Published: January 2007

In view of the resemblance of exercise-induced plethysmographic changes with those obtained by direct venous pressure measurement, we decided to use a combination of photo-plethysmography (PPG) and hydrostatic pressure calibration to determine the PPG/pressure relationship. A standard foot dorsiflexion exercise involving stepwise position changing was performed which induced hydrostatic pressure changes that were recorded as the heart-probe distance. A logarithmic PPG/pressure relationship was identified and the resulting ambulatory venous pressure (AVP) was obtained from the PPG/pressure curve. Simultaneous direct AVP was recorded in 14 patients scheduled for venous surgery. `Non-invasive AVP only' was determined in 24 normal control subjects with a mean value of 19.24 mmHg (±8.79 SD). In the patient group, the direct AVP values were 40.00 mmHg (±10.83 SD) compared with the PPG values of 33.07 mmHg (±12.94 SD). The resulting correlation was r = 0.8850. By utilizing stepwise leg elevation, a reliable PPG/pressure curve can be established which, in turn, permits AVP determination. It is suggested that this non-invasive AVP determination may serve as a screening test to evaluate non-invasively venous hemodynamics.