Multiple Sclerosis References 2003; Authors: W-Z
(52 References)
Wade, D. T., P. Robson, et al. (2003). "A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms." Clin Rehabil 17(1): 21-9.
OBJECTIVES: To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects. DESIGN: A consecutive series of double-blind, randomized, placebo-controlled single-patient cross-over trials with two-week treatment periods. SETTING: Patients attended as outpatients, but took the CME at home. SUBJECTS: Twenty-four patients with multiple sclerosis (18), spinal cord injury (4), brachial plexus damage (1), and limb amputation due to neurofibromatosis (1). INTERVENTION: Whole-plant extracts of delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), 1:1 CBD:THC, or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5-120 mg/24 hours. Measures used: Patients recorded symptom, well-being and intoxication scores on a daily basis using visual analogue scales. At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales, administered standard measures of disability (Barthel Index), mood and cognition, and recorded adverse events. RESULTS: Pain relief associated with both THC and CBD was significantly superior to placebo. Impaired bladder control, muscle spasms and spasticity were improved by CME in some patients with these symptoms. Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME. CONCLUSIONS: Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings.
Wallberg, M., J. Wefer, et al. (2003). "Vaccination with myelin oligodendrocyte glycoprotein adsorbed to alum effectively protects DBA/1 mice from experimental autoimmune encephalomyelitis." Eur J Immunol 33(6): 1539-47.
To prevent an organism from developing autoimmunity the body limits the number of autoreactive cells through thymic negative selection and regulates their activity through induction of suppressor T cells. Development of antigen-specific therapies provides an interesting opportunity to imitate the body's own, often effective, method of protection. Our study demonstrates that DBA/1 mice could be protected from experimental autoimmune encephalomyelitis induced through injection of recombinant myelin oligodendrocyte glycoprotein (rMOG) when they were previously immunized intraperitoneally with rMOG adsorbed to aluminium hydroxide. This protection was associated with a decreased IFN-gamma production by rMOG-specific cells, but not a decreased proliferative response. Protection was long lasting, indicating that MOG-alum vaccination might be developed as a prophylactic therapy in multiple sclerosis.
Wandinger, K. P., J. D. Lunemann, et al. (2003). "TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis." Lancet 361(9374): 2036-43.
BACKGROUND: Many patients with multiple sclerosis do not respond to interferon beta, which is widely used as an immunomodulatory treatment in this disease. We aimed to assess the functional relevance of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), which is upregulated on incubation with interferon beta, for clinical treatment response. METHODS: We quantified gene expression longitudinally by realtime-PCR of the peripheral immune cells of 82 patients with multiple sclerosis. In a first cohort of 62 patients, 20 were classified as first-year responders since they did not have relapses during treatment with interferon beta 1a; 19 were classified as first-year non-responders; and 23 developed neutralising antibodies to interferon beta. A second cohort, also characterised by MRI, consisted of 11 patients on interferon beta 1a and nine patients who were not treated. Concentrations of soluble TRAIL were determined by ELISA in serum samples of nine non-treated patients, 49 patients before treatment (29 responders, 20 non-responders), as well as longitudinally in a subset of 23 patients. FINDINGS: In both patient cohorts, drug-responders could be distinguished from non-responders by early and sustained induction of TRAIL (p<0.0001, each). In the presence of neutralising antibodies, initial upregulation of TRAIL expression was subsequently abrogated. Raised concentrations of soluble TRAIL in patients' serum samples before the start of treatment allowed prediction of the treatment response in the first year (ROC analysis with area under the curve 0.879 [0.785-0.974]). INTERPRETATION: Our data suggest that TRAIL expression is a candidate for pretreatment assessment and might thus be used as a prognostic marker of treatment response to interferon beta in multiple sclerosis. Furthermore, our observations have implications for the development of future immunoregulatory strategies in multiple sclerosis therapy.
Warren, S., K. G. Warren, et al. (2003). "Geographic and temporal distribution of mortality rates for multiple sclerosis in Canada, 1965-1994." Neuroepidemiology 22(1): 75-81.
Statistics Canada data were used to calculate multiple sclerosis (MS) mortality rates per 100,000 population in the Canadian provinces from 1965 to 1994. For the period 1965-1994, the highest average annual MS mortality rates were in Quebec (4.4) and Ontario (3.9), while the Western Provinces had an intermediate rate (2.1) and the Atlantic Provinces had the lowest rate (1.2). Female mortality rates exceeded male rates in each of the four regions. Average annual MS mortality rates in Canada overall fluctuated during the past 30 years, with rates of 3.4 in 1965-1969, 4.2 in 1970-1974, 3.2 in 1975-1979, 2.3 in 1980-1984, 2.8 in 1985-1989 and 3.9 in 1990-1994. Female mortality rates exceeded male rates during each 5-year period. The highest mortality rates for both genders were in the 65 years plus age group. Rates in the under 45 years age group have remained stable, while rates in both the 45-64 and 65 years plus age groups have fluctuated. There is no apparent relationship between prevalence and mortality rates among the Canadian provinces.
Wassem, R. and W. Dudley (2003). "Symptom management and adjustment of patients with multiple sclerosis: a 4-year longitudinal intervention study." Clin Nurs Res 12(1): 102-17.
The researchers studied the effectiveness of a nursing intervention in promoting adjustment and symptom management in individuals with multiple sclerosis (MS). This was a 4-year longitudinal study to determine whether the 4-week intensive outpatient program was effective in increasing adjustment to MS and if the treatment effect would last over time. A sample of 27 individuals with MS participated in the study. Treatment participants had significant improvements in symptom management at the 4-year follow up. This improvement was attributable to signficant improvements in sleep and fatigue levels. Although adjustment and self-efficacy scores improved in the treatment group over time, this improvement was not superior to the control group. This was anticipated because the behavioral changes would precede improvement in adjustment to life following the diagnosis of MS.
Waubant, E., S. Vukusic, et al. (2003). "Clinical characteristics of responders to interferon therapy for relapsing MS." Neurology 61(2): 184-9.
OBJECTIVE: To determine the proportion of patients with multiple sclerosis (MS) who respond to interferon-beta (IFNB) therapy and assess whether clinical characteristics differ in IFNB responders vs nonresponders. METHODS: Data on all patients who received IFNB who were entered in the prospective European Database for Multiple Sclerosis (EDMUS) database in Lyon as of March 31, 2001, were reviewed. Responders were defined as having a lower relapse rate on IFNB compared with the year or 2 years prior to IFNB therapy. RESULTS: Two hundred sixty-two patients with relapsing MS received at least 6 months of IFNB: 200 relapsing remitting (RR) and 62 relapsing secondary progressive (SP). One-third of patients experienced a higher or identical annual relapse rate while on IFNB treatment. Compared with nonresponders, responders were older and had longer disease duration at the time IFNB was initiated. RRMS responders also had a higher relapse rate during the year prior to IFNB therapy and SPMS responders had a higher Disability Status Scale score at initiation of IFNB. CONCLUSION: Clinical profiles of patients with relapsing MS who respond to IFNB may differ from those who do not with a more inflammatory and less neurodegenerative disease at the time IFNB is initiated.
Waubant, E., D. Goodkin, et al. (2003). "IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS." Neurology 60(1): 52-7.
OBJECTIVE: To 1)determine serum levels of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in patients with secondary progressive (SP) MS; 2)determine the relationship between these serum levels and MRI activity; and 3) evaluate the effect of interferon (IFN) therapy on these measures. BACKGROUND: High serum levels of MMP-9 and low levels of TIMP-1 predict the appearance of new gadolinium-enhancing (Gd+) lesions in relapsing-remitting (RR) MS. METHODS: Monthly Gd+ brain MRI and measures of serum MMP-2, MMP-9, TIMP-1, and TIMP-2 at 3-month intervals were performed for up to 3 years in 33 patients with SPMS participating in a phase III study of IFNbeta-1b. RESULTS: Patients who developed new Gd+ lesions had higher levels of MMP-9 than patients who did not develop Gd+ lesions (median 351 vs 226 ng/mL, p = 0.049). The ratio of MMP-9/TIMP-1 predicted new Gd+ lesion on the concurrent scan (OR = 2.23, 95% CI 0.99 to 4.99, p = 0.052) and on the following scan (OR = 2.16, 95% CI 1.01 to 4.63, p = 0.048), whereas levels of MMP-2/TIMP-2 did not. Median levels of TIMP-1 were higher and MMP-9 trended lower for IFNbeta compared to placebo recipients (TIMP-1: 1,450 vs 1,185 ng/mL, p = 0.024; MMP-9: 225 vs 339 ng/mL, p = 0.081). IFNbeta did not influence levels of MMP-2 and TIMP-2. CONCLUSION: The ratio of MMP-9/TIMP-1 may predict MRI activity in SPMS. The effect of IFNbeta-1b in MS, as measured by reduction in new Gd+ lesions, may be partly explained by altering MMP-9/TIMP-1 ratio.
Wayne Moore, G. R. (2003). "MRI-clinical correlations: more than inflammation alone-what can MRI contribute to improve the understanding of pathological processes in MS?" J Neurol Sci 206(2): 175-9.
Magnetic resonance imaging (MRI) is a sensitive technique in the detection and follow-up of multiple sclerosis (MS) lesions. However, the pathologic basis of these changes is poorly understood. It is becoming increasingly apparent that routine MRI techniques do not represent specific histopathologic changes but reflect a variety of pathological changes in tissue. This review will outline the findings in MRI-pathology correlation in MS to date, and the current understanding of the evolution of pathologic changes in the MS lesion and non-lesional white matter as reflected by MRI. Possible future contributions of MRI to unveiling the dynamic pathology of MS will also be discussed.
Weatherby, S. J. (2003). "Organic solvents and the risk of multiple sclerosis." Epidemiology 14(4): 506; author reply 507.
Wegner, C. and P. M. Matthews (2003). "A new view of the cortex, new insights into multiple sclerosis." Brain 126(Pt 8): 1719-21.
Weinshenker, B. G. (2003). "Neuromyelitis optica: what it is and what it might be." Lancet 361(9361): 889-90.
Weinstock-Guttman, B., L. D. Jacobs, et al. (2003). "Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium." Mult Scler 9(3): 293-8.
The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in African American (AA) patients in the New York State Multiple Sclerosis Consortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AAs comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in AA registrants versus nonAfrican Americans (NAA). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. AA patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. Our findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility.
Wekerle, H. and R. Hohlfeld (2003). "Molecular mimicry in multiple sclerosis." N Engl J Med 349(2): 185-6.
Whitmarsh, T. E. (2003). "Homeopathy in multiple sclerosis." Complement Ther Nurs Midwifery 9(1): 5-9.
Multiple sclerosis (MS) is the most common disease of the central nervous system affecting people between the ages of 20 and 40 years in the UK, Northern Europe and the USA. No definitive treatment yet exists to halt the almost inevitable decline in function and accumulation of disability over the years in sufferers. Management is largely directly of symptoms which arise variably in the course of the condition. Such problems as urinary incontinence, sexual dysfunction, cramps and spasms, tremor and trigeminal neuralgia can often be helped to some extent using conventional therapies. These treatments though are not effective in everyone, or cause unacceptable side-effects and there are some commonly reported symptoms, such as fatigue or emotional lability for which there are no generally accepted treatments. Here, a knowledge of complementary and alternative medicine (CAM) can bring benefits to the person with MS. CAM is widely used by people with MS and some studies in this area are briefly summarised. It is interesting to reflect what lies behind all this CAM use and what that might tell conventional medicine about just what it is the MS sufferer really wants from their carers.Homeopathy is a form of CAM unique in the UK in having been available in the NHS since the foundation in 1948. Medical homeopaths in the UK have always been concerned with the integration of the best of conventional and complementary treatments for the benefit of their patients. Glasgow Homeopathic Hospital has around 100 admissions each year of people with MS at different stages of the condition and aims at an integrated response to their distress. Different therapeutic modalities are employed, but a homeopathic approach in particular is of benefit in MS. By its nature, it is a whole-person approach and allows for complete individualisation of treatment, taking account of the minutiae of someone's life. This is discussed and some examples of homeopathic treatments, which seem to be more generalisable for commonly encountered MS symptoms, are given.
Wiendl, H., O. Neuhaus, et al. (2003). "The CD28 related molecule ICOS: T cell modulation in the presence and absence of B7.1/2 and regulational expression in multiple sclerosis." J Neuroimmunol 140(1-2): 177-87.
Costimulatory signals play a key role in regulating T cell activation and are believed to have decisive influence in the inciting and perpetuating cellular effector mechanisms in autoimmune diseases such as multiple sclerosis (MS). Inducible costimulator protein (ICOS), a recently identified member of the CD28-family, presumably affects the differentiation of Th1/Th2 cells after primary activation and modulates the immune response of effector/memory T cells.This study examines the expression and functional role of ICOS costimulation in healthy donors and patients with MS. After nonspecific or antigen-specific stimulation, ICOS is preferentially expressed on CD4 Th2-T cells. ICOS-costimulation affects the production of Th1 and Th2 cytokines both in the absence and presence of B7/CD28 costimulation, thus suggesting that ICOS costimulation can modulate cytokine secretion also in a CD28-independent manner. Levels of constitutive and inducible ICOS expression on human T cell subsets from peripheral blood were quantified in healthy donors and patients with MS. Constitutive expression of ICOS on T cells varies between 0.1% and 42.3%. There were no significant differences between both groups in the baseline expression or inducibility of ICOS on CD4 or CD8 T cells. ICOS expression could be demonstrated on CSF T lymphocytes in patients with acute MS relapses but was not elevated compared with peripheral blood.In essence we show that ICOS is upregulated on human T cells after stimulation and can modulate both Th1 and Th2 cytokine production in the absence and presence of B7-costimulation. In MS patients we demonstrate the functionality of the ICOS costimulatory pathway. Potential implications of ICOSL/ICOS interactions for MS immunopathogenesis are discussed.
Wiendl, H. and B. C. Kieseier (2003). "Disease-modifying therapies in multiple sclerosis: an update on recent and ongoing trials and future strategies." Expert Opin Investig Drugs 12(4): 689-712.
Multiple sclerosis (MS) is the prototype inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults exhibiting considerable clinical, radiological and pathological heterogeneity. Novel insights in the immunopathological processes, advances in biotechnology, development of powerful magnetic resonance imaging technologies together with improvements in clinical trial design led to a variety of evaluable therapeutic approaches. Therapy has changed dramatically over the past decade, yielding significant progress for the treatment of relapsing-remitting and secondary progressive MS. A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of MS patients. This review summarises recent progress with currently available disease-modifying therapies and - on the basis of present immunopathogenetic concepts - outlines ongoing studies as well as future treatment strategies.
Wiertlewski, S., E. Auffray-Calvier, et al. (2003). "[Multinodular presentation of multiple sclerosis]." Rev Neurol (Paris) 159(5 Pt 1): 590-2.
Wiles, C. M., R. G. Newcombe, et al. (2003). "Use of videotape to assess mobility in a controlled randomized crossover trial of physiotherapy in chronic multiple sclerosis." Clin Rehabil 17(3): 256-63.
OBJECTIVES: To determine to what degree assessment of mobility based on comparison of videotape recordings before and after courses of physiotherapy in patients with chronic multiple sclerosis (MS) is reliable, correlates with 'live' assessments and indicates benefit. DESIGN: Prospective data collection within a randomized crossover controlled trial of physiotherapy at home, as an outpatient, or 'no therapy' in 40 patients. SETTING: Hospital outpatients: outpatient and home physiotherapy. OUTCOMES: Mobility change based on a comparison of short video recordings before and after each treatment period was scored independently by two physiotherapists blinded to therapy type and other measures of outcome. Scores were compared with changes in the Rivermead Mobility Index (RMI) and other indices assessed by a physiotherapist in the patient's home. RESULTS: The two video observers agreed substantially on patient outcome. Changes in walking based on video correlated with RMI for home treatment (r = 0.41, p = 0.008) but not for hospital or no treatment periods (r = 0.14 and 0.15): video changes correlated with the 'live' assessor's global change score inconsistently ('no therapy' r = 0.48, p = 0.002, hospital r = 0.30, p = 0.06 and home r = 0.17, p = 0.30 treatment periods). Based on video data alone, improved mobility was evident following home therapy for only one observer but not for the other or the averaged scores of both. CONCLUSION: There was substantial agreement between two observers deciding on change in mobility based on independent blinded evaluation of short video sequences. However the correlations of these with 'live' assessments were variable. Physiotherapy had a less clear benefit on mobility based on video analysis alone compared with 'live' assessments. The study highlights the need for more objective measures of habitual mobility over longer periods.
Wilken, J. A., R. Kane, et al. (2003). "The utility of computerized neuropsychological assessment of cognitive dysfunction in patients with relapsing-remitting multiple sclerosis." Mult Scler 9(2): 119-27.
Traditional paper-and-pencil neuropsychological batteries used to document cognitive deficits in multiple sclerosis (MS) patients lack timing precision. This makes it difficult to accurately measure psychomotor slowing, a central cognitive symptom of MS. Additionally, traditional batteries lack multiple alternate forms necessary to control for practice effects when assessing cognition over time. Finally such batteries are lengthy and expensive. Computerized neuropsychological batteries address many of these shortcomings. They measure response time more precisely, require less administration time, include alternate forms, and are ideal for rapid screening/triage. Although there are normative data on the reliability and validity of computerized measures, there have been no controlled validation studies with MS patients. The current study was designed to validate a computerized neuropsychological battery (ANAM) for use with relapsing-remitting (RR) MS patients. Prior to initiation of interferon-beta-1a (Avonex) treatment, subjects participated in a neuropsychological evaluation consisting of traditional and computerized measures. Moderate-to-high correlations were found between computerized and traditional measures. Computerized tests accurately predicted performance on key traditional tests. The battery was also concordant with traditional measures in identifying RR MS patients with and without neurocognitive impairment. Findings are discussed with respect to increased accuracy and accessibility of neuropsychological evaluations for MS patients.
Willenborg, D. O. and M. A. Staykova (2003). "Cytokines in the pathogenesis and therapy of autoimmune encephalomyelitis and multiple sclerosis." Adv Exp Med Biol 520: 96-119.
Wilson, M. T. and L. Van Kaer (2003). "Natural killer T cells as targets for therapeutic intervention in autoimmune diseases." Curr Pharm Des 9(3): 201-20.
Natural killer T (NKT) cells are a subset of lymphocytes that express receptors characteristic of conventional T cells together with receptors typically found on natural killer cells. A key feature of NKT cells is the expression of a semi-invariant T cell receptor that is specific for glycolipid antigens presented by the unusual major histocompatibility complex class I-like molecule CD1d. While their precise immunological functions remain unknown, NKT cells have been implicated in the regulation of adaptive immune responses, including those directed against autoantigens. These findings raise the possibility that specific stimulation of NKT cells may be exploited for therapeutic purposes. A number of laboratories have tested this hypothesis, utilizing the sea sponge-derived agent alpha-galactosylceramide (alpha-GalCer), a specific agonist of NKT cells. Administration of alpha-GalCer to mice results in potent activation of NKT cells, rapid and robust cytokine production, and activation of a variety of cells of the innate and adaptive immune systems. Most notably, repeated administration of alpha-GalCer to mice favors the generation of conventional T lymphocytes producing T helper (Th) type 2 cytokines such as IL-4 and IL-10. These findings suggest that alpha-GalCer can modulate inflammatory conditions that are mediated by pathogenic Th1 cells. Indeed, recent studies have demonstrated that alpha-GalCer prevents the development of Type 1 diabetes in non-obese diabetic mice and central nervous system inflammation in mouse models of multiple sclerosis. Collectively, these studies provide a solid foundation for the development of NKT cell ligands as pharmacological agents for treatment of autoimmune diseases.
Wilson, M., C. R. Tench, et al. (2003). "Pyramidal tract mapping by diffusion tensor magnetic resonance imaging in multiple sclerosis: improving correlations with disability." J Neurol Neurosurg Psychiatry 74(2): 203-7.
BACKGROUND: Current magnetic resonance imaging (MRI) outcome measures such as T2 lesion load correlate poorly with disability in multiple sclerosis. Diffusion tensor imaging (DTI) of the brain can provide unique information regarding the orientation and integrity of white matter tracts in vivo. OBJECTIVE: To use this information to map the pyramidal tracts of patients with multiple sclerosis, investigate the relation between burden of disease in the tracts and disability, and compare this with more global magnetic resonance estimates of disease burden. METHODS: 25 patients with relapsing-remitting multiple sclerosis and 17 healthy volunteers were studied with DTI. An algorithm was used that automatically produced anatomically plausible maps of white matter tracts. The integrity of the pyramidal tracts was assessed using relative anisotropy and a novel measure (L(t)) derived from the compounded relative anisotropy along the tracts. The methods were compared with both traditional and more recent techniques for measuring disease burden in multiple sclerosis (T2 lesion load and "whole brain" diffusion histograms). RESULTS: Relative anisotropy and L(t) were significantly lower in patients than controls (p < 0.05). Pyramidal tract L(t) in the patients correlated significantly with both expanded disability status scale (r = -0.48, p < 0.05), and to a greater degree, the pyramidal Kurtzke functional system score (KFS-p) (r = -0.75, p < 0.0001). T2 lesion load and diffusion histogram parameters did not correlate with disability. CONCLUSIONS: Tract mapping using DTI is feasible and may increase the specificity of MRI in multiple sclerosis by matching appropriate tracts with specific clinical scoring systems. These techniques may be applicable to a wide range of neurological conditions.
Wineman, N. M., K. M. Schwetz, et al. (2003). "Longitudinal analysis of illness uncertainty, coping, hopefulness, and mood during participation in a clinical drug trial." J Neurosci Nurs 35(2): 100-6.
The purpose of this longitudinal study was to examine the relationships among illness uncertainty, coping effectiveness, hopefulness, and mood in persons with chronic, progressive multiple sclerosis (MS) during participation in a double-blind clinical drug trial. The similarities and differences in the pattern of relationships among variables were investigated within each of four data collection time frames and across time. The convenience sample comprised 52 participants with clinically definite MS who participated in a 2-year trial using methotrexate to treat progressive MS. Participants with more severe disability were found to be less hopeful and more emotionally distressed. Participants with higher levels of hopefulness used more effective coping strategies and had more positive moods, and those with greater uncertainty about their MS were likely to experience less hopefulness and more negative moods. The pattern of relationships among uncertainty, coping, hopefulness, and mood did not change throughout participation in the drug trial. The findings may be used as a foundation for planning nursing interventions with patients involved in drug studies.
Wingerchuk, D. M. (2003). "Postinfectious encephalomyelitis." Curr Neurol Neurosci Rep 3(3): 256-64.
Postinfectious forms of encephalomyelitis, also termed acute disseminated encephalomyelitis (ADEM), form one of several categories of inflammatory demyelinating disorders of the central nervous system (CNS). Recent large, retrospective case series have refined our understanding of the clinical, laboratory, and neuroimaging characteristics of ADEM. The differences between childhood and adult ADEM, risks of development of multiple sclerosis, and the contributions of recent studies to refining the nosology of CNS demyelinating syndromes are discussed.
Wolinsky, J. S. (2003). "Rational therapy for relapsing multiple sclerosis." Lancet Neurol 2(5): 271-2.
Wolinsky, J. S. (2003). "The diagnosis of primary progressive multiple sclerosis." J Neurol Sci 206(2): 145-52.
Primary progressive multiple sclerosis (PPMS) is a rather unique form of the more common relapsing inflammatory demyelinative disease. The absence of attacks that typify relapsing forms of MS imposes special challenges for diagnosis, but also provides an opportunity to study the pathogenesis of the more progressive aspects of the disease process in isolation of confounding transient clinical events. In this review, recent advances in diagnostic approaches are considered in relationship to baseline data from a large multinational study designed to better characterize and treat this clinical phenotype. PPMS subjects with cerebral spinal fluid (CSF) findings consistent with intrathecal immunoglobulin production may have a more tissue destructive disease process than those whose CSF lacks evidence of a B-cell immunopathogenic disease component.
Wolswijk, G. and R. Balesar (2003). "Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis." Brain 126(Pt 7): 1638-49.
The presence of intact paranodal junctions on myelinated axons in the CNS and PNS is crucial for both myelin sheath attachment and saltatory impulse conduction. The axonal glycoprotein contactin-associated protein (Caspr) is expressed in the paranodal region and plays an important role in the creation and maintenance of these adhesive junctions. In the present study, antibodies to Caspr were used to assess the integrity of paranodal junctions on myelinated axons in brain and spinal cord tissue from subjects with longstanding multiple sclerosis, a neurological disorder that affects both myelin and axons. Triple immunofluorescence combined with confocal laser scanning microscopy showed that axons in the demyelinated centre of the 36 brain and 16 spinal cord multiple sclerosis lesions studied were devoid of Caspr immunoreactivity, suggesting that axons down regulate the expression of Caspr following demyelination. Additional data indicated that Caspr reappears in the paranodal region with the formation of new myelin sheaths. Immuno labelling further revealed that Caspr on myelinated axons in border regions was often no longer concentrated in the paranodal region, but was also present in the internodal region-a phenomenon particularly common in the borders of the more chronic lesions in the collection. Myelinated axons with long Caspr-positive stretches were often present at a considerable distance from the lesion edges. These findings raise the possibility that the aberrant location of Caspr is an early sign of impending myelin loss. This would imply that demyelination continues at a slow rate in established lesions. The diameters of Caspr-positive structures on some myelinated axons near the lesion edges were also increased. Moreover, the gap between individual myelin sheaths on these apparently swollen axons was widened occasionally and a very small myelin sheath plus additional Caspr-positive structures had sometimes formed in the enlarged space. This finding thus suggests that the formation of new myelin in multiple sclerosis is not only induced following the loss of complete internodes but also in response to broadening of the nodal region. Interestingly, alterations in the expression and localization of Caspr were observed in tissue from both subjects with the primary and secondary progressive form of multiple sclerosis. In summary, the present study provides immunohistochemical evidence that paranodal junctions on some myelinated axons in the borders of lesions of patients with chronic progressive multiple sclerosis are no longer intact. This may impair saltatory impulse conduction and lead to further myelin loss, thereby contributing to disease progression in multiple sclerosis.
Wosik, K., J. Antel, et al. (2003). "Oligodendrocyte injury in multiple sclerosis: a role for p53." J Neurochem 85(3): 635-44.
Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53-induced apoptosis using primary cultures of central nervous system-derived adult human oligodendrocytes. Adenovirus-mediated p53 overexpression resulted in up-regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase-mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53-induced cell death by blocking signaling through Fas and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.
Wulff, H., P. A. Calabresi, et al. (2003). "The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS." J Clin Invest 111(11): 1703-13.
Through a combination of fluorescence microscopy and patch-clamp analysis we have identified a striking alteration in K(+) channel expression in terminally differentiated human CCR7(-)CD45RA(-) effector memory T lymphocytes (T(EM)). Following activation, T(EM) cells expressed significantly higher levels of the voltage-gated K(+) channel Kv1.3 and lower levels of the calcium-activated K(+) channel IKCa1 than naive and central memory T cells (T(CM)). Upon repeated in vitro antigenic stimulation, naive cells differentiated into Kv1.3(high)IKCa1(low) T(EM) cells, and the potent Kv1.3-blocking sea anemone Stichodactyla helianthus peptide (ShK) suppressed proliferation of T(EM) cells without affecting naive or T(CM) lymphocytes. Thus, the Kv1.3(high)IKCa1(low) phenotype is a functional marker of activated T(EM) lymphocytes. Activated myelin-reactive T cells from patients with MS exhibited the Kv1.3(high)IKCa1(low) T(EM) phenotype, suggesting that they have undergone repeated stimulation during the course of disease; these cells may contribute to disease pathogenesis due to their ability to home to inflamed tissues and exhibit immediate effector function. The Kv1.3(high)IKCa1(low) phenotype was not seen in glutamic acid decarboxylase, insulin-peptide or ovalbumin-specific and mitogen-activated T cells from MS patients, or in myelin-specific T cells from healthy controls. Selective targeting of Kv1.3 in T(EM) cells may therefore hold therapeutic promise for MS and other T cell-mediated autoimmune diseases.
Wylezinska, M., A. Cifelli, et al. (2003). "Thalamic neurodegeneration in relapsing-remitting multiple sclerosis." Neurology 60(12): 1949-54.
OBJECTIVE: To define the extent of neuronal injury and loss in thalamic gray matter in patients with relapsing-remitting (RR) MS and to characterize how these neuronal pathologic changes are related to disease duration. METHODS: The authors studied 14 patients with RRMS (Expanded Disability Status Scale score, mean 3.25, range 2.0 to 6.0) and 14 (8 men, 6 women) age-matched healthy controls. Structural MR and MRS studies were performed in a single scanning session using a 3T MR system. RESULTS: N-acetylaspartate (NAA) concentrations (a measure of the apparent neuronal density) were decreased approximately 11% in the thalami of the patients with RRMS relative to controls (p < 0.05). The patients with RRMS also had an almost 25% lower mean normalized thalamic volume than controls (p < 0.005). Decreases in thalamic NAA concentration correlated strongly with thalamic volume loss for individual patients (r = 0.85, p < 0.01). Both the NAA concentration (r = -0.48, p = 0.044) and normalized thalamic volume (r = -0.60, p = 0.01) were correlated inversely with disease duration. There was a trend for a correlation between the thalamic NAA/creatine (Cr) ratio and the NAA/Cr in the frontal normal-appearing white matter (r = 0.56, p < 0.08). CONCLUSIONS: The reduction of both NAA concentration and thalamic volume suggests that a neurodegenerative component may contribute to the pathology of MS even in the earlier RR stage. The trend toward a relationship between thalamic NAA/Cr and distant normal-appearing white matter changes implies that there may be a common mechanism for the white matter axonal loss and thalamic neuronal injury.
Xie, J. H., N. Nomura, et al. (2003). "Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation." J Leukoc Biol 73(6): 771-80.
Naive T cells, when activated by specific antigen and cytokines, up-regulate adhesion molecules as well as chemokine receptors on their surface, which allows them to migrate to inflamed tissues. Human studies have shown that CXCR3 is one of the chemokine receptors that is induced during T cell activation. Moreover, CXCR3-positive T cells are enriched at inflammatory sites in patients with autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In this study, we use a mouse model of inflammation to demonstrate that CXCR3 is required for activated T cell transmigration to inflamed tissue. Using an anti- mCXCR3 antibody, we have shown that in vitro-differentiated T helper (Th) 1 and Th2 cells up-regulated CXCR3 upon stimulation with specific antigen/major histocompatibility complex. However, only Th1 cells, when adoptively transferred to syngeneic recipients, are efficiently recruited to the peritoneum in an adjuvant-induced peritonitis model. Furthermore, the neutralizing anti-mCXCR3 antibody profoundly inhibits the recruitment of Th1 cells to the inflamed peritoneum. Real-time, quantitative reverse transcriptase-polymerase chain reaction analysis demonstrates that the CXCR3 ligands, interferon (IFN)-inducible protein 10 (CXCL10) and IFN-inducible T cell alpha chemoattractant (CXCL11), are among the many chemokines induced in the adjuvant-treated peritoneum. The anti-mCXCR3 antibody is also effective in inhibiting a delayed-type hypersensitivity response, which is largely mediated by enhanced trafficking of activated T cells to peripheral inflammatory sites. Collectively, our results suggest that CXCR3 has a critical role in T cell transmigration to sites of inflammation and thus, may serve as a molecular target for anti-inflammatory therapies.
Yamamoto, T., T. Kawamoto, et al. (2003). "Multimodality imaging features of primary xanthoma of the calcaneus." Skeletal Radiol 32(6): 367-70.
Secondary xanthomatous features are histologically observed in various bone lesions, but primary xanthoma of bone is rare. We present a primary xanthoma of the right calcaneus in a 51-year-old woman who had no aberrant lipid metabolism. Roentgenograms showed a small osteolytic lesion in the calcaneal triangle, partially surrounded by bone sclerosis. Computed tomographic scans of the calcaneus showed multiple osteolytic areas, with an irregular trabecular pattern in the surrounding sclerotic bone. T1-weighted magnetic resonance images showed a lesion with central low signal intensity, surrounded by a peripheral ring with high signal intensity. The entire lesion showed high signal intensity on T2-weighted images, partially surrounded by areas with low signal intensity, concordant with reactive bone sclerosis. Histologically, the lesion consisted of numerous lipid-laden histiocytes arranged in sheets, scattered multinucleated giant cells and lymphocytes, and granulation tissues. There was no evidence of pre-existing lesions. Total excision of the tumor was curative.
Yamashita, K., T. Yokoyama, et al. (2003). "[Anesthetic management for a patient with multiple sclerosis at exacerbation stage under general anesthesia]." Masui 52(5): 521-3.
A 39-year-old woman with multiple sclerosis (MS) at exacerbation stage underwent dilatation and curettage. MS is characterized by chronic inflammation, demyelination, and gliosis in the central nervous system. Surgical stress often induces exacerbation of MS symptoms. Therefore, deep anesthesia is required for anesthetic management in cases of MS. We monitored electroencephalograph (EEG), spectral edge frequency 90 (SEF 90), spectral median frequency (SMF) and delta-amplitude for depth of anesthesia using pEEG (Drager, Germany). In this case, anesthesia was induced with sevoflurane and gradually increased to 5% in oxygen 4 l.min-1 and maintained with sevoflurane 2-3% in 2 nitrous oxide l.min-1 and 2 l.min-1 oxygen. Surgery was completed and no spike wave was observed by pEEG monitoring during surgery. In conclusion, sevoflurane anesthesia was useful for a patient with MS during exacerbation stage.
Yan, S. S., Z. Y. Wu, et al. (2003). "Suppression of experimental autoimmune encephalomyelitis by selective blockade of encephalitogenic T-cell infiltration of the central nervous system." Nat Med 9(3): 287-93.
Multiple sclerosis (MS) is a devastating neuroinflammatory disorder of the central nervous system (CNS) in which T cells that are reactive with major components of myelin sheaths have a central role. The receptor for advanced glycation end products (RAGE) is present on T cells, mononuclear phagocytes and endothelium. Its pro-inflammatory ligands, S100-calgranulins, are upregulated in MS and in the related rodent model, experimental autoimmune encephalomyelitis (EAE). Blockade of RAGE suppressed EAE when disease was induced by myelin basic protein (MBP) peptide or encephalitogenic T cells, or when EAE occurred spontaneously in T-cell receptor (TCR)-transgenic mice devoid of endogenous TCR-alpha and TCR-beta chains. Inhibition of RAGE markedly decreased infiltration of the CNS by immune and inflammatory cells. Transgenic mice with targeted overexpression of dominant-negative RAGE in CD4+ T cells were resistant to MBP-induced EAE. These data reinforce the importance of RAGE-ligand interactions in modulating properties of CD4+ T cells that infiltrate the CNS.
Yanai, H., H. Matsuura, et al. (2003). "Perivascular epithelioid cell tumor of the jejunum." Pathol Res Pract 199(1): 47-50.
Certain HMB-45-positive epithelioid cell tumors have recently been categorized under a unified concept: perivascular epithelioid cell tumor (PEComa). In this report, we describe ajejunal PEComa arising in a 32-year-old woman without other tumors or stigmata of tuberous sclerosis. The tumor consisted of nests of epithelioid cells with clear to granular eosinophilic cytoplasm. The nests were separated by thin fibrovascular septa. The tumor cells were positive for HMB-45 and progesterone receptor, and negative for cytokeratin, epithelial membrane antigen, vimentin, desmin, alpha-smooth muscle actin and CD34. RT-PCR analysis failed to reveal fusion transcript ETW/ATF1, which is characteristic of clear cell sarcoma of the soft parts. She developed a recurrent tumor at the pelvic wall and the left ovary at 13 and 25 months after the first operation, respectively. Each tumor was resected surgically, and no additional therapy was performed. We think the tumor of this case is a malignant form of PEComa because of the clinical history of multiple recurrences and the size of the primary tumor. Our case underscores that to make a correct diagnosis, clinical information and immunohistochemical examination are essential.
Yorkston, K., K. Johnson, et al. (2003). "Getting the work done: a qualitative study of individuals with multiple sclerosis." Disabil Rehabil 25(8): 369-79.
The Problem: Work can be defined as an activity performed to accomplish something in the presence of obstacles that may make accomplishing the goal difficult. For individuals with MS, work is not only limited by physical impairments but also by factors such as fatigue and cognitive changes Purpose: The aim of this study is to examine the experiences of individuals with mild to moderate MS as they carry out everyday work activities both inside and outside the home. Method: Eleven women and three men were recruited from the community to participate in a series of semi-structured interviews. Using qualitative research methodology that examined the experiences of the participants, two major themes and seven subthemes emerged. Results: The first theme, Defining the work, included Priorities: seeing what's important; Plans: learning about resources and requirements; and Perspectives: fixing it yourself. The second theme, Changing how things get done, includes Precipitating factors; Awareness; Constructing the strategies; and Evaluating the strategies. Conclusions: Individuals with MS develop strategies and utilize resources in order to get the work done. Comparisons are made between existing intervention theories or programmes and the experiences described by participants in this study.
Yoshihara, A., T. Yamanoi, et al. (2003). "[A case of childhood multiple sclerosis presented with meningitis and multiple silent plaques]." Rinsho Shinkeigaku 43(3): 98-101.
A 13-year-old girl presented herself with right optic neuritis and pleocytosis in the cerebrospinal fluid (CSF) in May 2000. Although her vision gradually improved after steroid therapy, the right optic neuritis relapsed a month later, and MRIs of the brain showed multiple high-signal intensity areas in the white matter of the right frontal and parietal lobes on T2-weighted and FLAIR images. She developed nuchal pain, low-grade fever, and general malaise in January 2002. Mononuclear pleocytosis and an elevation of myelin basic protein level were noted in CSF (33/microliter, 17.7 ng/ml, respectively). In addition to the plaque-like lesions seen in June 2000, MRI at this time showed an increase in the number of plaques in the medulla, pons, bilateral cerebellar peduncles and cerebellum. We thus considered this case as MS presenting with no focal neurological deficits but meningitis and asymptomatic MRI lesions. The past history of relapsed optic neuritis is supportive and compatible with that diagnosis. One might assume that the case belongs to that of relapsed type acute disseminated encephalomyelitis (ADEM). However, the cardinal pictures of the case are those of relapsing optic neuritis and multiple asymptomatic plaques despite clinical remission. Some atypical features like meningitis may predominate in clinical presentations of child MS, since immune response in child may differ from that of adult.
Zachoval, R., P. Palascak, et al. (2003). "[In Process Citation]." Prog Urol 13(2): 246-51.
OBJECTIVE: To establish an association between different types and degrees of neurological involv ement and lower urinary tract dysfunctions and their symptoms in patients with multiple sclerosis. PATIENTS AND METHODS: The studied group comprises 84 patients with multiple sclerosis with an average of 42.1 years in whom neurological and urological functional involvement had been evaluated. Neurological involvement had been evaluated using Expanded Disability Status Scale (EDSS) score; urinary tract dysfunctions have been diagnosed by urodynamic examinations and lower urinary tract symptoms (LUTS) using the micturition questionnaire. RESULTS: 1) An association between neurological involvement and lower urinary tract dysfunctions: detrusor hyperreflexia depends on the degree of pyramidal system involvement and the presence of detrusor-sphincter dyssynergia depends on overall disability and the degree of pyramidal system involvement. 2) An association between lower urinary tract dysfunctions and LUTS: obstructive symptoms depend on the presence of detrusor-sphincter dyssynergia. 3) An association between neurological involvement and LUTS has not been established. CONCLUSION: An association between neurological involvement, lower urinary tract dysfunctions and their symptoms has been found. Based on this knowledge, it is possible to simplify the diagnostic and therapeutic approaches in certain groups of patients.
Zachoval, R., J. Pitha, et al. (2003). "Augmentation cystoplasty in patients with multiple sclerosis." Urol Int 70(1): 21-6; discussion 26.
INTRODUCTION: Augmentation cystoplasty is an effective approach to the detrusor hyperreflexia which is refractory to conservative treatment. Sporadic data have been published in patients with progressive diseases such as multiple sclerosis (MS). MATERIALS AND METHODS: Augmentation ileocystoplasty (Goodwin 'cup-patch') was performed in 9 patients (7 females, 2 males). The average Expanded Disability Status Scale score was 4.1 (range 3.0-6.5); 7 patients had relapse-remitting MS and 2 patients secondary-progressive MS. The indication was a detrusor hyperreflexia refractory to conservative treatment in 8 patients and a detrusor hyperrefluxia with third degree bilateral vesico-ureteral reflux and renal insufficiency in 1 patient. Pre- and postoperative objective parameters were evaluated by urodynamic examination, imaging methods and laboratory examination. Subjective evaluation was performed using a questionnaire on micturition symptoms (score 0-5) and on quality of life (score 0-6). RESULTS: With a follow-up of 6-19 months, we recorded an average increase of the maximum detrusor capacity from 105 to 797 ml and decrease of maximum detrusor pressure from 53 to 30 cm H(2)O. Postmicturition residual urine >25% of the maximum capacity was present in 6 patients who performed clear intermittent autocatheterization postoperatively (2 patients preoperatively). In all patients there was a significant improvement in the irritation micturition symptomatology (pollakisuria, nycturia, urgency and urge incontinence) and the quality of life score improved on average from 5 to 0.7. In the case of the patient with renal insufficiency, the creatinine level decreased from 286 to 150 micromol/l; in the other patients renal function remained normal. CONCLUSIONS: Augmentation cystoplasty is a safe and effective method for indicated patients, which significantly enhances their quality of life.
Zamvil, S. S. and L. Steinman (2003). "Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis." Neuron 38(5): 685-8.
Multiple sclerosis (MS) is an autoimmune central nervous system (CNS) demyelinating disease that causes relapsing and chronic neurologic impairment. Recent observations have altered certain traditional concepts regarding MS pathogenesis. A greater diversity of cell types and molecules involved in MS is now evident. While remyelination can occur during the early inflammatory phase when damage may be reversible, it is impaired in the later stages, which involve axonal death. These observations have important therapeutic implications.
Zang, Y., J. Hong, et al. (2003). "Immune regulatory properties and interactions of copolymer-I and beta-interferon 1a in multiple sclerosis." J Neuroimmunol 137(1-2): 144-53.
The treatment efficacy of beta-interferon (beta-IFN) and Copolymer-1 (COP-1) for multiple sclerosis (MS) is potentially attributable to the immune regulatory properties of the drugs. In this study, we compared the regulatory effects of beta-IFN-1a and COP-1 used individually and in combination on the function of T cells derived from MS patients and healthy controls. The results revealed that the two drugs regulated predominantly CD4+ T cells with distinct properties. COP-1 activated both Th1 and Th2 cells while beta-IFN-1a was generally suppressive for Th1 cells and up-regulated IL-10 production. Furthermore, both drugs seemed to alter the T cell responses to myelin basic protein (MBP), a candidate myelin autoantigen for MS. The most significant finding is that COP-1 and beta-IFN-1a act individually through distinct regulatory properties and interact antagonistically when they are combined. The study has important clinical implications in the planned clinical trials to test treatment efficacy of combination therapy.
Zarei, M., S. Chandran, et al. (2003). "Cognitive presentation of multiple sclerosis: evidence for a cortical variant." J Neurol Neurosurg Psychiatry 74(7): 872-7.
BACKGROUND: Although neuropsychiatric complications are well recognised, the presentation of multiple sclerosis with cognitive or neuropsychiatric symptoms has generally been considered a rare occurrence and to reflect subcortical pathology. OBJECTIVES: To document the clinical, neuropsychological, and radiological features of six cases of cognitive presentation of multiple sclerosis, to review the relevant literature, and to propose a possible cortical basis for this clinical presentation. SUBJECTS: Six patients (five women; age range 38 to 60 years) presented to the memory and cognitive disorders clinic in Cambridge with an initially undiagnosed cognitive/neuropsychiatric syndrome. All underwent neuropsychological evaluation, brain imaging, and ancillary investigations to establish a diagnosis of multiple sclerosis. RESULTS: The six cases all had a progressive dementia syndrome with prominent amnesia, often accompanied by classic cortical features including dysphasia, dysgraphia, or dyslexia. Mood disturbance was ubiquitous and in three patients there was a long history of preceding severe depression. All six developed characteristic physical signs on follow up, with marked disabilities. A review of 17 previously reported cases highlighted the prominence of memory impairment and depression in the early stages. CONCLUSIONS: On clinical, pathological, and radiological grounds, the neuropsychiatric presentation of multiple sclerosis may represent a clinicopathological entity of "cortical multiple sclerosis." Failure to recognise this will delay diagnosis and may expose patients to potentially dangerous and invasive investigation. Because the neuropsychiatric features of cortical multiple sclerosis are a major cause of handicap, their early recognition may be particularly important in view of emerging treatments.
Zeinstra, E., N. Wilczak, et al. (2003). "Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7-1 and B7-2." J Neuroimmunol 135(1-2): 166-71.
Astrocytes in active lesions of multiple sclerosis (MS) express major histocompatibility (MHC) class II molecules, and may play an important role in the presentation of antigen to myelin-specific T cells.However, it has been postulated that astrocytes are unable to act as antigen-presenting cells (APCs) because they would lack the B7 co-stimulatory molecules to activate these T cells. By using double labeling immunofluorescence staining, we demonstrate that reactive astrocytes in chronic active plaques of multiple sclerosis express the co-stimulatory molecules B7-1 and B7-2, and hence have the necessary attributes to act as antigen-presenting cells.
Zephir, H., J. De Seze, et al. (2003). "Multiple sclerosis and depression: influence of interferon beta therapy." Mult Scler 9(3): 284-8.
BACKGROUND AND OBJECTIVES: Depression is frequently part of the clinical picture of multiple sclerosis (MS). Major depression affects one in two patients with MS during the course of their lifetime. Our objectives were to determine first, whether interferon beta-1a (IFNbeta-1a) treatment increases the risk or level of depression and, secondly, whether depression status and depression evolution are related to the clinical characteristics of the disease. PATIENTS AND METHODS: We investigated 106 consecutive patients with relapsing remitting MS treated with IFNbeta-1a (Avonex). Patients with evidence of severe depression were excluded. The depression status, scored on the Beck Depression Inventory (BDI-II) (stratified as minimum, mild, moderate or severe level), and disability, scored on the Expanded Disability Status Scale (EDSS), were evaluated before and after 12 months of IFNbeta-1a treatment. RESULTS: At baseline, 85% of patients had a minimum or a mild depression status and after 12 months of treatment most of them (83%) retained their baseline status. Beck scores before and after treatment were not significantly different (P = 0.63). There was no correlation between age, gender, duration of illness or EDSS score and Beck score at baseline (P = 0.696). Patients with disability progression after one year of IFNbeta-1a treatment had a significantly higher Beck score at baseline than patients without disability progression (P = 0.003). CONCLUSION: IFNbeta-1a (Avonex) does not seem to significantly influence the depression status of MS patients even in those with disability progression.
Zhu, B., L. Luo, et al. (2003). "Dendritic and synaptic pathology in experimental autoimmune encephalomyelitis." Am J Pathol 162(5): 1639-50.
Evidence has shown that excitotoxicity may contribute to the loss of central nervous system axons and oligodendrocytes in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Because dendrites and synapses are vulnerable to excitotoxicity, we examined these structures in acute and chronic models of EAE. Immunostaining for microtubule-associated protein-2 showed that extensive dendritic beading occurred in the white matter of the lumbosacral spinal cord (LSSC) during acute EAE episodes and EAE relapses. Retrograde labeling confirmed that most motoneuron dendrites were beaded in the white matter of the LSSC in acute EAE. In contrast, only mild swelling was observed in the gray matter of the LSSC. Dendritic beading showed marked recovery during EAE remission and after EAE recovery. In addition, synaptophysin, synapsin I, and PSD-95 immunoreactivities were significantly reduced in both the gray and white matter of the LSSC during acute EAE episodes and EAE relapses, but showed partial recovery during EAE remission and after EAE recovery. Pathologically, both dendritic beading and the reduction in synaptic protein immunoreactivity were well correlated with inflammatory cell infiltration in the LSSC at different EAE stages. We propose that dendritic and synaptic damage in the spinal cord may contribute to the neurological deficits in EAE.
Zhuang, H., Y. S. Kim, et al. (2003). "Prostaglandins of J series control heme oxygenase expression: potential significance in modulating neuroinflammation." Ann N Y Acad Sci 993: 208-16; discussion 287-8.
Cyclopentenone prostaglandins (cyPGs) are a subfamily of prostaglandins that are characterized by the cyclopentenone ring in their structure. They exert their effect after active transportation into the cell, probably by interacting with cellular target proteins or DNA sequences. The cyPGs have anti-inflammatory activities, especially important during the resolution of inflammation, anticancer, and cytoprotective properties. Here, we show that the cyPGs, especially the 15-deoxy-Delta(12,14) PGJ(2), can specifically induce heme oxygenase 1 in mouse primary neuronal cells. Heme oxygenase is the enzyme responsible for the degradation of heme into biliverdin, ferrous iron, and carbon monoxide. This enzyme conveys protection to oxidative cellular injury by degrading the pro-inflammatory heme; producing biliverdin and bilirubin, potent antioxidants; producing carbon monoxide, a neurotransmitter that also has anti-inflammatory and vasodilatory properties; and assisting in keeping iron cellular homeostasis. CyPGs appear to possess a promising future in designing therapeutics for many neurologic diseases, such as Alzheimer's disease, vascular-related dementia, multiple sclerosis, ischemic conditions, and many others in which inflammation is a part of the pathophysiology.
Zifko, U. A. (2003). "[Therapy of day time fatigue in patients with multiple sclerosis]." Wien Med Wochenschr 153(3-4): 65-72.
Fatigue is the most common symptom of multiple sclerosis. 75%-90% of patients with multiple sclerosis report having fatigue, and 50%-60% describe it as the worst symptom of their disease. Fatigue is significantly associated with reduced quality of life and is also a major reason for unemployment, especially for patients with otherwise minor disability. The mechanisms underlying abnormal levels of fatigue in multiple sclerosis are poorly understood. To date, drug treatment has been only partially successful in alleviating fatigue, and effects vary widely from patient to patient. Amantadine and modafinil showed to be effective in the treatment of fatigue in some studies. Non-pharmacological management of fatigue in multiple sclerosis includes inpatient rehabilitation and endurance training. There is also evidence, that pulsing electromagnetic fields may improve fatigue associated with multiple sclerosis. This paper summarizes the recent literature on pathophysiology, diagnosis and therapy of the most common symptom of multiple sclerosis.
Zittermann, A. (2003). "Vitamin D in preventive medicine: are we ignoring the evidence?" Br J Nutr 89(5): 552-72.
Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and by a renal 1alpha-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme 1alpha-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity. European children and young adults often have circulating 25(OH)D levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are often in the deficiency range. There is now general agreement that a low vitamin D status is involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a disturbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific types of cancer. Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much higher than the current recommendations of 5-15 microg/d.
Zivadinov, R., M. Zorzon, et al. (2003). "Sexual dysfunction in multiple sclerosis: a MRI, neurophysiological and urodynamic study." J Neurol Sci 210(1-2): 73-6.
We studied 31 patients with relapsing-remitting (RR) multiple sclerosis (MS) in which we performed an urodynamic study, the pudendal cortical evoked potentials, the tibial cortical evoked potentials and the cranial and cervical spinal cord magnetic resonance imaging (MRI). We calculated the T(1) and T(2) lesion load (LL) and brain parenchymal fraction (BPF) of whole brain, frontal lobes, pons and cervical spinal cord. We also estimated the cross-sectional area at C(2) level. Spearman's rank correlation analysis showed a relationship between symptoms of sexual dysfunction and age (r=0.73, p<0.0001), cognitive performances (r=-0.63, p<0.0001), level of independence (r=-0.63, p<0.0001), disability (r=0.56, p<0.001), symptoms of anxiety (r=0.55, p<0.001) and depression (r=0.50, p<0.005), disease duration (r=0.42, p<0.02) and parenchymal atrophy in the pons (r=-0.38, p=0.031). Sexual dysfunction was not correlated with any other MRI measure, urodynamic patterns or cortical evoked potentials. In multiple regression analysis, sexual dysfunction was predicted only by T(1) lesion load of the pons. In conclusion, we confirmed previous correlations of sexual dysfunction with various clinical variables and demonstrated an association between sexual dysfunction and destructive lesions in the pons, as detected by MRI, in patients with relapsing-remitting multiple sclerosis.
Zivadinov, R., L. Iona, et al. (2003). "The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. A meta-analysis study." Neuroepidemiology 22(1): 65-74.
OBJECTIVE: To demonstrate whether or not the age and sex adjustment of incidence and prevalence rates in multiple sclerosis (MS) could allow more reliable comparison between epidemiological studies performed in different areas of the world and to establish if the latitude gradient theory could be confirmed after the standardization for age and sex distribution. METHODS: A meta-analysis of population-based incidence and prevalence studies on MS from 1980 through 1998 using the terms 'multiple sclerosis', 'prevalence' and 'incidence' in the bibliographic databases MEDLINE and EMBASE was performed. We included studies that reported the diagnostic criteria, number of cases and the population studied, the date of the study, the latitude, and the age- and sex-specific crude incidence and prevalence rates. According to the inclusion criteria, 69 of 127 papers on prevalence and 22 of 70 papers on incidence were considered for age adjustment and 27 prevalence and 8 incidence studies for sex adjustment. The mean incidence and prevalencerates and the 95% confidence intervals age- and sex-adjusted to the World and the European standard populations were calculated. RESULTS: The Spearman rank correlation and the multiple regression analyses indicated that age adjustment to standard populations could overcome the limitations in comparing the crude prevalence and incidence rates of different epidemiological studies on MS. When the mean crude and age- and sex-adjusted prevalence and age-adjusted incidence rates were stratified by latitude (from south to north), the latitudinal gradient, which was highly significant for the crude rates, became less remarkable for the age- and sex-adjusted prevalence rates and not significant for the age-adjusted incidence rates. CONCLUSIONS: The crude incidence and prevalence rates in epidemiological studies on MS should be age- and sex-adjusted to a common standard population to permit a more reliable comparison among studies performed in different countries. Our findings support the opinion that the latitude does not play a key role in determining the onset of MS. Whenever possible, the crude incidence and prevalence rates should be adjusted to the ethnic origin and migration characteristics.
Zorzon, M., R. Zivadinov, et al. (2003). "Correlation of sexual dysfunction and brain magnetic resonance imaging in multiple sclerosis." Mult Scler 9(1): 108-10.
Sixty-two patients (40 women and 22 men) with multiple sclerosis (MS) were examined with 1.5 tesla magnetic resonance imaging (MRI) of the brain. Information on sexual and sphincteric disturbances has been collected, and data on disability, independence, cognitive performances and psychological functioning have been assessed. Calculations of T1- and T2-lesion load (LL) of total brain, frontal lobes and pons have been performed using a reproducible semiautomated technique. Whole brain, frontal and pontine atrophies were estimated using a normalized measure, the brain parenchymal fraction (BPF), obtained with a computerized interactive program. When comparing patients with and without sexual dysfunction (SD), there were no differences in total brain, frontal and pontine T1- and T2-LL, as well as in measures of whole brain and frontal atrophy. The only significant difference was in the pontine BPF (P = 0.026). In linear multiple regression analysis, SD was associated with depression (R = 0.56, P < 0.001) and, after adjusting for depression and anxiety, with bladder dysfunction (R = 0.43, P = 0.003) and pontine BPF (R = 0.56, P < 0.001). No association between SD and any of the measures of T1- and T2-LL was found. The findings showed a relationship between SD and pontine atrophy, confirmed the correlation of SD with bladder dysfunction and highlighted the role of psychological factors in determining SD.
Zoukos, Y., T. N. Thomaides, et al. (2003). "Expression of beta2 adrenoreceptors on peripheral blood mononuclear cells in patients with primary and secondary progressive multiple sclerosis: a longitudinal six month study." J Neurol Neurosurg Psychiatry 74(2): 197-202.
BACKGROUND: Beta(2) adrenoreceptor expression on peripheral blood mononuclear cells is increased in progressive multiple sclerosis. This increase has been correlated with disease activity in relapsing-remitting multiple sclerosis. OBJECTIVE: To determine the beta(2) adrenoreceptor expression in primary and secondary progressive multiple sclerosis in relation to findings on magnetic resonance imaging (MRI) and clinical disease activity. METHODS: 10 patients with multiple sclerosis were studied (five with primary progressive and five with secondary progressive forms of the disease) over a period of six months. Monthly clinical and MRI assessments of the brain and spinal cord were carried out. Beta(2) adrenoreceptor expression was assessed monthly using a ligand binding assay with [(125)I]iodocyanopindolol. Expression of beta(2) adrenoceptors on peripheral blood mononuclear cells was also assessed in five normal controls over a similar period. RESULTS: The mean (SEM) value of beta(2) adrenoreceptor density for the five normal controls was 1346 (183) sites/cell, with affinity Kd of 120 (40) pM. MRI disease activity in primary progressive multiple sclerosis was reported on two occasions and on those occasions the expression of beta(2) adrenoreceptors was increased in excess of 1900 sites/cell; in the remaining 28 observations beta(2) adrenoreceptor expression was within the normal range (800 to 1900 sites/cell). In patients with secondary progressive disease, MRI disease activity was observed on 16 occasions. In these patients expression of beta(2) adrenoreceptors was increased in excess of 2000 sites/cell in all measurements except in one subject who did not show MRI activity throughout the six months period of study. The affinity of the receptors was within the normal range in all cases. CONCLUSIONS: Increased expression of beta(2) adrenoreceptors was correlated with MRI disease activity in two patients with primary progressive multiple sclerosis. In secondary progressive multiple sclerosis, increased expression of beta(2) adrenoreceptors tended not to correlate with MRI disease activity. This may reflect a persistent Th1 immune reaction in the secondary progressive form of the disease.