Multiple Sclerosis References 2003; Authors: T-V
(53 References)
t Hart, B. A. and S. Amor (2003). "The use of animal models to investigate the pathogenesis of neuroinflammatory disorders of the central nervous system." Curr Opin Neurol 16(3): 375-83.
PURPOSE OF REVIEW: A major hurdle in the research of neuroinflammatory disorders of the central nervous system is the inaccessibility of the organ. Thus investigation is limited to end-stage disease and systemic changes that occur during disease progression, neither of which may reflect the pathological process in the central nervous system. These factors may explain the lack of effective therapies in multiple sclerosis, a common chronic inflammatory disease of the central nervous system. To overcome such limitations approaches using more relevant animal models have been developed to study pathological mechanisms as well as the design of rational therapeutic strategies. This review describes the animal models used to study pathological processes leading to inflammation within the central nervous system that may be operating in multiple sclerosis and the use of these models in the design of more rational therapeutic strategies. RECENT FINDINGS: The clinical heterogeneity of multiple sclerosis as well as the finding of different pathological patterns suggests that multiple sclerosis may be a spectrum of diseases that may represent different pathological processes. This and the renewed interest in the extent of axonal damage has led to the development of more relevant animal models, such as those in nonhuman primates, that both reflect the spectrum of multiple sclerosis and allow the development of species-specific therapeutic approaches. SUMMARY: While many animal models are available, the use of relevant animal models that mimic either the different forms of multiple sclerosis or the spectrum of multiple sclerosis is critical to examine those factors, for example genes or proteins, that are of pathogenic relevance and can be used as targets for therapy.
t Hart, B. A., J. T. Vogels, et al. (2003). "1H-NMR spectroscopy combined with pattern recognition analysis reveals characteristic chemical patterns in urines of MS patients and non-human primates with MS-like disease." J Neurol Sci 212(1-2): 21-30.
Proton nuclear magnetic resonance (1H-NMR) spectroscopy in combination with pattern recognition techniques were used to investigate the composition of organic compounds in urines from patients with multiple sclerosis (MS), patients with other neurological diseases (OND) and healthy controls (H). Using a valid animal model of MS, namely the common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE), the relation of disease progression and alteration of the urine composition was investigated. Urine samples were collected during different stages of EAE, either induced with whole human myelin or with the myelin protein MOG in complete adjuvant. The urine samples were analysed with 1H-NMR spectroscopy allowing simultaneous detection of an array of compounds. Spectral differences between urines from EAE-affected and healthy monkeys were assessed with multivariate analysis. Evidence is provided that development of EAE is associated with changes in the chemical composition of the urine, in particular of compounds with NMR peaks in the region of the spectrum between 0.5 and 3.50 ppm. In addition, we found preliminary evidence for differences between urines from MS, OND and H groups.
t'Hart, B. A., M. Vervoordeldonk, et al. (2003). "Gene therapy in nonhuman primate models of human autoimmune disease." Gene Ther 10(10): 890-901.
Before autoimmune diseases in humans can be treated with gene therapy, the safety and efficacy of the used vectors must be tested in valid experimental models. Monkeys, such as the rhesus macaque or the common marmoset, provide such models. This publication reviews the state of the art in monkey models for rheumatoid arthritis and multiple sclerosis and the (few) gene therapy experiments that have been performed in these models.
Tackenberg, B., M. Nitschke, et al. (2003). "CD45 isoform expression in autoimmune myasthenia gravis." Autoimmunity 36(2): 117-21.
In myasthenia gravis (MG), humoral and cellular immune mechanisms are involved in the autoimmune pathogenesis. In this study, we investigated the role of the CD45 molecule in MG, having recently reported an association in multiple sclerosis. CD45, a protein-tyrosine phophatase receptor type C (PTPRC), is essential for both thymic selection and peripheral activation of T and B cells. Our aims were to determine (a) the prevalence of a functional mutation in the CD45 gene (exon 4 77C --> G; prevalence analysis), and (b) the distribution of memory (CD45RO+) and naive (CD45RA+) T cells in the peripheral blood (subset analysis). T cells from 78 patients with generalised MG were stained with monoclonal antibodies against CD45RO, CD45RA, CD4 and CD8 and quantified by four-colour flow cytometry. The control panel for the prevalence analysis (a) consisted of 303 healthy individuals. (b) From those, 67 age- and sex-matched probands were randomly selected as controls for the subset analysis. Patients were stratified according to their MG onset age, thymic pathology and immunosuppressive treatment. Statistical analysis was performed by Fisher's exact test, asymptotic chi2 test, the two-sided Mann-Whitney test and Spearman's correlation coefficient. As a result, the 77C --> G mutation in exon 4 of the CD45 gene was found in 1 of 78 patients versus none of the 303 controls. Thus, no association was detected with this single nucleotide polymorphism in MG patients overall. Surprisingly, however, ratios of CD45RO+ to CD45RA+ T cells were lower among CD8+ T cells from patients with late-onset MG (P = 0.023). Thymoma patients also showed a similar trend among CD4+ and CD8+ T-cells, as expected. These differences were not related to immunosuppressive drug treatment or thymectomy (in the 67 informative patients). Since there is no other evidence for increased thymopoiesis in late-onset MG, we propose an altered subset balance in the circulation.
Taillefer, S. S., L. J. Kirmayer, et al. (2003). "Correlates of illness worry in chronic fatigue syndrome." J Psychosom Res 54(4): 331-7.
BACKGROUND: Anxiety about illness leading to restriction of activity and physical deconditioning has been hypothesized to contribute to the chronicity of fatigue. Pathological symptom attributions, personality traits, and depression have all been hypothesized to contribute to illness worry. METHODS: We compared 45 chronic fatigue syndrome (CFS) and 40 multiple sclerosis (MS) outpatients using a battery of psychometric instruments comprising the 12-item Illness Worry scale, the Symptom Interpretation Questionnaire (SIQ), the NEO Five-Factor Inventory (NEO-FFI), and a modified version of the SCL-90R Depression scale. RESULTS: There was no difference between the two diagnostic groups on neuroticism, depressive symptoms, as well as the three scales of the SIQ. On the illness worry index, the CFS group had significantly higher scores than the MS group. This difference was due to items tapping vulnerability to illness and the perception that others are not taking their illness seriously. Somatic attributional style, neuroticism, depressive symptoms, and age were all significant predictors of illness worry in both CFS and MS patients. CONCLUSIONS: Somatic attributions, neuroticism, and depression all contribute to illness worry in chronic illness. However, these factors do not account for the higher levels of illness worry in CFS as opposed to MS, which may be due to other specific cognitive and social interactional processes.
Takahashi, J. L., F. Giuliani, et al. (2003). "Interleukin-1beta promotes oligodendrocyte death through glutamate excitotoxicity." Ann Neurol 53(5): 588-95.
Glutamate excitotoxicity is implicated in the progressive loss of oligodendrocytes in multiple sclerosis, but how glutamate metabolism is dysregulated in the disease remains unclear. Because there is microglia activation in all stages of multiple sclerosis, we determined whether a microglia product, interleukin-1beta, could provide the mechanism for glutamate excitotoxicity. We found that whereas interleukin-1beta did not kill oligodendrocytes in pure culture, it produced apoptosis of oligodendrocytes in coculture with astrocytes and microglia. This requirement for a mixed glia environment suggests that interleukin-1beta impairs the well-described glutamate-buffering capacity of astrocytes. In support, antagonists at AMPA/kainate glutamate receptors, NBQX and CNQX, blocked the interleukin-1beta toxicity to oligodendrocytes. Another microglia/macrophage cytokine, tumor necrosis factor-alpha, also evoked apoptosis of oligodendrocytes in a mixed glia environment in an NBQX-blockable manner. These results provide a mechanistic link between the persistent and insidious microglia activation that is evident in all stages of multiple sclerosis, with the recent appreciation that glutamate excitotoxicity leads to the destruction of oligodendrocytes in the disease.
Tanvetyanon, T., E. A. Stadtmauer, et al. (2003). "Concurrent administration of interferon alfa-2b and beta-1a." Ann Pharmacother 37(1): 77-9.
OBJECTIVE: To describe the concurrent use of interferon (IFN) alfa and beta in a patient with multiple sclerosis (MS) and chronic myeloid leukemia (CML). CASE SUMMARY: A 60-year-old white man developed CML while receiving IFN beta-1a treatment for MS. The patient was started on IFN alfa-2b 1 million units 3 times weekly with IFN beta-1a 30 micro g weekly. The dosage of IFN alfa was increased to 3 million units/d 1 month later. He achieved complete hematologic remission in 3 months. The observed adverse effects were mild and included fatigue, somnolence, weight loss, and difficulty with memory. At 19 months after treatment, the patient remained in hematologic remission and his expanded disability status scale score remained unchanged. DISCUSSION: Concomitant treatment with interferon alfa and beta by a gradual increase in the dosage of IFN alfa was well tolerated. Although imatinib mesylate may be a preferred treatment for patients with CML and MS at this time, our experience with safe concurrent use of IFN alfa and beta may benefit other patients who require this combined treatment. CONCLUSIONS: Concurrent administration of interferon alfa-2b and beta-1a was well tolerated by our patient with CML and MS.
Tataroglu, C., A. Genc, et al. (2003). "Cortical silent period and motor evoked potentials in patients with multiple sclerosis." Clin Neurol Neurosurg 105(2): 105-10.
In order to determine the importance of central motor conduction time (CMCT) and silent period (SP) in patients with multiple sclerosis (MS), we enrolled this clinical and electrophysiological study. Additionally, we planned to compare the correlation between electrophysiological findings and clinical status. We examined 58 patients with definite MS and 31 controls. Patients were classified as relapsing-remitting (N: 37), secondary progressive (N: 21) groups. Eleven out of 58 patients with MS had no neurological findings (subclinical patients). We evaluated CMCT and the duration of SP. Prolonged CMCT latency was shown in 75.2% of patients. We observed SP abnormalities in 69% of patients. In subclinical patients, SP abnormalities (six of 11) were observed more common than CMCT (two of 11). The duration of SP was extremely prolonged in MS patients with cerebellar dysfunction. When the both electrophysiological parameters are taken into account, the abnormality ratio was determined as 89.7%. Our results indicate that CMCT and SP analysis are complementary tests in evaluating motor pathways of patients with MS. We observed a relationship between cerebellar dysfunction and SP prolongation. It is suggested that, SP can be applied in patients with pure cerebellar dysfunction and it can be a valuable test in subclinical cases with MS.
Taus, C., G. Giuliani, et al. (2003). "Amantadine for fatigue in multiple sclerosis." Cochrane Database Syst Rev(2): CD002818.
BACKGROUND: Fatigue is one of the most common and disabling symptoms of people with Multiple Sclerosis (MS). The effective management of fatigue has an important impact on the patient's functioning, abilities, and quality of life. Although a number of strategies have been devised for reducing fatigue, treatment recommendations are based on a limited amount of scientific evidence. Many textbooks report amantadine as a first-choice drug for MS-related fatigue because of published randomised controlled trials (RCTs) showing some benefit. We performed a systematic review in order to gather existing evidence, and contribute to the topic. OBJECTIVES: To determine the effectiveness and safety of amantadine in reducing fatigue in people with MS. SEARCH STRATEGY: RCTs of amantadine were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communications, manual searches of relevant journals, and information from drug companies. SELECTION CRITERIA: Randomised, placebo or other drugs-controlled, double-blind trials of amantadine in MS people with fatigue. DATA COLLECTION AND ANALYSIS: Three reviewers selected studies for inclusion in the review and they extracted the data reported in the original articles. Missing and unclear data were requested by correspondence with the trial's principal investigator. A meta-analysis was not performed due to the inadequacy of available data, heterogeneity of outcome measures. MAIN RESULTS: Out of twelve pertinent publications, four trials met the criteria for inclusion in this review: one study was a parallel arms study, and 3 were crossover trials. The number of randomised participants ranged between 10 and 115, and a total of 236 MS patients had been studied. Overall the quality of the studies considered was poor and all trials were open to bias. All studies reported small and inconstant improvements in fatigue, whereas the clinical relevance of these findings and the impact on patient's functioning and health related quality of life remains undetermined. The number of participants reporting side effects during amantadine therapy ranged from 10% to 57%, without significant differences between treatment and placebo. The side effects reported were generally mild, and discontinuation of the drug due to side effects occurred in less than 10% of the patients. REVIEWER'S CONCLUSIONS: Amantadine treatment is overall well tolerated, however its efficacy in reducing fatigue in people with MS is poorly documented and there is insufficient evidence to make recommendations to guide prescribing. It is advisable to (a) improve knowledge on the underlying mechanisms of MS-related fatigue; (b) achieve an agreement on accurate, reliable and responsive outcome measures of fatigue; (c) perform good quality RCTs.
Taylor, W. R., A. Rasley, et al. (2003). "Murine gammaherpesvirus-68 infects microglia and induces high levels of pro-inflammatory cytokine production." J Neuroimmunol 136(1-2): 75-83.
Murine gammaherpesvirus-68 (MHV-68) has been established as a tractable model for the study of human herpesvirus infections. Recent associations between herpesvirus infections and inflammatory central nervous system (CNS) disorders, including multiple sclerosis (MS), have prompted us to investigate the susceptibility of cultured microglia and astrocytes to MHV-68 infection. In the present study, we demonstrate that MHV-68 can infect both cell types. Importantly, we show that MHV-68-infected microglia and astrocytes can produce pro-inflammatory cytokines. Such cytokine production may either contribute to protective host responses to viral challenges or could exacerbate damaging CNS inflammation.
Teige, I., A. Treschow, et al. (2003). "IFN-beta Gene Deletion Leads to Augmented and Chronic Demyelinating Experimental Autoimmune Encephalomyelitis." J Immunol 170(9): 4776-84.
Since the basic mechanisms behind the beneficial effects of IFN-beta in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-beta gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN-beta knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells to proliferate or produce IFN-gamma in response to recall Ag. Consequently, we addressed the effect of IFN-beta on encephalitogenic T cell development and the disease initiation phase by passive transfer of autoreactive T cells from KO or wt littermates to both groups of mice. Interestingly, IFN-beta KO mice acquired a higher incidence and augmented EAE regardless of the source of T cells. This shows that the anti-inflammatory effect of endogenous IFN-beta is predominantly exerted on the effector phase of the disease. Histopathological investigations of CNS in the effector phase revealed an extensive microglia activation and TNF-alpha production in IFN-beta KO mice; this was virtually absent in wt littermates. This coincided with an increase in effector functions of T cells in IFN-beta KO mice, as measured by IFN-gamma and IL-4 production. We suggest that lack of endogenous IFN-beta in CNS leads to augmented microglia activation, resulting in a sustained inflammation, cytokine production, and tissue damage with consequent chronic neurological deficits.
Tejada-Simon, M. V., Y. C. Zang, et al. (2003). "Cross-reactivity with myelin basic protein and human herpesvirus-6 in multiple sclerosis." Ann Neurol 53(2): 189-97.
Viral infections are though to play an important role in the pathogenesis of multiple sclerosis (MS) potentially through molecular mimicry. An identical sequence was found in both myelin basic protein (MBP, residues 96-102), a candidate autoantigen for MS, and human herpesvirus-6 (HHV-6 U24, residues 4-10) that is a suspected viral agent associated with MS. In this study, we showed that greater than 50% of T cells recognizing MBP(93-105) cross-reacted with and could be activated by a synthetic peptide corresponding to residues 1 to 13 of HHV-6 U24 in MS patients. The estimated precursor frequency of these cross-reactive T cells recognizing both peptides, MBP(93-105) and HHV-6 (U24)(1-13), was significantly elevated in MS patients compared with that in healthy controls. These cross-reactive CD4+ T cells represented the same Th1 phenotype as that of monospecific T cells recognizing MBP(93-105). There were increased antibody titers for both peptide HHV-6 (U24)(1-13) and peptide MBP(93-105) in the same patients with MS compared with those in healthy controls, suggesting B-cell sensitization to the antigens in MS patients. The study provides important evidence in the understanding of the potential role of HHV-6 infection/reactivation in the activation of autoimmune reactivity to MBP and its implication in the pathogenesis of MS.
Tenser, R. B. (2003). "Epstein-barr virus and risk of multiple sclerosis." Jama 290(2): 192-3; author reply 193.
Terada, H. and N. Kamata (2003). "Contribution of the combination of (201)Tl SPECT and (99m)T(c)O(4)(-) SPECT to the differential diagnosis of brain tumors and tumor-like lesions." J Neuroradiol 30(2): 91-4.
This study was undertaken to assess the contribution of the combination of (201)Tl SPECT and (99m)TcO(4)(- )SPECT to the differential diagnosis of brain tumors and tumor-like lesions. In the 8 patients selected for this study, both (201)Tl SPECT and (99m)TcO(4)(-) SPECT were performed because of clinical or radiological suspicion of brain tumor, no therapy was initiated before either SPECTs, diagnosis was based on biopsy, and MRI findings were stable in the interval between SPECTs. Histological diagnoses consisted of low grade glioma (n=1), high grade glioma (n=2), lymphoma (n=1), metastasis (n=1), multiple sclerosis (n=2) and cavernous angioma (n=1). Two high grade astrocytomas, one malignant lymphoma and one metastatic tumor showed (201)Tl accumulation and were diagnosed as tumor. The combination of (201)Tl and (99m)TcO(4)(-) did not change the diagnosis. One cavernous angioma showed no (201)Tl accumulation and was diagnosed as non-tumor. The combination of (201)Tl and (99m)TcO(4)(-) did not change the diagnosis. One low grade astrocytoma showed faint (201)Tl accumulation and was diagnosed as non-tumor. As (201)Tl uptake was higher than (99m)TcO(4)(-) uptake, the combination of (201)Tl and (99m)TcO(4)(-) changed the diagnosis to tumor. Two multiple sclerosis showed (201)Tl accumulation and were diagnosed as tumor. As (99m)TcO(4)(-) uptake was higher than (201)Tl uptake, the combination of (201)Tl and (99m)TcO(4)(-) changed the diagnosis to non-tumor. In three of the eight patients (38%), the combination of (201)Tl SPECT and (99m)TcO(4)(-) SPECT altered the diagnosis made by (201)Tl SPECT alone. In all of these three cases, the diagnosis made by the combination of (201)Tl SPECT and (99m)TcO(4)(-) SPECT was correct.
Tesar, N., U. Baumhackl, et al. (2003). "Effects of psychological group therapy in patients with multiple sclerosis." Acta Neurol Scand 107(6): 394-9.
OBJECTIVES: The aim of this pilot study was to evaluate a psychological therapy program used in the treatment of multiple sclerosis (MS) and including cognitive/behavioral strategies, relaxation training and physical exercise. MATERIAL AND METHODS: The participants were 29 patients with MS recruited from an outpatient unit; 14 patients were assigned to the 7-week psychological therapy group (one session per week), the remainder formed a control group. Before and immediately after the course of therapy and after a 2-month follow-up, the participants completed a series of questionnaires measuring factors such as depression, anxiety, coping and body image. RESULTS: Compared with the control group the therapy group showed long-term improvements in depressive stress coping style and a short-term improvement in "vitality and body dynamics". CONCLUSION: Further studies should investigate the differential effects of specific units of the therapy program and how the short-term improvements in "vitality and body dynamics" could be maintained for longer periods.
Teutsch, S. M., D. R. Booth, et al. (2003). "Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis." Eur J Hum Genet 11(7): 509-15.
We have investigated the interleukin-7 receptor (IL-7R) alpha-chain gene as a positional and functional candidate gene for susceptibility to multiple sclerosis (MS), in view of its chromosomal location on 5p14-p12, a region that has shown suggestive linkage in MS genome screens, and its role in T- and B-cell proliferation and reactivity. Amplification and DNA sequencing of the IL-7Ralpha gene in pooled and individual samples identified 13 single nucleotide polymorphisms (SNPs), 11 of which are novel, including three in the promoter region, three in exons encoding amino-acid changes (ACC(Thr)66ATC(Ile), ATC(Ile)244ACC(Thr), ATC(Ile)336GTC(Val)), four in introns and one in the 3' untranslated region. Four IL-7R haplotypes were identified for nine SNPs, showing linkage disequilibrium across the gene, and allowing haplotype frequency determination from just three of the nine SNPs. Genotyping of the -504 polymorphism in 101 MS and 90 controls showed a suggestive (P=0.1) association of the T allele with MS; however, this was not supported by transmission disequilibrium testing in 186 MS trio families (P=0.8). There were trends towards an increase of the GTG+ haplotype (odds ratio=1.45), and under-representation of the TTA+ haplotype (OR=0.65) in DRB1*1501-positive MS cases, suggesting that larger sample sizes and comparison in more defined MS patient groups may support an association with the IL-7R gene. These polymorphisms would also be useful for studying genetic associations with other immunologic diseases.
Thibout, H., C. Martinerie, et al. (2003). "Characterization of human NOV in biological fluids: an enzyme immunoassay for the quantification of human NOV in sera from patients with diseases of the adrenal gland and of the nervous system." J Clin Endocrinol Metab 88(1): 327-36.
Immunochromatography has shown that human NOV (NOVH), a member of the CCN (CTGF/CYR61/NOV) family, forms a physiological complex with fibulin-1 in blood. We developed an enzyme immunoassay specific for NOVH and showed for the first time that the concentration of NOVH differs in each of these biological fluids. The normal concentration of NOVH circulating in the blood is 350-400 ng/ml, but this concentration varies with age. By using sera from patients with adrenal gland diseases we found that in vivo ACTH or glucocorticoids are not responsible for the high concentration of NOVH in this endocrine gland. However, the NOVH concentration was significantly modified in malignant adrenocortical tumors, but not in benign adrenocortical tumors. The concentration of NOVH was significantly decreased in patients suffering from astrocytomas or multiple sclerosis, two diseases of the nervous system. Thus, NOVH is a potentially useful marker for the diagnosis of these diseases.
Tintore, M., A. Rovira, et al. (2003). "New diagnostic criteria for multiple sclerosis: application in first demyelinating episode." Neurology 60(1): 27-30.
BACKGROUND: Recently developed diagnostic criteria for MS (McDonald criteria) indicate that in patients with a single demyelinating episode (clinically isolated syndromes [CIS]), evidence for dissemination in space and time, essential for diagnosis, may be provided by MRI. OBJECTIVE: To assess the usefulness of these new criteria in patients with CIS suggestive of MS. Methods: A total of 139 patients with CIS followed for a median of 3 years underwent brain MRI within 3 months of their first attack and again 12 months later. The number and location of lesions at baseline, the development of new lesions at follow-up, and the results of CSF examination (which, if positive, requires fewer MR abnormalities for diagnosis) were analyzed. The new McDonald criteria (incorporating MRI) were compared to the existing Poser diagnostic criteria and their accuracy was evaluated. RESULTS: At 12 months, 11% had clinically definite MS according to the Poser criteria compared to 37% with the McDonald criteria. Eighty percent of patients fulfilling these new criteria developed a second clinical episode within a mean follow-up of 49 months. The new criteria showed a sensitivity of 74%, specificity of 86%, and accuracy of 80% in predicting conversion to clinically definite MS. CONCLUSION: One year after symptom onset, more than three times as many patients with CIS were diagnosed with MS using new diagnostic criteria incorporating MRI results compared to older criteria. However, the proposed MRI criteria require further prospective studies to optimize sensitivity and specificity.
Tokmakova, K. P., R. P. Stanton, et al. (2003). "Factors influencing the development of osteonecrosis in patients treated for slipped capital femoral epiphysis." J Bone Joint Surg Am 85-A(5): 798-801.
BACKGROUND: Osteonecrosis is a serious complication of the treatment of slipped capital femoral epiphysis. The purpose of the present study was to identify factors influencing the development of osteonecrosis. METHODS: Two hundred and forty patients who had been treated for slipped capital femoral epiphysis between 1965 and 1999 were retrospectively evaluated. Treatment included stabilization with a spica cast or fixation with one to four pins or screws. Radiographs that had been made at the time of presentation, before and after the operation, and at consecutive follow-up examinations were reviewed. Osteonecrosis was defined retrospectively on the basis of radiographic evidence of sclerosis and collapse of the femoral head. The risk of development of osteonecrosis was correlated with various clinical and radiographic parameters. RESULTS: All twenty-one patients in whom osteonecrosis developed had presented with an unstable slipped capital femoral epiphysis. None of the 204 patients who had presented with a stable slipped capital femoral epiphysis, regardless of grade, had development of osteonecrosis. In the group of patients who had presented with an unstable slipped capital femoral epiphysis, the risk of development of osteonecrosis increased with the severity (grade) of the slip. Osteonecrosis was more likely to develop in patients who had been treated with multiple pins than in those who had been treated with a single cannulated screw. CONCLUSIONS: Patients who have a stable slipped capital femoral epiphysis are not at risk for the development of osteonecrosis when treated with pinning in situ. Patients who have an unstable slipped capital femoral epiphysis have a decreased risk of osteonecrosis when treated with pinning in situ. Complete or partial reduction of an unstable slipped capital femoral epiphysis increases the risk of development of osteonecrosis. Pinning in situ without reduction with a single cannulated screw is the method of choice for the treatment of a slipped capital femoral epiphysis.
Tola, M. R., L. M. Caniatti, et al. (2003). "Recurrent nephrotic syndrome in patient with multiple sclerosis treated with interferon beta-1a." J Neurol 250(6): 768-9.
Touchette, D. R., T. L. Durgin, et al. (2003). "A cost-utility analysis of mitoxantrone hydrochloride and interferon beta-1b in the treatment of patients with secondary progressive or progressive relapsing multiple sclerosis." Clin Ther 25(2): 611-34.
BACKGROUND: Information on the cost utility of interferon beta-1b and mitoxantrone hydrochloride, 2 disease-modifying agents approved by the US Food and Drug Administration for the treatment of secondary progressive (SP) multiple sclerosis (MS), is limited. OBJECTIVE: The aim of this study was to compare the cost utility of i.v. mitoxantrone hydrochloride administered every 3 months, s.c. interferon beta-1b administered every other day, and routine supportive care from the perspectives of both the insurer and society. METHODS: We used a Markov model with health states based on the Kurtzke Expanded Disability Status Scale (EDSS) scores from both an insurer's and a societal perspective (including direct and total costs, respectively). Theoretical patients entered the model with an EDSS score of 3; their progression was followed for 10 years. Transition probabilities were derived from clinical trial data. Cost and utility inputs were taken from the literature. Sensitivity analyses were conducted on all variables. RESULTS: From the insurer's perspective, the incremental cost-utility ratio of mitoxantrone hydrochloride therapy compared with routine supportive care was 58,272 dollars per quality-adjusted life year (QALY) gained. From a societal perspective, mitoxantrone hydrochloride was more effective and less costly than supportive care. From the perspectives of insurers and society, the cost-utility ratios of interferon beta-1b compared with routine supportive care were 338,738 dollars and 245,700 dollars per QALY gained, respectively. When compared with mitoxantrone hydrochloride, interferon beta-1b had an incremental cost-utility ratio of 741,331 dollars and 658,402 dollars per QALY from the insurer's and society's perspectives, respectively. Cost-utility ratios for mitoxantrone hydrochloride were sensitive to acquisition and administration costs of therapy and to effectiveness at slowing disease progression. Cost-utility ratios for interferon beta-1b were not sensitive to any of the variables included in the model. CONCLUSIONS: Mitoxantrone hydrochloride is likely to be a cost-effective treatment for patients with SPMS or progressive relapsing MS from an insurer' perspective and is cost saving from a societal perspective. Interferon beta-1b is not likely an efficient treatment using conventional comparisons for cost-effectiveness. This analysis has potentially important implications for policy implementation; however, decisions about which agent to use for each patient should consider the treatment's adverse-event profile, the method of administration, and the patient's preferences for these factors.
Toyka, K. V. and R. Gold (2003). "The pathogenesis of CIDP: Rationale for treatment with immunomodulatory agents." Neurology 60(8_ Suppl_3): S2-S7.
Current knowledge about the pathogenic mechanisms involved in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) supports an autoimmune etiology. Some of the cell and humorally mediated immune responses that contribute to the development of CIDP resemble those implicated in multiple sclerosis (MS). The effector role of circulating antibodies has recently been revisited. In addition, similar to the situation in MS, histopathologic studies support the heterogeneity of disease mechanisms in CIDP, with variants showing axon damage. In addition to intravenous immunoglobulin (IVIg), prednisone, and plasma exchange, immunomodulatory drugs also were used to treat CIDP, although no definitive trial data are available. One class of immunomodulators, interferon beta formulations, has proven efficacy in the treatment of MS, and because of clinical similarities between the two diseases it is attractive to investigate whether some agents that are effective in the treatment of MS would also be effective in CIDP. Preliminary studies have evaluated the effects of interferon beta formulations in the treatment of CIDP, one of which has shown promising results and warrants further investigation.
Tozer, D., A. Ramani, et al. (2003). "Quantitative magnetization transfer mapping of bound protons in multiple sclerosis." Magn Reson Med 50(1): 83-91.
Quantitative analysis of magnetization transfer images has the potential to allow a more thorough characterization of the protons, both bound and free, in a tissue by extracting a number of parameters relating to the NMR properties of the protons and their local environment. This work develops previously presented techniques to produce estimates of parameters such as the bound proton fraction, f, and the transverse relaxation time of the bound pool, T(2B), for the whole brain in a clinically acceptable imaging time. This is achieved by limiting the number of data collected (typically to 10); to collect 28 5-mm slices with a reconstructed resolution of 0.94 x 0.94 mm. The protocol takes 82 sec per data point. The fitting technique is assessed against previous work and for fitting failures. Maps and analysis are presented from a group of seven controls and 20 multiple sclerosis patients. The maps show that the parameters are sensitive to tissue-specific differences and can detect pathological change within lesions. Statistically significant differences in parameters such as T(2B) and f are seen between normal-appearing white matter, multiple sclerosis lesions, and control white matter. Whole-brain histograms of these parameters are also presented, showing differences between patients and controls.
Trebst, C., S. M. Staugaitis, et al. (2003). "CC chemokine receptor 8 in the central nervous system is associated with phagocytic macrophages." Am J Pathol 162(2): 427-38.
CC chemokine receptor 8 (CCR8) has been detected in vitro on type 2 helper and regulatory lymphocytes, which might exert beneficial functions in multiple sclerosis (MS) and on macrophages and microglia, possibly promoting tissue injury in MS lesions. To discriminate the relevant expression pattern in vivo, we defined the cell types that expressed CCR8 in MS lesions and determined the relationship of CCR8 expression and demyelinating activity. CCR8 was not expressed on T cells but was associated with phagocytic macrophages and activated microglia in MS lesions and directly correlated with demyelinating activity. To identify factors associated with CCR8 expression, the study was extended to other central nervous system (CNS) pathologies. CCR8 was consistently expressed on phagocytic macrophages and activated microglia in stroke and progressive multifocal leukoencephalopathy, but not expressed on microglia in pathologies that lacked phagocytic macrophages such as senile change of the Alzheimer's type. CCR8 was up-regulated by macrophage differentiation and activating stimuli in vitro. In summary CNS CCR8 expression was associated with phagocytic macrophages and activated microglial cells in human CNS diseases, suggesting that CCR8 may be a feasible target for therapeutic intervention in MS. CCR8 expression may also indicate a selective program of mononuclear phagocyte gene expression.
Tsunoda, I., L. Q. Kuang, et al. (2003). "Axonal injury heralds virus-induced demyelination." Am J Pathol 162(4): 1259-69.
Axonal pathology has been highlighted as a cause of neurological disability in multiple sclerosis. The Daniels (DA) strain of Theiler's murine encephalomyelitis virus infects the gray matter of the central nervous system of mice during the acute phase and persistently infects the white matter of the spinal cord during the chronic phase, leading to demyelination. This experimental infection has been used as an animal model for multiple sclerosis. The GDVII strain causes an acute fatal polioencephalomyelitis without demyelination. Injured axons were detected in normal appearing white matter at 1 week after infection with DA virus by immunohistochemistry using antibodies specific for neurofilament protein. The number of damaged axons increased throughout time. By 2 and 3 weeks after infection, injured axons were accompanied by parenchymal infiltration of Ricinus communis agglutinin I(+) microglia/macrophages, but never associated with perivascular T-cell infiltration or obvious demyelination until the chronic phase. GDVII virus infection resulted in severe axonal injury in normal appearing white matter at 1 week after infection, without the presence of macrophages, T cells, or viral antigen-positive cells. The distribution of axonal injury observed during the early phase corresponded to regions where subsequent demyelination occurs during the chronic phase. The results suggest that axonal injury might herald or trigger demyelination.
Turner, B., X. Lin, et al. (2003). "Cerebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years." Mult Scler 9(1): 21-7.
Pathology and magnetic resonance imaging (MRI) studies have provided evidence of widespread axonal loss and reductions of cerebral and spinal cord volume in multiple sclerosis (MS). Atrophy measures on MRI may be a useful surrogate marker of worsening disability in MS, but the published studies are of relatively short duration. Change in brain volume (atrophy) was measured over a four-year period in 20 patients with relapsing-remitting (RR) and 18 with secondary progressive (SP) MS using three-dimensional (3D) MRI acquired during treatment trials of interferon-beta-1a (Rebif). Brain parenchymal and lateral ventricle volume changes were determined and correlated with clinical measures. Over four years, brain parenchymal volume (BPV) decreased in RRMS and SPMS patients by 0.9% (P = 0.006) and 0.3% (P = 0.118), respectively, and the lateral ventricle volumes increased by 15% (P < 0.0001) and 13% (P < 0.0001), respectively. In RRMS patients both lateral ventricle volume (r = 0.63, P = 0.004) and BPV change (r = -0.47, P = 0.037) were related to disability change, as measured by the Expanded Disability Status Scale. Even though a small study and despite the possible confounding effects of interferon treatment, this study demonstrated an association between measures of cerebral atrophy and worsening disability. The data also provides evidence that brain atrophy can be detected early in the disease course and central white matter atrophy as reflected by ventricle enlargement appears to be a continuous process.
Twycross, R., M. W. Greaves, et al. (2003). "Itch: scratching more than the surface." Qjm 96(1): 7-26.
In origin, itch can be cutaneous ("pruritoceptive", e.g. dermatitis), neuropathic (e.g. multiple sclerosis), neurogenic (e.g. cholestasis), mixed (e.g. uraemia) or psychogenic. Although itch of cutaneous origin shares a common neural pathway with pain, the afferent C-fibres subserving this type of itch are a functionally distinct subset: they respond to histamine, acetylcholine and other pruritogens, but are insensitive to mechanical stimuli. Histamine is the main mediator for itch in insect bite reactions and in most forms of urticaria, and in these circumstances the itch responds well to H(1)-antihistamines. However, in most dermatoses and in systemic disease, low-sedative H(1)-antihistamines are ineffective. Opioid antagonists relieve itch caused by spinal opioids, cholestasis and, possibly, uraemia. Ondansetron relieves itch caused by spinal opioids (but not cholestasis and uraemia). Other drug treatments for itch include rifampicin, colestyramine and 17-alpha alkyl androgens (cholestasis), thalidomide (uraemia), cimetidine and corticosteroids (Hodgkin's lymphoma), paroxetine (paraneoplastic itch), aspirin and paroxetine (polycythaemia vera) and indometacin (some HIV+ patients). If the remedies specified fail, paroxetine and mirtazapine should be considered. Ultraviolet B therapy, particularly narrow-band UVB, may be superior to drug treatment for itch in uraemia.
Tyler, K. L. (2003). "Human herpesvirus 6 and multiple sclerosis: the continuing conundrum." J Infect Dis 187(9): 1360-4.
Vaithianathar, L., C. R. Tench, et al. (2003). "Magnetic resonance imaging of the cervical spinal cord in multiple sclerosis--a quantitative T1 relaxation time mapping approach." J Neurol 250(3): 307-15.
BACKGROUND: The spinal cord is a common site of involvement in multiple sclerosis (MS) where pathology contributes substantially to locomotor disability. Previous studies have demonstrated significant correlations between clinical disability and cervical cord atrophy, but not with cord T(2) lesion load. We evaluate cervical cord pathology using, for the first time, quantitative T(1) relaxation time (T(1)), which shows histopathological specificity for tissue damage in the cerebral white matter. METHOD: Cervical cord T(1) was compared in 15 MS patients [8 relapsing-remitting (RR), 7 secondary progressive (SP)] and 6 healthy controls, and related to normalised upper cervical cord area (UCCa), cerebral white matter T(1), T(2) lesion load and disability measures including the Expanded Disability Status Scale (EDSS), Ambulation index (AI) and timed 25-foot walk. T1 maps of the brain and cervical cord were acquired using a high-resolution, 3-dimensional fast low-angle shot sequence. Dual-echo sequences were also obtained. RESULTS: Median cervical cord T(1) [mean (standard deviation)] was significantly greater in RR [854 [28] ms] (p = 0.0006) and SP patients [927 [67] ms] (p < 0.0001) compared with controls [888 [61] ms], and in SP vs. RR patients (p = 0.002). In the overall patient cohort, it correlated significantly with median cerebral white matter T1 (r = 0.7, p = 0.0046), UCCa (r = -0.87, p < 0.0001), but not T2 lesion loads. Both median cervical cord T1 and UCCa (respectively) correlated significantly with the EDSS (r = 0.55, p = 0.03; r = -0.54, p = 0.04), AI (r = 0.77, p = 0.001; r = -0.60, p = 0.02) and timed 25-foot walk (r = 0.56, p = 0.03; r = -0.55, p = 0.04). CONCLUSION: Cervical cord T(1) distinguishes between MS subgroups and could also prove a useful surrogate outcome measure in MS. The relation of cervical cord T(1) to cerebral white matter T(1) suggests that cord pathology may be influenced by tissue damage upstream.
van de Beek, M. T., W. Taal, et al. (2003). "A woman with multiple sclerosis and pink saliva." Lancet Neurol 2(4): 254-5.
Van der Aa, A., N. Hellings, et al. (2003). "Functional properties of myelin oligodendrocyte glycoprotein-reactive T cells in multiple sclerosis patients and controls." J Neuroimmunol 137(1-2): 164-76.
Autoimmune T-cell reactivity to myelin components may be implicated in the initiation or maintenance of the inflammation leading to myelin destruction in multiple sclerosis (MS). Myelin oligodendrocyte glycoprotein (MOG), a quantitatively minor myelin protein, is an important candidate autoantigen in MS. We studied T-cell responses to recombinant MOG (extracellular domain, rMOG) and a panel of four peptides within this domain (amino acids 1-22, 34-56, 64-86 and 74-96) in MS patients and healthy controls (NS). Frequency analysis of T cells reactive to rMOG as measured by IFN-gamma ELISPOT did not reveal significant differences between MS patients and controls. MOG-reactive T-cell lines and clones (TCL/TCC) were generated by stimulating PBMC of four MS patients and three healthy subjects with a cocktail of the four MOG peptides. The functional properties of 50 MOG peptide-reactive TCL/TCC obtained were studied. All TCL were TCR alpha beta+CD4+ and 20 TCL showed reactivity to MOG peptides 1-22, 13 to 34-56, 1 to 64-86 and 16 to 74-96. No significant differences in peptide recognition were observed between MS patients and controls. The T-cell receptor (TCR) hypervariable regions of MOG-reactive TCL/TCC showed a heterogeneous usage of various TCR V(-D)-J elements. The data provide no evidence for clonal expansions within the MOG-reactive T-cell repertoire of the two study groups. Intracellular cytokine analysis demonstrated predominantly Th1-TCC (IFN-gamma+/IL-4-) in MS patients, while most MOG-reactive TCC of control subjects had a mixed Th0/Th1 phenotype. Furthermore, the MS-derived MOG-reactive TCC produced increased levels of TNF-alpha upon antigen stimulation as compared to controls. Most of the MS-derived MOG-TCC induced specific cytolysis of autologous MOG-pulsed PBMC (9/11) while none of the MOG-TCC isolated from control subjects showed this cytotoxicity (0/8). In conclusion, although the frequency of anti-MOG T cells was similar in MS patients and controls, our data indicate potential differences in the functional properties of MOG TCL in MS patients versus healthy controls which may relate to their role in the disease process.
Van der Aa, A., N. Hellings, et al. (2003). "T cell vaccination in multiple sclerosis patients with autologous CSF-derived activated T cells: results from a pilot study." Clin Exp Immunol 131(1): 155-68.
Myelin-reactive T cells are considered to play an essential role in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. We have previously studied the effects of T cell vaccination (TCV), a procedure by which MS patients are immunized with attenuated autologous myelin basic protein (MBP)-reactive T cell clones. Because several myelin antigens are described as potential autoantigens for MS, T cell vaccines incorporating a broad panel of antimyelin reactivities may have therapeutic effects. Previous reports have shown an accumulation of activated T cells recognizing multiple myelin antigens in the cerebrospinal fluid (CSF) of MS patients. We conducted a pilot clinical trial of TCV with activated CD4+ T cells derived from CSF in five MS patients (four RR, one CP) to study safety, feasibility and immune effects of TCV. CSF lymphocytes were cultured in the presence of rIL-2 and depleted for CD8 cells. After 5-8 weeks CSF T cell lines (TCL) were almost pure TCR alpha beta+CD4+ cells of the Th1/Th0 type. The TCL showed reactivity to MBP, MOG and/or PLP as tested by Elispot and had a restricted clonality. Three immunizations with irradiated CSF vaccines (10 million cells) were administered with an interval of 2 months. The vaccinations were tolerated well and no toxicity or adverse effects were reported. The data from this small open-label study cannot be used to support efficacy. However, all patients remained clinically stable or had reduced EDSS with no relapses during or after the treatment. Proliferative responses against the CSF vaccine were observed in 3/5 patients. Anti-ergotypic responses were observed in all patients. Anti-MBP/PLP/MOG reactivities remained low or were reduced in all patients. Based on these encouraging results, we recently initiated a double-blind placebo-controlled trial with 60 MS patients to study the effects of TCV with CSF-derived vaccines in early RR MS patients.
van der Stelt, M., H. H. Hansen, et al. (2003). "Biosynthesis of endocannabinoids and their modes of action in neurodegenerative diseases." Neurotox Res 5(3): 183-200.
Endocannabinoids are thought to function as retrograde messengers, which modulate neurotransmitter release by activating presynaptic cannabinoid receptors. Anandamide and 2-arachidonoylglycerol (2-AG) are the two best studied endogenous lipids which can act as endocannabinoids. Together with the proteins responsible for their biosynthesis, inactivation and the cannabinoid receptors, these lipids constitute the endocannabinoid system. This system is proposed to be involved in various neurodegenerative diseases such as Parkinson's and Huntington's diseases as well as Multiple Sclerosis. It has been demonstrated that the endocannabinoid system can protect neurons against glutamate excitotoxicity and acute neuronal damage in both in vitro and in vivo models. In this paper we review the data concerning the involvement of the endocannabinoid system in neurodegenerative diseases in which neuronal cell death may be elicited by excitotoxicity. We focus on the biosynthesis of endocannabinoids and on their modes of action in animal models of these neurodegenerative diseases.
van der Werf, S. P., A. Evers, et al. (2003). "The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis." Mult Scler 9(1): 89-94.
The aim of this study was to test, in patients with multiple sclerosis (MS), whether the concept of helplessness might improve the understanding of the relationship between disease severity (neurological impairment) and personality characteristics (emotional instability) on one hand, and depressive mood and fatigue severity on the other hand. Data pertain to 89 patients with a definite diagnosis of MS (Expanded Disability Status Scale [EDSS] ratings: 1-8). Helplessness, fatigue severity, depressive mood and emotional instability were rated with validated questionnaires. Model testing revealed that more neurological impairment and more emotional instability were associated with more helplessness, while higher levels of helplessness were associated with more fatigue and depressive mood. The initially observed direct relationship between EDSS and fatigue disappeared. Emotional instability also had a direct significant relationship with depressive mood, and depressive mood had only a small relationship with fatigue severity. The results indicated that helplessness affected both depressive mood and fatigue severity and that fatigue was not merely a symptom of depressive mood. The correlation between neurological impairment and fatigue severity was largely explained by the mediating effect of helplessness. These findings suggest that MS patients troubled by disabling fatigue might benefit from a psychological intervention targeting unfavourable illness cognitions.
van Veen, T., J. B. Crusius, et al. (2003). "CTLA-4 and CD28 gene polymorphisms in susceptibility, clinical course and progression of multiple sclerosis." J Neuroimmunol 140(1-2): 188-93.
The balance between CD28 and CTLA-4 signalling is important for regulation of the immune response. We were interested whether a genetically mediated disturbance of this balance could be related to susceptibility or severity of multiple sclerosis (MS). We examined three polymorphisms in these genes, CTLA-4-318, CTLA-4+49 and CD28-I3+17, in 514 patients with MS and 181 controls. As the loci cannot be assumed independent of each other, we analysed the effects of each of the three polymorphisms corrected for the presence of the other two. We found no association between carriership of any of the alleles either with susceptibility to MS or with clinical features. For a subgroup of patients, longitudinal magnetic resonance imaging (MRI) data were available. We observed no effects of the polymorphisms on brain and lesion volumes. These data suggest that the polymorphisms under investigation do not affect the risk of developing MS and have no influence on the course of disease.
Vanage, S. M., K. K. Gilbertson, et al. (2003). "Effects of an energy conservation course on fatigue impact for persons with progressive multiple sclerosis." Am J Occup Ther 57(3): 315-23.
OBJECTIVE: Fatigue is a common, troublesome symptom for persons with multiple sclerosis. This study evaluated the effects of an energy conservation course on fatigue impact for persons with multiple sclerosis whose symptoms cause moderate to severe disability. METHODS: Thirty-seven persons with progressive multiple sclerosis participated in an 8-week experimental energy conservation course treatment and an 8-week control period of traditional treatment using a crossover design. The Fatigue Impact Scale (FIS) was used to assess fatigue impact before and after the experimental and control periods, and 8 weeks post-energy conservation course. RESULTS: After participation in the energy conservation course, the average FIS total score and physical, cognitive, and psychosocial subscale scores decreased significantly, whereas the total and subscale scores did not change significantly during the control period. Additionally, decreased fatigue impact was maintained 8 weeks after course completion for evaluated participants. CONCLUSION: This study provides evidence that this energy conservation course can be a beneficial intervention for persons with progressive multiple sclerosis.
Vandenbark, A. A., C. Rich, et al. (2003). "Recombinant TCR ligand induces tolerance to myelin oligodendrocyte glycoprotein 35-55 peptide and reverses clinical and histological signs of chronic experimental autoimmune encephalomyelitis in HLA-DR2 transgenic mice." J Immunol 171(1): 127-33.
In a previous study, we demonstrated that myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide could induce severe chronic experimental autoimmune encephalomyelitis (EAE) in HLA-DR2(+) transgenic mice lacking all mouse MHC class II genes. We used this model to evaluate clinical efficacy and mechanism of action of a novel recombinant TCR ligand (RTL) comprised of the alpha(1) and beta(1) domains of DR2 (DRB1*1501) covalently linked to the encephalitogenic MOG-35-55 peptide (VG312). We found that the MOG/DR2 VG312 RTL could induce long-term tolerance to MOG-35-55 peptide and reverse clinical and histological signs of EAE in a dose- and peptide-dependent manner. Some mice treated with lower doses of VG312 relapsed after cessation of daily treatment, but the mice could be successfully re-treated with a higher dose of VG312. Treatment with VG312 strongly reduced secretion of Th1 cytokines (TNF-alpha and IFN-gamma) produced in response to MOG-35-55 peptide, and to a lesser degree purified protein derivative and Con A, but had no inhibitory effect on serum Ab levels to MOG-35-55 peptide. Abs specific for both the peptide and MHC moieties of the RTLs were also present after treatment with EAE, but these Abs had only a minor enhancing effect on T cell activation in vitro. These data demonstrate the powerful tolerance-inducing therapeutic effects of VG312 on MOG peptide-induced EAE in transgenic DR2 mice and support the potential of this approach to inhibit myelin Ag-specific responses in multiple sclerosis patients.
Vandenberghe, N., M. Debouverie, et al. (2003). "Cerebral venous thrombosis in four patients with multiple sclerosis." Eur J Neurol 10(1): 63-6.
We report four new cases of cerebral venous thrombosis (CVT) occurring in patients with multiple sclerosis (MS). Each patient had undergone lumbar puncture at varying times prior to clinical presentation (4 days to over 1 year). Only two of the patients had received intravenous (i.v.) methylprednisolone 48 h prior to CVT and were under oral contraception, a risk factor for cerebral thrombophlebitis. The other two patients had not undergone recent lumbar puncture, were not taking corticosteroids and did not present vascular risk factors. The patients all had normal routine blood work-ups and none had thrombophilia. All patients dramatically improved with full systemic heparinization. Minor sequelae were noticed in two patients. The pathogenesis underlying the occurrence of CVT in MS patients remains unclear and we discuss the relationship between lumbar puncture, steroid treatment and CVT.
Vartanian, T. (2003). "An examination of the results of the EVIDENCE, INCOMIN, and phase III studies of interferon beta products in the treatment of multiple sclerosis." Clin Ther 25(1): 105-18.
BACKGROUND: Three interferon (IFN) beta products are currently available for the treatment of relapsing multiple sclerosis (MS). Each of these agents showed effectiveness in the treatment of MS in the respective randomized, double-blind, placebocontrolled Phase III trials. However, there have been no randomized, double-blind, placebo-controlled trials directly comparing the efficacy and safety of these formulations. OBJECTIVE: The objective of this article was to compare the results of available comparative studies with the results of the pivotal Phase III trials of each IFN beta product. METHODS: BIOSIS, Current Contents/Clinical Medicine, and MEDLINE were searched for English-language articles published from 1996 to the present comparing the efficacy and safety of IFN beta formulations in the treatment of MS. Search terms included interferon beta 1a, interferon beta 1b, and multiple sclerosis. Articles or abstracts that reported the results of Phase III trials or studies directly comparing IFN beta formulations in the treatment of relapsing or relapsing-remitting MS were included in the review. RESULTS: Seven head-to-head studies were identified that directly compared the efficacy of IFN beta products in the treatment of MS. Two of these studies- INCOMIN (Independent Comparison of Interferon) and EVIDENCE (Evidence for Interferon Dose-Effect: European-North American Comparative Efficacy)- found significant differences in clinical efficacy between IFN beta products, whereas the remaining studies showed equal clinical efficacy between products. CONCLUSION: Inconsistencies within and between the results of the reviewed studies suggest that clinicians should use caution in interpreting the findings of the INCOMIN and EVIDENCE comparative trials.
Velazquez Quintana, M., M. Macias Islas Ma, et al. (2003). "[Multiple sclerosis in Mexico: a multicentre study]." Rev Neurol 36(11): 1019-22.
INTRODUCTION. Multiple sclerosis (MS) is considered to be a low prevalence disease in Mexico; its characteristics have been described in isolated studies in small populations concentrated in a single region of the country and using heterogeneous methodological tools. AIMS. In this study, our aim was define the clinical profile and some socio demographic aspects of MS in Mexico using validated homogeneous criteria and tools. PATIENTS AND METHODS. Eight hospitals representing the five most densely populated regions of the country, the north, centre and south of Mexico, took part in the study. Data were obtained through a survey created, validated and published in Spanish (k interobserver 0.73 and k intraobserver 0.76), which consisted of 142 questions arranged in 10 sections and which was applied by 12 neurologists. The procedure was verified with 50 randomly selected surveys. A total of 337 surveys were applied, which were analysed by descriptive statistics using the EPI INFO, version 6.04b, software application. All the patients presented MS that had been clinically defined with the help of paraclinical studies according to Schumaher and Poser s criteria. RESULTS. A sample of 337 patients was studied; 99.1% were mestizos, with an average age of 37 9 years, 69.7% were females and 30.3% males. 95% had access to the Social Security system and 96% had been born in Mexico to Mexican parents. No cases were found among native Mexicans. The clinical profile of the disease did not differ to that reported in other countries; the pattern observed corresponded to that found in northern latitudes. CONCLUSION. This is the first multicentre study carried out in Mexico with a population that is highly representative of the whole country and with a homogeneous methodology.
Velez, L., F. Shirazi, et al. (2003). "Opisthotonic posturing with neuromuscular irritability attributable to 4-aminopyridine ingestion by a healthy pediatric patient." Pediatrics 111(1): e82-4.
INTRODUCTION: 4-Aminopyridine (4-AP) is a potassium channel blocker used to increase muscle strength in the treatment of demyelinating diseases such as multiple sclerosis. We describe a case of ingestion by an 8-month-old child that resulted in severe but transient symptoms. CASE REPORT: An 8-month-old boy was found with greenish saliva, and a capsule with green 4-AP powder was missing. On arrival to an emergency department, he was jittery, tachycardic, and tachypneic. Activated charcoal, a cathartic, and midazolam (0.5 mg/kg) were administered before transfer to a tertiary pediatric hospital. On arrival, the infant remained tachycardic and tachypneic. His eyes deviated upward and he was noted to have 3+ deep tendon reflexes bilaterally. He was administered 0.9% normal saline (20 mL/kg) for a wide pulse pressure with low diastolic blood pressure. The patient developed dramatic opisthotonic posturing and vermiform tongue fasciculations. The symptoms responded well to repeated intravenous doses of benzodiazepines. In this case, we used 2 doses of lorazepam (0.05 mg/kg each). During opisthotonic posturing, an electroencephalogram performed in the intensive care unit revealed no evidence of seizure activity. Within 20 hours after admission, the patient became asymptomatic. CONCLUSION: This case is, to our knowledge, the first documented pediatric 4-AP ingestion. Clinical signs and symptoms are described as well as the response to therapy with benzodiazepines. The electroencephalogram performed while the patient was symptomatic was negative for seizures.
Versijpt, J., K. Van Laere, et al. (2003). "Scintigraphic visualization of inflammation in neurodegenerative disorders." Nucl Med Commun 24(2): 209-21.
In the past few decades, our understanding of the central nervous system has evolved from one of an immune-privileged site, to one where inflammation is pathognomonic for some of the most prevalent and tragic neurodegenerative diseases. Current research indicates that diseases as diverse as multiple sclerosis, stroke and Alzheimer's disease exhibit inflammatory processes that contribute to cellular dysfunction or loss. Inflammation, whether in the brain or periphery, is almost always a secondary response to a primary pathogen. In head trauma, for example, the blow to the head is the primary event. What typically concerns the neurologist and neurosurgeon more, however, is the secondary inflammatory response that will ensue and likely cause more neuron loss than the initial injury. This paper reviews the basic neuroinflammatory mechanisms, the potential neurotoxic mediators during activation of microglia, the brain resident macrophages, and their role in neurodegeneration. Alzheimer's disease is taken as a prototype for exploring these mechanisms, as it expresses more than 40 inflammatory mediators, it is the most extensively studied disorder in terms of immune-related pathogenesis, and because of its importance as the most prevalent type of dementia. Tools for the visualization of these neuroinflammatory processes, both structural and mainly functional, are critically reviewed and discussed.
Vieira, P. L., H. C. Heystek, et al. (2003). "Glatiramer acetate (copolymer-1, copaxone) promotes th2 cell development and increased IL-10 production through modulation of dendritic cells." J Immunol 170(9): 4483-8.
Glatiramer acetate (GA; copolymer-1, Copaxone) suppresses the induction of experimental autoimmune encephalomyelitis and reduces the relapse frequency in relapsing-remitting multiple sclerosis. Although it has become clear that GA induces protective degenerate Th2/IL-10 responses, its precise mode of action remains elusive. Because the cytokine profile of Th cells is often regulated by dendritic cells (DC), we studied the modulatory effects of GA on the T cell regulatory function of human DC. This study shows the novel selective inhibitory effect of GA on the production of DC-derived inflammatory mediators without affecting DC maturation or DC immunostimulatory potential. DC exposed to GA have an impaired capacity to secrete the major Th1 polarizing factor IL-12p70 in response to LPS and CD40 ligand triggering. DC exposed to GA induce effector IL-4-secreting Th2 cells and enhanced levels of the anti-inflammatory cytokine IL-10. The anti-inflammatory effect of GA is mediated via DC as GA does not affect the polarization patterns of naive Th cells activated in an APC-free system. Together, these results reveal that APC are essential for the GA-mediated shift in the Th cell profiles and indicate that DC are a prime target for the immunomodulatory effects of GA.
Viel, E., J. Pelissier, et al. (2003). "[Alcohol neurolytic blocks for pain and muscle spasticity]." Neurochirurgie 49(2-3 Pt 2): 256-62.
Peripheral nerve blockade is one of the therapeutic options for spasticity of various muscles. Percutaneous nerve stimulation allows accurate location of nerves and neurolysis can be performed using intraneural injection of 65% ethanol or 5 to 12% phenol. Spastic contraction of various muscle groups is a common source of pain and disability which prevents efficient rehabilitation. Neurolytic blocks are possible in most of motor nerves of the upper and lower limbs and main indications are spastic sequelae of stroke and spinal trauma but also of multiple sclerosis, cerebral palsy and chronic coma. The use of percutaneous nerve stimulation allows accurate location and four nerves are more frequently treated: pectoral nerve loop, median, obturator and tibial nerves. In patients with spasticity of the adductor thigh muscles, nerve blocks are performed via a combined approach using fluoroscopy and nerve stimulation to identify the obturator nerve. No complications occur and minor side effects are transient painful phenomena during injection. These approaches have proved to be accurate, fast, simple, highly successful and reproducible. Percutaneous neurolytic procedures, should be performed as early as possible, as soon as spasticity becomes painful and disabling in patients with neurological sequelae of stroke, head trauma or any lesion of the motor neurons.
Villar, L. M., J. Masjuan, et al. (2003). "Intrathecal IgM synthesis is a prognostic factor in multiple sclerosis." Ann Neurol 53(2): 222-6.
Intrathecal IgM synthesis (ITMS) predicts a worse evolution in the first stages of multiple sclerosis (MS). The aim of this study was the follow-up of a group of relapsing-remitting MS patients for a longer time to evaluate whether the ITMS implies a poor prognosis. Oligoclonal IgM bands were performed in 29 MS patients followed up from 5 to 16 years. Time to conversion to secondary-progressive MS (SPMS), time elapsed to reach a disability of 6 in the Expanded Disability Status Scale (EDSS), percentage of patients with a benign MS, and changes in EDSS score were evaluated. During the follow-up, 70.8% of patients with ITMS converted to SPMS. None of the patients without ITMS did. At the end of the study, 63.6% of patients with ITMS had reached EDSS 6, whereas none of the patients lacking ITMS reached values above EDSS 3. When patients with benign MS were analyzed, 82% lacked ITMS. All patients with a nonbenign MS had ITMS. At the end of the study, the mean EDSS score was 4.64 in patients with ITMS and 1.31 in those without. The presence of oligoclonal IgM bands in cerebrospinal fluid is an unfavorable prognostic marker in MS.
Villaverde Gonzalez, R., E. Fernandez Villalba, et al. (2003). "[Foreign language syndrome as a first sign of multiple sclerosis]." Rev Neurol 36(11): 1035-9.
INTRODUCTION. Foreign accent syndrome (FAS) is a little known disorder affecting language which has been described in a few cases after acute strokes or traumatic brain injuries, but until now has not been reported in multiple sclerosis (MS). It is characterised by the appearance of what is perceived to be a foreign accent in the language of the patient. Although it could be included within the dysprosodias that accompany motor aphasias, it should be considered as an entity in its own right, since it may appear without the accompanying aphasia. Aphasia is an infrequent manifestation of MS and even less so when it appears as an initial symptom of the disease. When it does occur it usually accompanies large demyelinating lesions in the dominant hemisphere, and it is usually of a motor type. CASE REPORT. Patient, aged 38 years, who presented FAS that accompanied mild non fluent aphasia as the first manifestation of MS with pseudotumoral lesions. Initially the clinical features were interpreted as a somatoform disorder, which delayed diagnosis. CONCLUSIONS. Like aphasia, FAS can occur in MS as a manifestation of a cortical language disorder. It is important to recognise this in order to prevent mistaken diagnoses.
Vlaar, A. M. and D. T. Wade (2003). "The Adult Memory and Information Processing Battery (AMIPB) test of information-processing speed: a study of its reliability and feasibility in patients with multiple sclerosis." Clin Rehabil 17(4): 386-93.
OBJECTIVE: To investigate how useful the Adult Memory and Information Processing Battery Task A (AMIPB) is as a test of the speed of information processing in patients with multiple sclerosis (MS) by comparing various methods of presenting the test and assessing the reliability (test-retest and inter-rater) and utility of each version. DESIGN: Each patient was assessed twice verbally by the same assessor 1-2 weeks apart. Then 1-2 weeks later half were assessed by another observer, and half were assessed by the first observer using a written method. SETTING: A specialist young disabled unit. SUBJECTS: Thirty-three patients with MS. MEASURES: The AMIPB, the Short Memory-Orientation-Concentration Test (SOMC) and the Barthel ADL Index. RESULTS: The average (SD) number of correct responses after 4 min was 23.3 (18.6), median 21. The test-retest reliability (n = 24) of the 4-min AMIPB was high (r = 0.98) and the difference of the score ranged from -7 to 9: median 3, mean (SD) 1.88 (4.01) and interquartile range 0 to 3.25. The inter-observer reliability (n = 12) of the 4-min AMIPB was also high (r = 0.97) and the mean (SD) differences between scores were 4.3 (5.8), median 4, range +19 to -2. The score at 60 seconds and the score at 240 seconds were highly correlated (r = 0.98). The scores obtained verbally and by writing were closely correlated (r = 0.99). CONCLUSIONS: The AMIPB used over 120 seconds with verbal responses is a reliable and reasonable test for major information-processing deficits.
Vogt, M. H., L. Lopatinskaya, et al. (2003). "Elevated osteopontin levels in active relapsing-remitting multiple sclerosis." Ann Neurol 53(6): 819-22.
In the search for proteins that might play a role in the pathogenesis of multiple sclerosis (MS), osteopontin (OPN) has been identified as the most prominent cytokine-encoding gene expressed within MS lesions. Here, we report significantly increased OPN protein levels in plasma of relapsing-remitting MS patients. In contrast, OPN protein levels in primary progressive and secondary progressive MS patients were similar to healthy control levels. Interestingly, active relapsing-remitting patients had higher OPN protein levels than patients without relapses.
von Andrian, U. H. and B. Engelhardt (2003). "Alpha4 integrins as therapeutic targets in autoimmune disease." N Engl J Med 348(1): 68-72.
Vos, C. M., E. S. van Haastert, et al. (2003). "Matrix metalloproteinase-12 is expressed in phagocytotic macrophages in active multiple sclerosis lesions." J Neuroimmunol 138(1-2): 106-14.
Matrix metalloproteinases (MMPs) are proteases involved in extracellular matrix (ECM) remodeling, leukocyte infiltration into lesions and myelin degradation in the central nervous system (CNS) disease multiple sclerosis (MS). We have investigated whether MMP-12 (macrophage metalloelastase) is expressed in MS lesions at various stages. In control patient tissue and (p)reactive MS lesions, only occasional microglial and astrocyte staining was detected. In contrast, in active demyelinating lesions, phagocytic macrophages were MMP-12 positive. A lower proportion of phagocytes was positive for MMP-12 in chronic active demyelinating lesions and inactive lesions. This suggests a role for MMP-12 during demyelination in MS.
Vrethem, M., E. Mattsson, et al. (2003). "Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid." Mult Scler 9(3): 239-45.
OBJECTIVE: The aim of this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency. METHODS: We measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid (CSF) MMA and tHcy in 72 patients with MS and 23 controls. RESULTS: The mean plasma tHcy level was significantly increased in MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (P = 0.002). Seven patients showed low serum vitamin B12 levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MCV), haemoglobin concentration, CSF tHcy or CSF MMA between patients and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum MMA, plasma tHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age. CONCLUSIONS: The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism relevant for the development of neuroinflammation/degeneration. Our findings indicate that, regardless of a significant increase in plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF tHcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.
Vukusic, S. and C. Confavreux (2003). "Primary and secondary progressive multiple sclerosis." J Neurol Sci 206(2): 153-5.
The progressive phase of multiple sclerosis (MS) is the one most often associated with irreversible accumulation of disability. An important question remains about the place of primary progressive MS (PP-MS): does it form an integral part of the disease spectrum, or is it maybe a distinct entity? This question could apparently be very theoretical, but it is not, as patients with PP-MS remain orphans when regarding disease-modifying treatments. Thus, they are usually excluded from therapeutic trials. A clue to this question could be the comparison between the different MS subtypes with a progressive phase. We discuss here the clinical similarities and differences between secondary and primary progressive MS.
Vukusic, S. and C. Confavreux (2003). "Prognostic factors for progression of disability in the secondary progressive phase of multiple sclerosis." J Neurol Sci 206(2): 135-7.
Predicting clinical outcome is one of the major and most interesting issues in MS patients. If the global evolution of disability (usually chosen levels on the Kurtzke's Disability Status Scale) has been widely studied, much less is known about the progression of disability during the secondary progressive phase of the disease. It is usually said that there is a poorer prognosis once patients enter a progressive phase, whether from onset (like in primary progressive MS) or after an initial relapsing-remitting phase. The secondary progressive phase of multiple sclerosis (MS) is the one most often associated with the development of severe and irreversible disability. Despite this fact, there is a lot of information about the initial relapsing-remitting phase in the literature, but much less about the secondary progressive one. We review here information available from the literature and from the Lyon MS database about this secondary progressive phase.